Immunosuppressive action of ASCs
1.1. The adipose-derived stem cell — A pluripotent adult stem cell?
In 2001, the journal Tissue Engineering published an article describing the isolation of a population of putative multipotent stem cells from adipose tissue termed Processed Lipoaspirate Cells or PLA cells . Based on isolation methods designed for the harvest of adherent, fibroblastic cells from the adipose stroma capable of adipogenic differentiation in vitro , this work by Zuk et al. described the differentiation of their PLA cells toward multiple mesodermal lineages, including fat, bone and cartilage. This ground-breaking article has since been followed by over 3500 studies published and available through PubMed, describing the differentiation capacity of ASCs in a variety of in vitro and in vivo model systems. Early works continued the characterization of PLA cells – now termed ASCs for Adipose-derived Stem Cells - identifying a unique CD “signature” for these cells - and studying their mesodermal differentiation capacity at a molecular and biochemical level . Subsequent studies have since confirmed the ASC’s mesodermal differentiation capacity in vitro reporting osteogenic, adipogenic, chondrogenic and skeletal myogenic capacities -. These works have since been expanded into in vivo translational models using a variety of animal systems for bone formation -, cartilage -, fat - and skeletal muscle -. In addition, recent years have presented some exciting results, expanding ASC potential to add smooth muscle ,  and cardiac myogenesis ,  to the growing list of ASC capacities.
With these increased capacities, it became natural to ask if the ASC possessed pluripotent potential and initial in vitro studies appeared to answer this question, reporting ectodermal , and endodermal differentiation , . However, the true test of these germ line potentials still lies in the in vivo model. Consistent with the in vitro studies, numerous in vivo model systems have reported possible ectodermal and endodermal potentials, describing the repair of nervous and epithelial tissues , , together with hepatic and pancreatic regeneration -. With these in vivo results, combined with earlier in vitro analysis, it becomes easier to conclude that the ASC is an adult pluripotent stem cell population.
1.2. ASC-mediated tissue regeneration: Secretion of soluble factors
Despite the in vivo translational studies above suggesting that ASCs are capable of enhancing tissue healing and regeneration, many of these studies cannot confirm the direct differentiation of the ASC into a specific cell type. For example, while bone regeneration is observed upon implantation of ASCs, very few studies report the presence of the ASC within the newly formed bone. Whether this is an oversight by the research team or an indication that the ASC does not directly form part of the new tissue is unclear. It is entirely possible that the ASC does not directly differentiate into the desired regenerating tissue, but simply directs tissue formation “from the sidelines”. Tissue development and healing is incredibly complex and the role of paracrine signaling is still not entirely understood. Therefore, it is possible that ASCs may be intimately involved in tissue regeneration and health through their ability to mediate the host’s regenerative capacity using paracrine signaling.
Two arguments can be made in support of this theory. First, in many translational models, it does not appear that the ASC has any difficulty in surviving within the transplantation region for extended periods of time. In addition, the range of tissues capable of engrafting ASCs appears to be quite broad. Initial studies by Nolta and researchers show that systemic administration of human ASCs is followed by multi-organ engraftment in nude mice . In support of this, human ASCs administered via tail vein migrate and home efficiently to multiple tissues (epithelial and endothelial) in irradiated mice , . The specific migration of ASCs to injured tissues has also been shown by the Longaker group, who confirm the presence of ASCs specifically in parietal bone defects and their persistence as the defect heals . Second, stem cells like bone marrow MSCs and ASCs are known to secrete numerous factors and cytokines, including VEGF, HGF, NGF, BDNF and multiple interleukins , . In fact, Salgado’s article calls these factors the “secretome” of ASCs. This secretome may have powerful paracrine effects on the health, repair and function of a tissue and has resulted in an exciting, new theory that proposes the ASC as a mediator of tissue regeneration through the secretion of specific soluble factors. In this regard, the ASC could be used in an incredibly broad range of applications. However, the most popular are reviewed below.
2. The use of ASCs in transplantation — Immunomodulatory and anti-inflammatory actions
Successful transplantation is reliant upon tolerance by the host’s immune system. In 2000, human MSCs were transplanted into immunocompetent sheep without significant rejection , suggesting that adult stem cells might survive in a xenogeneic environment. Subsequent work with MSCs has described their ability to immunosuppress mixed lymphocyte reactions and to suppress stimulated T cell proliferation -. MSCs are also known to inhibit cytotoxic T lymphocyte toxicity ,  and inhibit B cell proliferation by altering the G0/G1 transition . Likewise ASC-mediated immunosuppression has been confirmed through a series of elegant in vitro experiments that describe the suppression of mixed lymphocyte reactions and/or proliferation of key immune cells like the T cell -. Immunosuppression has also been observed in a variety of in vivo model systems (Table 1). For example, reduced inflammatory infiltration and airspace enlargement results from the systemic administration of human ASCs to murine models of emphysema . Moreover, the ASCs are capable of rescuing the suppressive effects of cigarette smoke on bone marrow hematopoietic progenitor function . Experimental autoimmune hearing loss can be treated in mice through the systemic infusion of human ASCs, resulting in protection of hair cells possibly through the production of the anti-inflammatory cytokine IL10 by splenocytes  and decreasing the proliferation of antigen-specific Th1 and Th17 cells. Similar immunosuppression and amelioration of disease is reported upon injection of ASCs in models of rheumatoid arthritis  and IgA nephropathy , resulting in decreased inflammatory markers and Th1 cytokine activity, together with the generation of regulatory T cells capable of suppressing T cell responses. Finally significant anti-inflammatory responses are observed upon the transplantation of allogeneic murine ASCs into dystrophin-deficient mice, decreasing markers of oxidative stress and inflammation, including TNFα and IL6, decreasing production of CD3+ T cells, and enhancing the synthesis of anti-inflammatory IL4 and IL10 . While these studies are supportive of the role for ASCs in modulating immune responses, what remains unknown is the mechanism. One theory proposes that cell-cell contact is required . However, others dispute this finding, suggesting that it is the secretion of soluble factors by the ASC that mediates the eventual reaction by the host’s immune system . In support of this, inhibition of prostaglandin E2 production in ASCs by indomethacin can abolish the immunosuppressive properties of ASCs. Alternatively, neutralizing leukemia inhibitory factor has had similar effects . Finally, there are those that suggest a role for IL-6 .
|Pinheiro et al. 2012 ||human||murine dystrophy||decreased CD3+ve T cells, increased IL-4, IL-10 synthesis|
|Payne et al. 2012 ||human||autoimmune demyelination – IL-4 overexpressing ASCs||increased T cell responses|
|Zhou et al. 2011 ||human||autoimmune hearing loss||secretion of IL-10, decreased proliferation of Th1, Th17 cells|
|Hyun et al. 2011,||mouse||IgA-induced nephropathy||decreased inflammatory markers, decreased Th1 activity|
|Schweitzer et al. 2011 ||human, mouse||emphysema||decreased inflammatory infiltration|
|Lai 2011 et al. ||human||systemic lupus erythamatosis||decreased Th17 production, decrease IL-17 synthesis|
|Zhou 2011 et al. ||human||rheumatoid arthritis||decreased Th1, Th17 proliferation/expansion, increased IL10 synthesis|
|Kuo 2011 et al. ||rat||hind limb allotransplantion||increased Treg proliferation|
|Gonzalez-Rey et al. 2010 , Gonzalez et al. 2009 ||human||rheumatoid arthritis||inhibition of CD4+ T cell proliferation, increase in IL-10 producing T cells and monocytes, stimulation of Treg cell development|
|Cho et al. 2010 ||mouse||airway allergic disease||decreased airway inflammation, shift from a Th2 to a Th1-biased immune reponse|
|Gonzalez-Rey et al. 2009 , Gonzalez et al. 2009 ||human||experimental colitis||decrease in Th1-driven inflammation, decrease inflammatory cytokines, increased IL-10 activity|
|Kim et al. 2007 ||human||hemorrhagic stroke||decreased brain inflammation markers|
|Wan et al. 2008 ||rat||orthotopic liver transplant||increased IL-2 and IL-10 synthesis|
|Constatin et al. 2009 ||mouse||autoimmune encephalolyelitis (multiple sclerosis)||increased Th2-type shift in cytokine production|
The immunosuppressive properties of ASCs may make it possible to use more xenogeneic transplantation model systems without the fear of significant immune reactions in animal hosts. Such models would allow for a more direct study of human ASCs in vivo, thus allowing researchers to more accurately predict what these cells could do clinically. An excellent review of these models can be found in a recent article by Lin et al. . In this article, they present a detailed table outlining many of the recent xenogeneic model systems, such as one by Paul and colleagues , who perform a xenogeneic transplantation of human ASCs into myocardial infarcts produced in immunocompetent rats. Histology confirms human ASCs in the infarct region after 6 weeks, with no detectable inflammatory reaction even in the absence of immunosuppressive action. Furthermore, these animals show improvement of cardiac function and reduced infarct size, together with significant improvement in myocardial anti-inflammatory cytokine levels. The success of such xenogeneic transplantation models may be explained, in part, by the immunogenic profile of the ASC. Immunophenotyping of ASCs has not only provided researchers with a CD antigen profile but has confirmed the absence of the HLA-DR antigen on the ASC surface. Divided into classes such as HLA-A, B and C (or MHC class I) and HLA-DP, DM and DR (or MHC class II), HLA receptors display proteins on the cell surface for immune surveillance. Of particular interest is the HLA/MHC class II protein, which is found on the surface of antigen-presenting cells and plays critical roles in immunotolerance and transplantation (for reviews see , ). The absence of this class of HLA protein may allow the ASC to evade the host’s immune surveillance machinery. Of additional interest is a recent study by DelaRosa et al. , who note that human ASCs have lower susceptibility to natural killer (NK) cell-mediated lysis in comparison to bone marrow MSCs. This finding may be part of the reason for xenogeneic tolerance of ASCs in that NK-ASC crosstalk does not result in immediate recognition. Continued research in this area is sure to expand the possible uses of ASCs in translational model systems.
3. Vascularization by ASCs in tissue repair
Tissue repair and regeneration is reliant upon vascularization. Newly formed tissues must have sufficient blood flow to maintain their health and support their growth. Early in vitro studies with ASCs suggest the capacity to differentiate into endothelial cells and to form vessel-like structures. For example, using simple in vitro induction conditions, ASCs express typical markers of endothelial cells, such as von Willebrand Factor (vWF) and function as endothelial cells, taking up acetylated LDL and forming tubular structures on Matrigel substrates , , . Tubule formation, LDL uptake and CD31 expression by ASCs are also found upon in vitro exposure to shear stress , . Such evidence provides strong support for the use of ASCs in the induction of vessel formation and some have attempted to isolate the specific ASC subpopulation that might be responsible for endothelial differentiation. For example, Wosnitza et al. postulate that a population of CD31-ve, S100+ve ASCs are capable of endothelial differentiation , while CD34-ve ASCs have been observed to undergo differentiation by others .
|Ribeiro et al. 2012 ||human||VEGF, HGF, bFGF, NGF, SCF|
|Ii et al. 2012 ||human||VEGF, bFGF, SDF1α|
|Kim et al. 2011 ||human||VEGF|
|Lu et al. 2011 ||human||VEGF, HGF, BDNF, NGF|
|Liu et al. 2011 ||rat||HGF|
|Nie et al. 2011 ||rat||VEGF, HGF, bFGF|
|Salgado et al. 2010 ||human||VEGF, HGF, BDNF|
|Zhu et al. 2010 ||human||VEGF|
|Grewal et al. 2009 ||human||VEGF|
|Rubina et al. 2009 ||mouse||VEGF, HGF, bFGF, PDGFB, TGFb|
|Park et al. 2008 ||human||VEGF, HGF, PDGF|
|Prichard et al. 2008 ||rat||VEGF|
|Kilroy et al. 2007 ||human||HGF|
|Wang et al. 2006 ||human||VEGF, HGF, IGF-1|
|Cao et al. 2005 ||human||VEGF, HGF, bFGF, KGF, TGFβ|
|Rehman et al. 2004 ||human||VEGF|
However, the efficacy of ASCs in tissue repair may not be entirely due to their direct differentiation into endothelial lineages, but also to their secretion of paracrine factors capable of increasing vascularization. In support of this, co-culture of ASCs with postnatal cardiomyocytes results in the formation of stable, branching CD31+ve vessel-like structures that disassemble in the absence of ASCs . Similarly, ASC-conditioned media can induce the formation of vessel-like tubules within Matrigel . More recently, while rat ASCs express Flt-1, CD31 and vascular endothelial cadherin, when injected into a wire injury model in the rat femoral artery, induction of endothelial repair occurs without any observable differentiation of these ASCs into endothelial cells – a finding that can be explained if repair is driven through the production of soluble factors. In the hopes of identifying what angiogenic factors improve a tissue’s vasculature, numerous studies have characterized the secretion of growth factors by ASCs (Table 2). Of all of these factors, perhaps the most commonly reported is VEGF, with secretion of this factor being reported under normal culture conditions , hypoxic conditions  in models of wound healing ,  and cell-assisted lipotransfer . The ability of VEGF to stimulate neoangiogenesis is well known -. Consistent with this, conditioned medium from ASCs, maintained under hypoxic culture conditions in order to increase production of HGF, VEGF and TGFβ, has been found to increase endothelial cell (EC) growth and reduce their apoptosis . In addition, VEGF secretion by ASCs is significantly upregulated in vitro upon metabolic induction of ischemia . However, the role of other secreted factors cannot be ruled out as suppression of HGF production by ASCs through RNA interference significantly impairs ischemic tissue revascularization  and SDF-1α from ASCs has been identified as being involved in myocardial vascularization 
3.1. Ischemia/ischemia-reperfusion injury
Today, there are several model systems that study the paracrine-mediated vascularization potential of ASCs but some of the most common are: ischemia and ischemia-reperfusion (IR) injuries, wound healing and cardiac infarct treatment. Enhanced angiogenesis within ischemic limbs has been reported following treatment with freshly isolated ASCs (i.e. the stromal vascular fraction) and vessels derived from these cells confirmed . However, the use of such a heterogenous population makes it difficult to confirm direct ASC involvement. Fortunately, there have been numerous studies describing the beneficial use of cultured/purified ASCs in the treatment of ischemia , , , -. Consistent with paracrine action, improved vascularization within ischemic limbs has been associated with increased levels of plasma VEGF . In addition, human ASCs cultured in vitro as spheroids improve neovascularization and limb survival when compared to the implantation of dissociated ASCs – a finding thought to be due to the induction of vascular factors, like HGF, VEGF and bFGF, by the hypoxic conditions of the spheroid . In support of this, decreases in the ability of ASCs to induce reperfusion in ischemic hindlimbs are observed if secretion of HGF by the ASC is inhibited . However, the role of the ASC in angiogenesis may not be restricted to their secretion of established angiogenic factors. Transplantation of ASCs transfected with siRNA to either MMP3 or MMP9 to ischemic hind-limbs results in lower blood flow recovery and higher tissue injury , suggesting that ASCs may also promote angiogenesis through their secretion of matrix-remodelling enzymes.
Whereas prolonged ischemia can cause significant tissue damage, there is evidence now that the reperfusion period is also associated with injury, amplified by the production of reactive oxygen species and inflammatory cascades . Events such as these are a major obstacle to successful tissue transplantation. However, the ASC may ameliorate IR injury through its secretion of pro-angiogenic factors, thus increasing the density of developing capillaries within the reperfused tissue. Consistent with this, a significant increase in pro-angiogenic factors can be confirmed in IR skin flap models treated with ASCs . Long-lasting improvement in cardiac function with increased angiogenesis and vasculogenesis can also be observed in IR in minipigs treated with a trans-endocardial injection of ASCs  and a higher number of CD31+ve and vWF+ve cells have been found in models of lung IR followed by ASC injection . While the finding that ASCs can form vessel-like structures in Matrigel in vitro and re-endothelialize carotid injuries in vivo ,  may suggest that the observed angiogenesis is due to differentiation by ASCs, the failure to observe significant ASC engraftment in IR models  again suggests that the role of ASCs may be paracrine in nature.
In addition to stimulating angiogenesis, the ASC may also lessen the damaging effects of IR through paracrine secretion of a combination of anti-inflammatory and anti-oxidant factors. The production of oxidative toxins such as free radicals and reactive oxygen species in ischemia and IR is well-established -. The synthesis of enzymatic anti-oxidants, such as superoxide dismutase and glutathione peroxidase, not only can be detected by proteomic analysis in ASC-conditioned media, but this media is able to protect dermal fibroblasts from oxidative damage . Therefore, the ASC may be an excellent candidate for protection against oxidative damage. In support of this, Chen and co-workers, using a model of kidney IR treated with either conditioned medium from ASCs or direct injection of ASCs during reperfusion, find increased clearance of creatinine and urea from blood plasma in ASC/IR groups together with higher levels of the anti-oxidant markers NAD(P)H quinine oxidoreductase, heme-oxygenase 1/HO-1, glutathione peroxidase and glutathione reductase . Increased anti-oxidant marker levels (i.e. NAD(P)H quinine oxidoreductase and HO-1) have also been reported, together with increased eNOS expression and decreased hepatic oxidative stress versus controls upon multiple injections of ASCs in hepatic IR models . These anti-oxidant actions by ASCs are not only likely to protect the reperfused tissue from oxidative damage but may also protect the ASC itself. A recent study by Suga and colleagues suggests that resident ASCs are resistant to ischemia-mediated damage, surviving within ischemic adipose grafts . Moreover, this work specifically postulates that the actions of these resident ASCs may be responsible for the observed increases in vascular density and the number of new adipocytes over time. Therefore, ASCs may be resistant to the toxic environment of ischemic tissues and may retain their functional capacities, thus being able to either differentiate or secrete paracrine factors for critical for angiogenesis.
3.2. Wound healing
Paracrine action is also likely to play a significant role in the beneficial effects of ASCs in wound healing models. ASCs isolated from debrided skin are capable of producing an epithelial layer when seeded into collagen gels, together with a dermis when seeded fibrin gels are co-cultured with ASC/collagen/epithelial constructs, suggesting that the ASC would be an excellent cell source for healing skin wounds . In support of this, increased collagen density has been reported in full-thickness rat skin grafts injected with ASCs  and Lim et al.  note improved wound healing rates upon implantation of ASCs. These wound healing rates are significantly higher than in controls treated with ASC extracts, suggesting that production of paracrine factors by viable ASCs are necessary in order to direct the formation of new tissue within the wound. In vitro culture of immortalized keratinocytes or dermal fibroblasts with ASC-conditioned medium results in increased proliferation of these cells, in addition to increased transcription and production of collagen type I, suggesting that secreted ASC-derived factors may ultimately influence keratinocyte-mediated healing in skin grafts , . Finally, Jung and colleagues have reported that conditioned medium from ASCs can increase CNI, CNIII and hyaluronic acid synthesis by human dermal fibroblasts and that neutralizing antibodies to TGFβ1 can abolish this effect . However, it is equally likely that improved wound-healing using ASCs is due to their secretion of angiogenic factors, thus improving healing through augmentation of vascularization. As proponents of this theory, Reichenberger et al.  and Gao et al.  report higher blood flow and skin flap survival, respectively when the flaps are combined with ASCs. In addition, Gao and colleagues report increased capillary density, together with increased expression of VEGF within the dermis in the ASC-treated groups. In support of this, increased VEGF expression and microvascular density is also measured in ASC-treated rat skin grafts . Interestingly, recent studies suggest that AKT/c-myc signaling pathways may mediate increased VEGF secretion in ASCs as injection of constitutively active AKT/v-myc-expressing ASCs promote better wound healing compared to normal controls . How exactly the ASC promotes wound healing is likely to be a combination of increased tissue healing and vascularization as directed by their secretion of specific paracrine factors. In support of this, GFP-labelled ASCs not only secrete the angiogenic factors VEGF, HGF and bFGF in vivo, but co-stain with keratin and CD31 in excisional wound healing models in normal and diabetic rats, possibly undergoing both epithelial and endothelial differentiation . Similar differentiation by human ASCs, implanted into skin wounds via silk/chitosan scaffolds, has also been reported by Altman and colleagues . Therefore, the successful use of ASCs in wound healing models may be due to their paracrine action in promoting angiogenesis by the host and their autocrine action in promoting differentiation in themselves.
3.3. Infarct treatment
In a 2007 study by Fotuhi, freshly isolated ASCs injected into porcine transmural infarcts were shown not to cause arrhythmia, bradycardia or conduction block. Moreover, these ASC-treated hearts required extra-stimuli to induce an arrhythmia, suggesting that ASCs could be used in the treatment of cardiac infarcts . With in vitro studies confirming the cardiomyogenic potential of these stem cells, infarct treatment could be mediated through the differentiation of ASCs into cardiomyocytes. However, there is a debate on whether the ASC contributes directly to cardiac muscle regeneration or supports this event through the production of angiogenic growth factors and cytokines. An example of this debate can be seen in the 2007 article by Zhang et al. . Rabbit ASCs injected into transmural infarcts in hearts three wks after occlusion decrease transmural scar and improve left ventricle ejection fraction (LVEF), end-diastolic pressure and myocardial performance relative to saline controls, with ASCs pre-induced with 5-azacytidine for 24 hours giving slightly better results versus untreated controls. When the infarct region is examined histologically, the ASCs form islands of cardiac tissue in and around the scar. However, all infarcts treated with ASCs also show greater capillary density, with the ASCs also differentiating into endothelial cells. Increased capillary densities/angiogenesis have previously been reported using bone marrow mononuclear cells and endothelial progenitors and MSCs are known to cause improvement in cardiac function by incorporating into newly formed capillaries and releasing angiogenic factors . Similar events may also be induced by ASCs. In support of this, mouse ASCs injected into murine infarcts take up residence in the infarct area, with EKGs showing stability of LVEF . Murine ASCs  or rat ASCs  transplanted into rat infarcts result in significant improvement in heart function and tissue viability. Human ASCs not only increase peri-infarct capillary density in rat infarcts but increase numbers of nerve sprouts . Finally, while Beitnes and co-workers show significant improvement in LVEF, smaller infarct sizes and increased vascularization when human ASCs are injected into infarcts in nude rats, they specifically observe an absence of ASC engraftment . However, it is important to note that ASC engraftment was examined in this study 4 weeks post-transplant. It is possible that the long-term beneficial effects of ASCs on infarct treatment can result from short-term engraftment. In support of this, while transdifferentiation of human ASCs into cardiomyocytes or endothelial cells is also not observed in rat cardiac infarcts, the expression of VEGF, bFGF and SDF-1α can be confirmed in these hearts within the first few days of transplant and improved heart function and vascular density is ultimately observed . Therefore, long-term survival of ASCs within the myocardium may not be necessary for their beneficial effects on cardiac function to be realized. Such a possibility would be extremely exciting if this treatment modality is translated into the clinic.
3.4. Other vascularization systems
In addition to wound healing, infarct treatment and ischemia-reperfusion, there are numerous other vascularization systems that might benefit from the putative angiogenic action of ASCs. Hemodynamic abnormalities may be reversed with the treatment of pulmonary arterial hypertension with ASCs through their augmented expression of HGF for angiogenesis and increased number of small pulmonary arteries . Small-for-size liver injury may be treated through their secretion of VEGF. Inhibition of VEGF secretion by ASCs through RNA interference (RNAi) does not prevent apoptosis of liver sinusoidal endothelial cells in vitro and when cells are transplanted syngeneically results in significant disturbances to graft microcirculation, serum liver functional parameters and graft survival . Finally, at the cosmetic level, cell-assisted lipotransfer fat grafts survive at higher levels, are 35% larger and show increased neoangigogenesis when compared to grafts transplanted without isolated ASCs .
4. Neuroprotection by ASCs — Demyelination, stroke, spinal cord injury
Early translational studies do suggest that ASCs can be safely administered to nervous tissue injuries and that functional improvement is noted. Transplanted ASCs have been reported to improve functional deficits following middle cerebral occlusion or ischemic stroke -, spinal cord contusion injury  and peripheral nerve gaps , . Histologic analysis of these injury sites has suggested that ASC differentiation into neurons and/or glial cells may play a role in the functional recovery, with transplanted cells staining positively for MAP2 , GFAP, Tuj-1 and an oligodendrocyte marker . However, this functional improvement may be due to paracrine actions on the host more than ASC differentiation, as less then 1% of transplanted ASCs can be found within a spinal contusive injury model, with those remaining appearing to be oligodendrocytes . In addition, extremely low levels ASC differentiation into mature neurons is noted in a model of cerebral cortex injury . However, both of these studies note significant changes in the host tissue with Nakada et al. observing improvements in microvasculature and Zhang et al. measuring increases in host oligodendrocyte formation. Therefore, like wound healing and IR models, ASCs are likely to exert paracrine actions within nervous tissue.
In 2002, Zhao et al. suggested that functional recovery in ischemic brain injury was not due to MSC differentiation but to secreted paracrine factors that act on the host . A similar hypothesis has been put forth by bone marrow MSC groups who have noted increased survival and differentiation of Tuj1+ve neurons and neuroblastoma cells in co-cultures  and increased neuronal viability and glial cell differentiation using MSC conditioned media . Consistent with this, ASC/Matrigel constructs implanted into models of mice limb re-innervation stimulate the regeneration of nerves and induce axon growth, likely through the expression numerous neurotrophins . Moreover, enhanced nerve fiber growth is observed if the ASCs are pre-induced toward the neural lineage thus enhancing their production of brain-derived neurotrophic factor (BNDF). BDNF secretion (together with nerve growth factor/NGF and glial cell-derived neurotrophic factor/GDNF) by ASCs pre-differentiated toward a Schwann Cell (SC) phenotype is thought to be the basis for axonal regeneration in sciatic nerve gap models - although these authors speculate that this regeneration is likely due to the neuroprotective function of these three neurotrophins . In support of this, studies using ASC-conditioned media appeared to further strengthen this theory. Protection against cortical and hippocampal volume loss in rats can be achieved through the infusion of ASC-conditioned medium . ASC-conditioned medium containing VEGF, BDNF and NGF is shown to have a protective effect against glutamate excitotoxicity on PC12 cells (a key factor implicated in stroke and neurodegenerative diseases) and increase PC12 viability 94. Conditioned media from pre-differentiated ASCs infused over one week into a rat model of ischemic stroke 8 days after stroke induction increases the number of CD31+ve cells . Finally, functional deficits in a model of middle cerebral artery occlusion can be dramatically improved using ASC transduced to overexpress BDNF .
While these neurotrophic factors may act to protect neurons, ASCs may also play roles in decreasing inflammation and gliosis (i.e. glial cell-mediated scar formation) – two critical events that specifically affect healing in the both the central and peripheral nervous system. Systemic transplantation of human ASCs can attenuate cerebral degeneration in rats, reducing both brain atrophy and glial proliferation . Rats implanted with ASC-derived SCs show significant locomotor function recovery compared with untreated ASCs and also reduction in gliosis . Pre-differentiated canine ASCs in Matrigel scaffolds show better functional recovery and reduced fibrosis and inflammation when implanted into spinal cord injuries . Decreased gliosis is also noted upon intrathecal administration of ASCs in a model of IR neuronal damage in rabbits – an event accompanied by increased expression of BDNF within the first 72 hours following ASCs administration . Finally, a possible anti-inflammatory role for ASCs in sciatic nerve repair might be seen in a recent model describing possible immunosuppression of xenogeneic acellular nerve matrices combined with autologous ASCs . Implantation of this construct does not result in host rejection, making it possible that peripheral nerves repair can be accomplished using commercial nerve matrices combined with the patient’s own ASCs.
4.1. Controlled release from ASCs — ASCs as a cellular biopump
It is possible that the paracrine action of ASCs may be “fine-tuned” so that the ASC secretes a desired factor, hence turning the ASC into a “cellular biopump”. This is not a recent concept as the engineering of numerous cell types to secrete a variety of factors has been reported in the literature for over a decade. In the field of stem cell research, bone marrow MSCs have been modified to secrete various factors, including BMP2 , , bFGF , IFN-β  and IL12 . Similar to these studies, ASCs have been engineered for the delivery of BMP4 , BMP2 , , and BMP6  in several bone regeneration models. Delivery of TGFβ2 by ASCs for the induction of chondrogenesis has been reported . Adenovirally- mediated VEGF secretion by ASCs has been used to induce vascular growth in a bone defect model  and adipose tissue grafts . Finally, as described above, BDNF delivery by transduced ASCs into a model of middle cerebral artery occlusion improves functional deficits when compared to control ASCs .
However, a more exciting idea might be in the engineering of ASCs in the treatment of disease. In 2007, ASCs engineered to express cytosine deaminase were found to decrease the growth of colon carcinoma cells . ASCs have recently been described in the delivery of an oncolytic myxoma virus that will specifically target gliomas . ASC viability is not impacted with transduction and successful cross-infection of gliomablastoma cells is observed upon 3D co-culture with glioblastoma cells, leading to their cell death. More importantly, rat survival is increased with this myxoma virus delivery, with the size of the gliomas significantly decreasing upon injection of transduced ASCs in comparison to non-transduced ASCs controls. Localization of ASCs and increased apoptosis within tumors has also been reported following intravenous or subcutaneous injection of ASCs engineered to express TRAIL, having no effect on the surrounding healthy tissue . Finally, this approach may have far-reaching effects on autoimmune diseases through the delivery of interleukins and interferons. ASCs engineered to overexpress IL4 and administered at the time of T cell priming attenuate autoimmune encephalomyelitis and reduce peripheral T cell responses shifting the host pro-inflammatory response to an anti-inflammatory one . With the development of inducible viral systems, there is the possibility that the ASC cellular biopump could be controlled not only at the dose level through the number of cells delivered but at the temporal level, giving clinicians more precise control over their therapeutic regimen.
4.2. ASC uses in the clinic
In light of their differentiative capacity and paracrine actions, there is great interest in the use of ASCs within the clinic. As source of regenerative stem cells, the ASC may have no equal. Bone marrow aspirates yield on average 6x106 nucleated cells per ml, of which, only 0.001 to 0.01% are thought to be stem cells , . In comparison, approximately three-fold more cells can be obtained per gram adipose tissue   with 10% of these cells thought to be stem cells , . The abundance of ASCs within adipose tissue, combined with the relative ease of its harvest and isolation also makes the ASC a good choice for clinical work. Patient’s could conceivably have their adipose tissue harvested relatively painlessly a few weeks prior to their procedure in a simple outpatient procedure, the ASCs isolated and expanded under good manufacturing protocols and then used for regenerative purposes. With the confirmed absence of HLA/MHC class II proteins and continuing xenogeneic animal models, the patient may not even need to use their own stem cells. Donated allogeneic ASC lines could be used in lieu of autologous cells without the fear of immunorejection or inflammatory complications. Such a situation might be perfect in the case of myocardial infarct treatment where a delay in treatment could have serious consequences.
The first published article using ASCs in a clinical setting was in 2004, in which freshly harvested SVF cells were combined with fibrin glue and used in the repair of a traumatic calvarial injury . Three months after reconstruction, CT scans showed new bone formation within the injury. However, it is important to point out that the cells used in this study were not ASCs, purified through plastic adherence and culture time, but the SVF - a heterogenous mixture of ASCs, endothelial cells, pre-adipocytes, pericytes, fibroblasts and red blood cells. Therefore, it is difficult to attribute the observed healing to the action of the ASC itself. Since that time, other clinical studies using the SVF have been attempted  and a review by Casteilla et al. does an excellent job of summarizing these works . It is worth noting that with the exception of some cysts and microcalcifications being observed upon breast reconstruction , the use of SVFs clinically has not resulted in any serious complications.
Because of its heterogeneity, clinical studies using purified ASCs have also been performed for the treatment of such disorders as critical limb ischemia and radiation therapy (,  – for a more comprehensive review, see ). Bone regeneration using ASCs has recently been reported in 2009 with the reconstruction of the maxilla being induced using ASC in combination with BMP2 . Bony healing using BMPs has been documented in numerous translational animal models -, making this clinical study an exciting addition to the ways bone regeneration and healing can be brought about in the clinic. However, many of these translational models fail to report the appropriate control – the amount of bone being formed just by the BMP itself. The first translational study to combine ASCs and a BMP (i.e. BMP2) failed to measure any significant improvement in bone formation when BMP2 and ASC+BMP2 groups were compared . Since this study, others have appeared to suggest that BMP2 may not promote the in vivo osteogneic capacity of the ASC  but may, in fact, may have a deleterious effect on bone regeneration . Since it is not possible to perform similarly controlled studies clinically, it remains unknown if the addition of ASCs to BMP-treated scaffolds provides any more advantage. However, It is worth noting that, as with the use of SVFs, administration of ASCs into human patients has not been associated with any adverse effects .
The first phase I clinical trials using ASCs were not conducted on bone formation or even fat grafting but in the healing of chronic fistulae in Crohn’s disease -. In 2005, nine rectovaginal fistulae in four patients were treated with ASCs, purified and cultured for up to one month. Of the eight fistulae examined, six showed complete healing in 8 weeks . These fistulae had previously failed to heal using conventional surgical treatments, thus justifying progression to more comprehensive phase II trials. In 2009, a larger phase II trial using patients with and without Crohn’s fistulae were treated with ASCs . As seen with their earlier clinical trial, the majority of Crohn’s and non-Crohn’s fistulae were healed completely using ASCs in comparison to controls. Currently, there are three phase II clinical trials recruiting for the use of ASCs in Crohn’s disease fistulae (Clinicaltrials identifiers: NCT01011244, NCT01157650, NCT00999115, http://clinicaltrials.gov/ct2/results?term=adipose+derived+cells), in addition to one phase III trial (NCT00475410) recently completed .
One of the reasons ASCs are considered in the treatment of Crohn’s disease is their ability to suppress inflammation. This review includes numerous examples of how the ASC may be capable of suppressing the immune system and recent clinical trials have attempted to take direct advantage of this quality. The treatment of multiple sclerosis (MS) with SVFs, containing ASCs, has been described by Riordan and colleagues in 2009, with the 3 enrolled patients showing improvement in numerous functional categories including balance and coordination . The use of culture expanded ASCs in autoimmune diseases like hearing loss, MS and rheumatoid arthritis was recently discussed in 2011 . Prior to this, ASCs have been proposed as a viable therapy for suppression of graft vs. host disease (GVHD) -. Each of these studies report favorable functional outcomes and propose ASCs, or their SVF counterpart, for the treatment of immune system disorders.
The most obvious application of the ASC clinically should be in breast reconstruction. In the lab, the combination of ASC-containing SVFs with fat grafts through a protocol called cell-assisted lipotransfer has enjoyed success . Clinically, treatment of facial lipoatrophy has been reported  and two recent trials overseas has suggested that the ASCs within the SVF are capable of increasing breast volume and improving contour 6 months post-surgery , . However, the use of ASCs in breast reconstruction is being pursued carefully in light of recent findings that link stem cells to cancer. Bone marrow MSCs have been found to increase proliferation of breast cancer cell lines  and subcutaneous injection of MSCs with tumor cells can favor their growth . Similar to this, ASCs can increase tumorigenesis of established breast cancer lines . In this study, ASCs not only promote the growth of metastatic pleural effusion cells both in vitro and in vivo but the ASC also secretes adipsin and leptin – both of which are known to promote breast cancer growth . Additional work in MSCs has documented their ability to secrete large amounts of IL-6 and the corresponding increase in the growth of estrogen receptor alpha-positive cell lines . Increased expression of IL4 and IL10 have also been reported by ASCs isolated from breast cancer tissue , leading many to speculate that the ASC may be capable of altering the immune environment within the breast, resulting in the “protection” of the cancerous cells. Such a possibility could have far-reaching effects in the development of breast cancer and in its possible reoccurrence if ASCs are used in reconstruction. However, it is encouraging to find that cultured ASCs are resistant to the chemotherapies cisplatin, vincristine or comptothecin and that they still retain their stem cell characteristics . Such findings could make it possible for a more natural reconstruction of the breast if ASCs are found not to contribute to the cancer itself.
4.3. “Paracrines gone wild” — ASCs and adipose disorders
With the proposed paracrine function of ASCs now well accepted, a re-examination of certain disorders and how the ASC might play a role might now be in order. The most obvious of these disorders would be obesity. However, studying the ASC might allow more information into lesser known dysfunctions such as lipedema and rare adipose disorders (RADs) like Dercum’s and Madelung’s disease. Normal fat has been described as having an anti-inflammatory milieu with adipocytes storing lipid, regulating energy metabolism, and, together with resident macrophages, secreting anti-inflammatory mediators such as IL-10 and adiponectin to protect against the possible development of inflammation-driven obesity -. However, with chronic nutrient overload, existing adipocytes increase their fat storage to become hypertrophic and resident pre-adipocytes (or ASCs) are thought to undergo increased differentiation to increase adipocyte number (i.e. hyperplasia). The hypertrophic adipocytes increase their secretion of “adipokines” - soluble factors known to affect angiogenesis and inflammation , . Specifically, these adipocytes shift their adipokine production from anti-inflammatory to inflammatory, producing a series of feedback cascades that ultimately manifests in obesity .
Obesity has been recognized since the 1950s as a chronic state of low-level inflammation associated with excess accumulation of adipose tissue . This inflammation is now thought to be a complex response to cellular events, such as hypoxia and oxidative stresses within the adipocyte. Figure 1 outlines the possible interacting events underlying obesity starting with the creation of hypertrophic adipocytes. These adipocytes become too large to be adequately supplied by the existing vasculature in the adipose depot, resulting in localized areas of hypoxia. This hypoxic state induces the production of numerous pro-inflammatory adipokines (e.g. IL1Rα, IL6, IL8, TNFα, MCP-1, leptin) and decreases the secretion of several key anti-inflammatory factors (e.g. IL10, adiponectin). Excellent reviews on these adipokines in obesity can be found in Fain et al. 2010 and Balistreri 2010. In these hypertrophic adipocytes, hypoxia is thought to induce oxidative stress , . Oxidative stress is defined as an imbalance in the levels of reaction oxygen species (ROS) relative to the tissue’s antioxidant capacity, resulting in the accumulation of oxidative products such as superoxide and hydroxyl radicals, reactive nitrogen species (RNS) and hydrogen peroxide . Excess nutrients and hypertrophic adipocytes can produce ROS through: the nicotinamide dinucleotide phosphate oxidase (NOX) system , incomplete mitochondrial respiration due to excess free fatty acids  and endoplasmic reticulum (ER) stress due to excess lipid storage . Both mitochondrial and ER dysfunction have been demonstrated to increase the secretion of inflammatory adipokines ,  and numerous studies in obesity models and obese subjects now exist linking hypoxia, oxidative stress and inflammation (reviewed in ). Concomitant with the development of hypertrophic adipocytes, there is a shift within the adipose tissue from M2 macrophages, found in normal adipose tissue, to a more pro-inflammatory M1 macrophage subset -. This shift is likely, in part, a consequence of the production of pro-inflammatory adipokines by adipocytes – such as MCP-1, but this infiltration is also likely to be due to the death of these adipocytes . Consistent with this, “crown-like” structures of macrophages are known to be associated with necrotic adipocytes in obese murine adipose tissue . These macrophages may directly contribute to the production of inflammatory agents within obese adipose tissue . However, they may also augment adipokine production by the adipocyte through possible cross-talk mechanisms. While these mechanisms are unclear at this point, there are many who postulate that adipocyte-macrophage interaction is the key factor in inflammation and resulting obesity , , .
|Blaber et al. 2012 ||IFNγ, IL8, IL9, IL12, IL17, TNFα|
|Hsiao et al. 2012 ||IL6, IL8, MCP-1, MCSF, RANTES|
|Bhang et al. 2011 ||HIF1α|
|Salgado et al. 2010 49||TNFα, IL6, IL8|
|Banas et al. 2008 ||IL6, IL8, IL1Rα, MCP-1, GMCSF|
|Kilroy et al. 2007||IL6, IL8, TNFα, MCSF, GMSCF|
So obesity results from a complex series of cellular events that ultimately increases the production of inflammatory adipokines within the tissue. These adipokines are known to further increase adipocyte hypertrophy producing a positive feedback system. This feedback system could be augmented further by the secretory activity of non-fat cells – i.e. the pre-adipocyte and even the ASC. Pre-adipocytes and adipocytes secrete many of the same pro-inflammatory factors listed above - with the exception of leptin and adiponectin, factors secreted by the adipocyte (reviewed in ). Furthermore, a review of the current literature turns up many studies that document the secretion of similar pro-inflammatory factors by ASCs (Table 3). It is possible that the secretion of inflammatory factors, like IL6 or TNFα, by ASCs may play a crucial role in inflammation and the development of obesity. Alternatively, it is possible that inflammation and obesity may result from “defective” ASCs that fail to secrete key anti-inflammatory factors such as IL-10 or have lost their ability to ameliorate oxidative stresses, thus allowing inflammation to go on unchecked. Unfortunately, the effect of inflammation and the ASC is under-represented in today’s literature. Those studies that do exist document the inhibition of ASC adipogenesis under inflammatory conditions . This is an interesting finding, as the ASC might be thought of as the logical source for adipocyte hyperplasia observed in obesity. However, if it is the paracrine activity of the ASC that plays a crucial role in the development or maintenance of obesity, then ASC differentiation capacity might be sacrificed in the name of maintaining this function. In light of what we know about adipocytes and pre-adipocytes in obesity, more in-depth studies on the ASC are certainly warranted.
A similar argument for ASCs could be made for other adipose disorders such lipedema and rare adipose disorders (RADs) such as Dercum’s (aka Adiposa Dolorosa)  and Madelung’s disease or Multiple Symmetric Lipomatosis (MSL) . Lipedema (LD), or edema of the fat, is defined as the symmetrical accumulation of adipose tissue in the lower extremities . Because the fat may also be painful as the disorder progresses, LD is often described in the same spectrum as Dercum’s . While lipedema and obesity share many similarities – leading to the misdiagnosis of lipedema in up to 15% of the population as obesity, there are some significant differences between LD and obesity. Specifically, excess fat accumulates almost exclusively in the lower limbs in LD and this adipose tissue is stubbornly resistant to loss through dieting . LD is almost exclusively seen in women in their 30s or older, suggesting a hormonal component . Despite these differences, the etiology of obesity and LD may share some commonalities, in that LD is thought to be mediated, in part, through hypoxia and the production of inflammatory cytokines (Figure 2). Like obesity, LD is initially characterized by adipocyte hypertrophy and hyperplasia , although the reason for this hypertrophy cannot be attributed to nutrient overload and currently remains unknown. This hypertrophy results in hypoxia, which is thought to result in inflammatory adipokine secretion and a putative positive feedback cascade as seen in obesity. Like obesity, LD fat is characterized by macrophage “crowns” in close association with hypertrophic and/or necrotic adipocytes . These macrophages will almost certainly contribute to the inflammatory reactions occurring in LD fat. Furthermore, when examining adipose tissues isolated from Dercum’s, similar immune infiltrations in association with perivascular cells and hypertrophic adipocytes are also seen, again, suggesting that LD and Dercum’s may be points along the same spectrum . In light of these commonalities with obesity, it would be logical to assume that the ASC would also play some critical role in mediating inflammation in LD or RADs through its production of paracrine factors. Unfortunately, these studies do not exist at this point.
Despite sharing many of the same characteristics, there are some important distinctions between obesity and LD that may also be at work. These distinctions are also likely to be found in RADs like Dercum’s and Madelung’s disease. Specifically, LD (and possibly Dercum’s and Madelung’s) is associated with defects in the microvasculature, together with lymphatic dysfunction . Current theories propose that adipocyte hypertrophy leads to hypoxia, which results in increased angiogenesis. However, this angiogenesis is pathologic and the resulting capillaries are said to be “fragile” or “leaky” . In support of this, perivascular cells, indicative of vascular damage, can be found in LD adipose tissue  and pathologic angiogenesis producing fragile capillaries have been found in many eye diseases , . What produces this pathology is unknown but studies have shown that leptin can increase the number of fenestrations in capillaries  and increased plasma VEGF levels can be found in LD patients . Increased plasma VEGF levels can also be found in LD patients , so it is possible that paracrine secretion from hypertrophic and hypoxic adipocytes could disrupt angiogenesis within LD adipose tissue. With studies showing ASCs capable of secreting numerous paracrine factors, including VEGF, and inducing endothelial differentiation and vessel formation, the question of whether the ASC plays a role in this vascular pathology should be asked. The fragile capillaries allow the filtration of protein-rich plasma into the interstitial space, driving the formation of edema . In the early stages of LD, lymphatic drainage can keep up . However with progression of the disorder, lymphatic drainage does decrease as the patient ages . Added to this, the hypertrophic adipocytes are thought to physically restrict fluid drainage and the smaller lymphatic vessels themselves are thought to become “leaky”, possibly through the appearance of microaneurysms in these vessels . All of this results in the accumulation of lymph within the adipose tissue. Recent studies now suggest that “lymph can make you fat” . In support of this, adipogenesis in vitro increases when cells are cultured in the presence of lymph , . Furthermore, the removal of axillary lymphs nodes in individuals with breast cancer is frequently associated with increased fat deposition within the arm . More recently, mice heterozygous for a mutation in the Prox1 gene not only exhibit leaky lymphatics, but develop obesity as they age -. What it is in the lymph that enhances adipogenesis is unclear. It simply could be the result of edema causing hypoxia, inflammation and adipocyte hypertrophy – not unlike obesity. Alternatively, factors in the lymph could directly induce the ASC to differentiate or the mature adipocyte to store more fat. Since lymph is interstitial fluid combined with emulsified fats, non-reabsorbed proteins and immunocompetent leukocytes, any of these factors could conceivably alter the behavior of the ASC. As it stands, more studies investigating the exact consequences of lymph accumulation on ASC and adipocyte behavior are needed.
So while the mechanisms may differ at points, at the basis of obesity, LD and RADs is inflammation. How the ASC participates in this inflammation remains to be seen, but the ASC could be used in the treatment of these disorders. If inflammation results in adipocyte hypertrophy, then ameliorating this process could decrease the size and number of these cells. In this regard, the anti-inflammatory, anti-oxidant properties of ASCs could be taken advantage of and enhanced in the hopes of mitigating the damaging effects of inflammation in these adipose disorders. However, before this could be attempted, more information is definitely required on the exact roles the ASC plays in adipose tissue formation and how these roles can go wrong when adipose disorders develop.
Since 2001, the number of studies characterizing and utilizing the ASC is truly staggering. It appears that the ASC is even passing the bone marrow MSC as the preferred adult stem cell for regenerative medicine. With its ease of isolation from adipose tissue, its availability within the tissue, its long term viability in culture and its persistence when implanted in vivo, the ASC is not only a great stem cell choice for studying mechanisms in vitro but for how it can regenerate tissues in vivo. In response, the studies using ASCs are incredibly diverse and range from their direct differentiation in regenerating tissues such as bone, muscle, nerve and liver to their indirect use in mediating inflammation, protecting nervous tissue and directing vascularization and wound healing through their production of paracrine factors. Finally, a truly exciting use for the ASC may be based on this paracrine activity, in that ASC appears to be easily engineered for the delivery of key factors capable of regenerating many tissue types and maintaining their health. Only time will tell how far the ASC will go.
ASC = adipose-derived stem cell; EC = endothelial cell; LD = lipedema; MSC = mesenchymal stem cell; GFAP = glial fibrillary acidic protein; HLA = human leukocyte antigen; IR = ischemia reperfusion; LVEF = left ventricular ejection fraction; MAP2 = microtubule associated protein-2; MLR = mixed lymphocyte reaction; PLA = processed lipoaspirate; RAD = rare adipose disorder; SVF = stromal vascular fraction; SC = Schwann cell; Tuj-1 = class III beta-tubulin; vWF = von Willebrand factor
Zuk PA, Zhu, M., Mizuno, H., Huang, J.I., Futrell, W.J, Katz, A.J., Benhaim, P., Lorenz, H. P., and Hedrick, M. H. Multi-lineage cells from human adipose tissue: implications for cell-based therapies. Tissue Engineering. 2001;7:211-226.
Pozanski WJ, Waheed, I., and Van, R. Human fat cell precursors: morphologic and metabolic differentiation in culture. Lab Invest. 1973;29(5):570-576.
Gronthos S, Franklin DM, Leddy HA, Robey PG, Storms RW, Gimble JM. Surface protein characterization of human adipose tissue-derived stromal cells. J Cell Physiol. 2001;189(1):54-63.
Mitchell JB, McIntosh K, Zvonic S, Garrett S, Floyd ZE, Kloster A, Di Halvorsen Y, Storms RW, Goh B, Kilroy G, Wu X, Gimble JM. Immunophenotype of human adipose-derived cells: temporal changes in stromal-associated and stem cell-associated markers. Stem Cells. 2006;24(2):376-385.
Varma MJ, Breuls RG, Schouten TE, Jurgens WJ, Bontkes HJ, Schuurhuis GJ, van Ham SM, van Milligen FJ. Phenotypical and functional characterization of freshly isolated adipose tissue-derived stem cells. Stem Cells Dev. 2007;16(1):91-104.
Zannettino AC, Paton S, Arthur A, Khor F, Itescu S, Gimble JM, Gronthos S. Multipotential human adipose-derived stromal stem cells exhibit a perivascular phenotype in vitro and in vivo. J Cell Physiol. 2008;214(2):413-421.
Katz AJ, Tholpady A, Tholpady SS, Shang H, Ogle RC. Cell surface and transcriptional characterization of human adipose-derived adherent stromal (hADAS) cells. Stem Cells. 2005;23(3):412-423.
Zuk PA, Zhu M., Ashjian, P., De Ugarte, D.A., Huang, J.I., Mizuno, H., Alfonso, Z.C., Fraser, J.K., Benhaim, P., Hedrick, M.H. Human adipose tissue is a source of multipotent stem cells. Mol. Biol. Cell. 2002;13:4279-4295.
Hattori H, Sato M, Masuoka K, Ishihara M, Kikuchi T, Matsui T, Takase B, Ishizuka T, Kikuchi M, Fujikawa K, Ishihara M. Osteogenic potential of human adipose tissue-derived stromal cells as an alternative stem cell source. Cells Tissues Organs. 2004;178(1):2-12.
Leong DT, Khor WM, Chew FT, Lim TC, Hutmacher DW. Characterization of osteogenically induced adipose tissue-derived precursor cells in 2-dimensional and 3-dimensional environments. Cells Tissues Organs. 2006;182(1):1-11.
Hao W, Hu YY, Wei YY, Pang L, Lv R, Bai JP, Xiong Z, Jiang M. Collagen I gel can facilitate homogenous bone formation of adipose-derived stem cells in PLGA-beta-TCP scaffold. Cells Tissues Organs. 2008;187(2):89-102.
Lee JH, Rhie JW, Oh DY, Ahn ST. Osteogenic differentiation of human adipose tissue-derived stromal cells (hASCs) in a porous three-dimensional scaffold. Biochem Biophys Res Commun. 2008;370(3):456-460.
Huang JI, Beanes SR, Zhu M, Lorenz HP, Hedrick MH, Benhaim P. Rat extramedullary adipose tissue as a source of osteochondrogenic progenitor cells. Plast Reconstr Surg. 2002;109(3):1033-1041; discussion 1042-1033.
Huang JI, Zuk, P.A., Jones, N.F., Zhu, M., Lorenz, H.P., Hedrick, M.H., Benhaim, P. Chondrogenic potential of multipotential cells from human adipose tissue. Plast. Reconstr. Surg. 2003; 2004; 113(2):585-594
Tholpady SS, Katz AJ, Ogle RC. Mesenchymal stem cells from rat visceral fat exhibit multipotential differentiation in vitro. Anat Rec A Discov Mol Cell Evol Biol. 2003;272(1):398-402.
Ogawa R, Mizuno H, Hyakusoku H, Watanabe A, Migita M, Shimada T. Chondrogenic and osteogenic differentiation of adipose-derived stem cells isolated from GFP transgenic mice. J Nippon Med Sch. 2004;71(4):240-241.
Ogawa R, Mizuno H, Watanabe A, Migita M, Hyakusoku H, Shimada T. Adipogenic differentiation by adipose-derived stem cells harvested from GFP transgenic mice-including relationship of sex differences. Biochem Biophys Res Commun. 2004;319(2):511-517.
Awad HA, Wickham MQ, Leddy HA, Gimble JM, Guilak F. Chondrogenic differentiation of adipose-derived adult stem cells in agarose, alginate, and gelatin scaffolds. Biomaterials. 2004;25(16):3211-3222.
Rodriguez AM, Elabd C, Delteil F, Astier J, Vernochet C, Saint-Marc P, Guesnet J, Guezennec A, Amri EZ, Dani C, Ailhaud G. Adipocyte differentiation of multipotent cells established from human adipose tissue. Biochem Biophys Res Commun. 2004;315(2):255-263.
Mizuno H, Zuk, P.A., Zhu, M., Lorenz, H.P., Benhaim, P., and Hedrick, M.H. Myogenic differentiation of human processed lipoaspirate cells. Plastic and Reconstr. Surg. 2001;109(1):199-209.
Hicok KC, Du Laney TV, Zhou YS, Halvorsen YD, Hitt DC, Cooper LF, Gimble JM. Human adipose-derived adult stem cells produce osteoid in vivo. Tissue Eng. 2004;10(3-4):371-380.
Yoon E, Dhar S, Chun DE, Gharibjanian NA, Evans GR. In Vivo Osteogenic Potential of Human Adipose-Derived Stem Cells/Poly Lactide-Co-Glycolic Acid Constructs for Bone Regeneration in a Rat Critical-Sized Calvarial Defect Model. Tissue Eng. 2007;13(3):619-627.
Conejero JA, Lee JA, Parrett BM, Terry M, Wear-Maggitti K, Grant RT, Breitbart AS. Repair of palatal bone defects using osteogenically differentiated fat-derived stem cells. Plast Reconstr Surg. 2006;117(3):857-863.
Lee JA, Parrett, B.M., Conejero, J.A., Laser, J., Chen, J., Kogon, A.J., Nanda, D., Grant, R.T., Breitbart, A.S. Biological alchemy: engineering bone and fat from fat-derived stem cells. Ann. Plast. Surg. 2003;50(610-617.
Cowan CM, Shi YY, Aalami OO, Chou YF, Mari C, Thomas R, Quarto N, Contag CH, Wu B, Longaker MT. Adipose-derived adult stromal cells heal critical-size mouse calvarial defects. Nat Biotechnol. 2004;22(5):560-567.
Jin XB, Sun YS, Zhang K, Wang J, Ju XD, Lou SQ. Neocartilage formation from predifferentiated human adipose derived stem cells in vivo. Acta Pharmacol Sin. 2007;28(5):663-671.
Mehlhorn AT, Zwingmann J, Finkenzeller G, Niemeyer P, Dauner M, Stark B, Sudkamp NP, Schmal H. Chondrogenesis of adipose-derived adult stem cells in a poly-lactide-co-glycolide scaffold. Tissue Eng Part A. 2009;15(5):1159-1167.
Lin Y, Luo E, Chen X, Liu L, Qiao J, Yan Z, Li Z, Tang W, Zheng X, Tian W. Molecular and cellular characterization during chondrogenic differentiation of adipose tissue-derived stromal cells in vitro and cartilage formation in vivo. J Cell Mol Med. 2005;9(4):929-939.
Lu F, Gao JH, Ogawa R, Mizuro H, Hykusoku H. Adipose tissues differentiated by adipose-derived stem cells harvested from transgenic mice. Chin J Traumatol. 2006;9(6):359-364.
Mizuno H, Itoi Y, Kawahara S, Ogawa R, Akaishi S, Hyakusoku H. In vivo adipose tissue regeneration by adipose-derived stromal cells isolated from GFP transgenic mice. Cells Tissues Organs. 2008;187(3):177-185.
Hong L, Peptan IA, Colpan A, Daw JL. Adipose tissue engineering by human adipose-derived stromal cells. Cells Tissues Organs. 2006;183(3):133-140.
Mauney JR, Nguyen T, Gillen K, Kirker-Head C, Gimble JM, Kaplan DL. Engineering adipose-like tissue in vitro and in vivo utilizing human bone marrow and adipose-derived mesenchymal stem cells with silk fibroin 3D scaffolds. Biomaterials. 2007;28(35):5280-5290.
Rodriguez AM, Pisani D, Dechesne CA, Turc-Carel C, Kurzenne JY, Wdziekonski B, Villageois A, Bagnis C, Breittmayer JP, Groux H, Ailhaud G, Dani C. Transplantation of a multipotent cell population from human adipose tissue induces dystrophin expression in the immunocompetent mdx mouse. J Exp Med. 2005;201(9):1397-1405.
Goudenege S, Pisani DF, Wdziekonski B, Di Santo JP, Bagnis C, Dani C, Dechesne CA. Enhancement of myogenic and muscle repair capacities of human adipose-derived stem cells with forced expression of MyoD. Mol Ther. 2009;17(6):1064-1072.
Liu Y, Yan X, Sun Z, Chen B, Han Q, Li J, Zhao RC. Flk-1+ adipose-derived mesenchymal stem cells differentiate into skeletal muscle satellite cells and ameliorate muscular dystrophy in mdx mice. Stem Cells Dev. 2007;16(5):695-706.
Jack GS, Almeida FG, Zhang R, Alfonso ZC, Zuk PA, Rodriguez LV. Processed lipoaspirate cells for tissue engineering of the lower urinary tract: implications for the treatment of stress urinary incontinence and bladder reconstruction. J Urol. 2005;174(5):2041-2045.
Harris LJ, Abdollahi H, Zhang P, McIlhenny S, Tulenko TN, DiMuzio PJ. Differentiation of adult stem cells into smooth muscle for vascular tissue engineering. J Surg Res. 2011;168(2):306-314.
Choi YS, Dusting GJ, Stubbs S, Arunothayaraj S, Han XL, Collas P, Morrison WA, Dilley RJ. Differentiation of human adipose-derived stem cells into beating cardiomyocytes. J Cell Mol Med. 2010;14(4):878-889.
Planat-Benard V, Menard C, Andre M, Puceat M, Perez A, Garcia-Verdugo JM, Penicaud L, Casteilla L. Spontaneous cardiomyocyte differentiation from adipose tissue stroma cells. Circ Res. 2004;94(2):223-229.
Colazzo F, Chester AH, Taylor PM, Yacoub MH. Induction of mesenchymal to endothelial transformation of adipose-derived stem cells. J Heart Valve Dis. 2010;19(6):736-744.
Cao Y, Sun Z, Liao L, Meng Y, Han Q, Zhao RC. Human adipose tissue-derived stem cells differentiate into endothelial cells in vitro and improve postnatal neovascularization in vivo. Biochem Biophys Res Commun. 2005;332(2):370-379.
Long JL, Zuk P, Berke GS, Chhetri DK. Epithelial differentiation of adipose-derived stem cells for laryngeal tissue engineering. Laryngoscope. 2010;120(1):125-131.
Kumai Y, Kobler JB, Park H, Lopez-Guerra G, Karajanagi S, Herrera VL, Zeitels SM. Crosstalk between adipose-derived stem/stromal cells and vocal fold fibroblasts in vitro. Laryngoscope. 2009;119(4):799-805.
Chandra V, Swetha G, Muthyala S, Jaiswal AK, Bellare JR, Nair PD, Bhonde RR. Islet-like cell aggregates generated from human adipose tissue derived stem cells ameliorate experimental diabetes in mice. PLoS One. 2011;6(6):e20615.
Bassi EJ, Moraes-Vieira PM, Moreira Sa CS, Almeida DC, Vieira LM, Cunha CS, Hiyane MI, Basso AS, Pacheco-Silva A, Camara NO. Immune Regulatory Properties of Allogeneic Adipose-Derived Mesenchymal Stem Cells in the Treatment of Experimental Autoimmune Diabetes. Diabetes. 2012; 61(10):2534-2545.
Li YY, Liu HH, Chen HL, Li YP. Adipose-derived mesenchymal stem cells ameliorate STZ-induced pancreas damage in type 1 diabetes. Biomed Mater Eng. 2012;22(1):97-103.
Meyerrose TE, De Ugarte DA, Hofling AA, Herrbrich PE, Cordonnier TD, Shultz LD, Eagon JC, Wirthlin L, Sands MS, Hedrick MA, Nolta JA. In vivo distribution of human adipose-derived mesenchymal stem cells in novel xenotransplantation models. Stem Cells. 2007;25(1):220-227.
Fang B, Li Y, Song Y, Li N, Cao Y, Wei X, Lin Q, Zhao RC. Human adipose tissue-derived adult stem cells can lead to multiorgan engraftment. Transplant Proc. 2010;42(5):1849-1856.
Salgado AJ, Reis RL, Sousa NJ, Gimble JM. Adipose tissue derived stem cells secretome: soluble factors and their roles in regenerative medicine. Curr Stem Cell Res Ther. 2010;5(2):103-110.
Levi B, James AW, Nelson ER, Hu S, Sun N, Peng M, Wu J, Longaker MT. Studies in adipose-derived stromal cells: migration and participation in repair of cranial injury after systemic injection. Plast Reconstr Surg. 2011;127(3):1130-1140.
Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006;98(5):1076-1084.
Liechty KW, MacKenzie, T.C., Shaaban, A.F., Radu, A., Moseley, A.M., Deans, R., Marshak,D.R., Flake, A.W. Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep. Nat. Med. 2000;6:1282-1286.
Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, Gianni AM. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99(10):3838-3843.
Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E, Dazzi F. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood. 2003;101(9):3722-3729.
Djouad F, Plence P, Bony C, Tropel P, Apparailly F, Sany J, Noel D, Jorgensen C. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood. 2003;102(10):3837-3844.
Angoulvant D, Clerc A, Benchalal S, Galambrun C, Farre A, Bertrand Y, Eljaafari A. Human mesenchymal stem cells suppress induction of cytotoxic response to alloantigens. Biorheology. 2004;41(3-4):469-476.
Rasmusson I, Ringden O, Sundberg B, Le Blanc K. Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells. Transplantation. 2003;76(8):1208-1213.
Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V, Cazzanti F, Risso M, Gualandi F, Mancardi GL, Pistoia V, Uccelli A. Human mesenchymal stem cells modulate B-cell functions. Blood. 2006;107(1):367-372.
Wan CD, Cheng R, Wang HB, Liu T. Immunomodulatory effects of mesenchymal stem cells derived from adipose tissues in a rat orthotopic liver transplantation model. Hepatobiliary Pancreat Dis Int. 2008;7(1):29-33.
Cui L, Yin S, Liu W, Li N, Zhang W, Cao Y. Expanded adipose-derived stem cells suppress mixed lymphocyte reaction by secretion of prostaglandin E2. Tissue Eng. 2007;13(6):1185-1195.
Puissant B, Barreau C, Bourin P, Clavel C, Corre J, Bousquet C, Taureau C, Cousin B, Abbal M, Laharrague P, Penicaud L, Casteilla L, Blancher A. Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br J Haematol. 2005;129(1):118-129.
Wolbank S, Peterbauer A, Fahrner M, Hennerbichler S, van Griensven M, Stadler G, Redl H, Gabriel C. Dose-dependent immunomodulatory effect of human stem cells from amniotic membrane: a comparison with human mesenchymal stem cells from adipose tissue. Tissue Eng. 2007;13(6):1173-1183.
Yoo KH, Jang IK, Lee MW, Kim HE, Yang MS, Eom Y, Lee JE, Kim YJ, Yang SK, Jung HL, Sung KW, Kim CW, Koo HH. Comparison of immunomodulatory properties of mesenchymal stem cells derived from adult human tissues. Cell Immunol. 2009;259(2):150-156.
Schweitzer KS, Johnstone BH, Garrison J, Rush NI, Cooper S, Traktuev DO, Feng D, Adamowicz JJ, Van Demark M, Fisher AJ, Kamocki K, Brown MB, Presson RG, Jr., Broxmeyer HE, March KL, Petrache I. Adipose stem cell treatment in mice attenuates lung and systemic injury induced by cigarette smoking. Am J Respir Crit Care Med. 2011;183(2):215-225.
Zhou Y, Yuan J, Zhou B, Lee AJ, Ghawji M, Jr., Yoo TJ. The therapeutic efficacy of human adipose tissue-derived mesenchymal stem cells on experimental autoimmune hearing loss in mice. Immunology. 2011;133(1):133-140.
Zhou B, Yuan J, Zhou Y, Ghawji M, Jr., Deng YP, Lee AJ, Nair U, Kang AH, Brand DD, Yoo TJ. Administering human adipose-derived mesenchymal stem cells to prevent and treat experimental arthritis. Clin Immunol. 2011;141(3):328-337.
Hyun YY, Kim IO, Kim MH, Nam DH, Lee MH, Kim JE, Song HK, Cha JJ, Kang YS, Lee JE, Kim HW, Han JY, Cha DR. Adipose-Derived Stem Cells Improve Renal Function in a Mouse Model of IgA Nephropathy. Cell Transplant. 2012 in press.
Pinheiro CH, de Queiroz JC, Guimaraes-Ferreira L, Vitzel KF, Nachbar RT, de Sousa LG, de Souza-Jr AL, Nunes MT, Curi R. Local injections of adipose-derived mesenchymal stem cells modulate inflammation and increase angiogenesis ameliorating the dystrophic phenotype in dystrophin-deficient skeletal muscle. Stem Cell Rev. 2012;8(2):363-374.
Cui L, Yin S, Yang P, Liu B, Zhang Y, Liu W, Cao YL. [Human adipose derived stem cells suppress lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli]. Zhonghua Yi Xue Za Zhi. 2005;85(27):1890-1894.
Najar M, Raicevic G, Boufker HI, Fayyad-Kazan H, De Bruyn C, Meuleman N, Bron D, Toungouz M, Lagneaux L. Adipose-tissue-derived and Wharton's jelly-derived mesenchymal stromal cells suppress lymphocyte responses by secreting leukemia inhibitory factor. Tissue Eng Part A. 2010;16(11):3537-3546.
Payne NL, Dantanarayana A, Sun G, Moussa L, Caine S, McDonald C, Herszfeld D, Bernard CC, Siatskas C. Early intervention with gene-modified mesenchymal stem cells overexpressing interleukin-4 enhances anti-inflammatory responses and functional recovery in experimental autoimmune demyelination. Cell Adh Migr. 2012;6(3):179-189.
Lai K, Zeng K, Zeng F, Wei J, Tan G. Allogeneic adipose-derived stem cells suppress Th17 lymphocytes in patients with active lupus in vitro. Acta Biochim Biophys Sin (Shanghai). 2011;43(10):805-812.
Kuo YR, Chen CC, Goto S, Lee IT, Huang CW, Tsai CC, Wang CT, Chen CL. Modulation of immune response and T-cell regulation by donor adipose-derived stem cells in a rodent hind-limb allotransplant model. Plast Reconstr Surg. 2011;128(6):661e-672e.
Gonzalez-Rey E, Gonzalez MA, Varela N, O'Valle F, Hernandez-Cortes P, Rico L, Buscher D, Delgado M. Human adipose-derived mesenchymal stem cells reduce inflammatory and T cell responses and induce regulatory T cells in vitro in rheumatoid arthritis. Ann Rheum Dis. 2010;69(1):241-248.
Gonzalez MA, Gonzalez-Rey E, Rico L, Buscher D, Delgado M. Treatment of experimental arthritis by inducing immune tolerance with human adipose-derived mesenchymal stem cells. Arthritis Rheum. 2009;60(4):1006-1019.
Cho KS, Roh HJ. Immunomodulatory effects of adipose-derived stem cells in airway allergic diseases. Curr Stem Cell Res Ther. 2010;5(2):111-115.
Gonzalez-Rey E, Anderson P, Gonzalez MA, Rico L, Buscher D, Delgado M. Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut. 2009;58(7):929-939.
Gonzalez MA, Gonzalez-Rey E, Rico L, Buscher D, Delgado M. Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses. Gastroenterology. 2009;136(3):978-989.
Kim JM, Lee ST, Chu K, Jung KH, Song EC, Kim SJ, Sinn DI, Kim JH, Park DK, Kang KM, Hyung Hong N, Park HK, Won CH, Kim KH, Kim M, Kun Lee S, Roh JK. Systemic transplantation of human adipose stem cells attenuated cerebral inflammation and degeneration in a hemorrhagic stroke model. Brain Res. 2007;1183:43-50.
Constantin G, Marconi S, Rossi B, Angiari S, Calderan L, Anghileri E, Gini B, Bach SD, Martinello M, Bifari F, Galie M, Turano E, Budui S, Sbarbati A, Krampera M, Bonetti B. Adipose-derived mesenchymal stem cells ameliorate chronic experimental autoimmune encephalomyelitis. Stem Cells. 2009;27(10):2624-2635.
Lin CS, Lin G, Lue TF. Allogeneic and Xenogeneic Transplantation of Adipose-Derived Stem Cells in Immunocompetent Recipients Without Immunosuppressants. Stem Cells Dev. 2012; 21(15):2770-2778.
Paul A, Srivastava S, Chen G, Shum-Tim D, Prakash S. Functional Assessment of Adipose Stem Cells for Xenotransplantation Using Myocardial Infarction Immunocompetent Models: Comparison with Bone Marrow Stem Cells. Cell Biochem Biophys. 2011; in press.
Bradley BA. The role of HLA matching in transplantation. Immunol Lett. 1991;29(1-2):55-59.
Lombardi G, Lechler R. The molecular basis of allorecognition of major histocompatibility complex molecules by T lymphocytes. Ann Ist Super Sanita. 1991;27(1):7-14.
DelaRosa O, Sanchez-Correa B, Morgado S, Ramirez C, del Rio B, Menta R, Lombardo E, Tarazona R, Casado JG. Human adipose-derived stem cells impair natural killer cell function and exhibit low susceptibility to natural killer-mediated lysis. Stem Cells Dev. 2012;21(8):1333-1343.
Moon MH, Kim SY, Kim YJ, Kim SJ, Lee JB, Bae YC, Sung SM, Jung JS. Human adipose tissue-derived mesenchymal stem cells improve postnatal neovascularization in a mouse model of hindlimb ischemia. Cell Physiol Biochem. 2006;17(5-6):279-290.
Fischer LJ, McIlhenny S, Tulenko T, Golesorkhi N, Zhang P, Larson R, Lombardi J, Shapiro I, DiMuzio PJ. Endothelial differentiation of adipose-derived stem cells: effects of endothelial cell growth supplement and shear force. J Surg Res. 2009;152(1):157-166.
DiMuzio P, Tulenko T. Tissue engineering applications to vascular bypass graft development: the use of adipose-derived stem cells. J Vasc Surg. 2012; in press.
Wosnitza M, Hemmrich K, Groger A, Graber S, Pallua N. Plasticity of human adipose stem cells to perform adipogenic and endothelial differentiation. Differentiation. 2007;75(1):12-23.
Planat-Benard V, Silvestre JS, Cousin B, Andre M, Nibbelink M, Tamarat R, Clergue M, Manneville C, Saillan-Barreau C, Duriez M, Tedgui A, Levy B, Penicaud L, Casteilla L. Plasticity of human adipose lineage cells toward endothelial cells: physiological and therapeutic perspectives. Circulation. 2004;109(5):656-663.
Ribeiro CA, Fraga JS, Graos M, Neves NM, Reis RL, Gimble JM, Sousa N, Salgado AJ. The secretome of stem cells isolated from the adipose tissue and Wharton jelly acts differently on central nervous system derived cell populations. Stem Cell Res Ther. 2012;3(3):18.
Ii M, Horii M, Yokoyama A, Shoji T, Mifune Y, Kawamoto A, Asahi M, Asahara T. Synergistic effect of adipose-derived stem cell therapy and bone marrow progenitor recruitment in ischemic heart. Lab Invest. 2011;91(4):539-552.
Kim EK, Li G, Lee TJ, Hong JP. The effect of human adipose-derived stem cells on healing of ischemic wounds in a diabetic nude mouse model. Plast Reconstr Surg. 2011;128(2):387-394.
Lu S, Lu C, Han Q, Li J, Du Z, Liao L, Zhao RC. Adipose-derived mesenchymal stem cells protect PC12 cells from glutamate excitotoxicity-induced apoptosis by upregulation of XIAP through PI3-K/Akt activation. Toxicology. 2011;279(1-3):189-195.
Liu K, Liu R, Cao G, Sun H, Wang X, Wu S. Adipose-derived stromal cell autologous transplantation ameliorates pulmonary arterial hypertension induced by shunt flow in rat models. Stem Cells Dev. 2011;20(6):1001-1010.
Nie C, Yang D, Xu J, Si Z, Jin X, Zhang J. Locally administered adipose-derived stem cells accelerate wound healing through differentiation and vasculogenesis. Cell Transplant. 2011;20(2):205-216.
Zhu M, Zhou Z, Chen Y, Schreiber R, Ransom JT, Fraser JK, Hedrick MH, Pinkernell K, Kuo HC. Supplementation of fat grafts with adipose-derived regenerative cells improves long-term graft retention. Ann Plast Surg. 2010;64(2):222-228.
Grewal N, Yacomotti L, Melkonyan V, Massey M, Bradley JP, Zuk PA. Freezing adipose tissue grafts may damage their ability to integrate into the host. Connect Tissue Res. 2009;50(1):14-28.
Rubina K, Kalinina N, Efimenko A, Lopatina T, Melikhova V, Tsokolaeva Z, Sysoeva V, Tkachuk V, Parfyonova Y. Adipose stromal cells stimulate angiogenesis via promoting progenitor cell differentiation, secretion of angiogenic factors, and enhancing vessel maturation. Tissue Eng Part A. 2009;15(8):2039-2050.
Park BS, Jang KA, Sung JH, Park JS, Kwon YH, Kim KJ, Kim WS. Adipose-derived stem cells and their secretory factors as a promising therapy for skin aging. Dermatol Surg. 2008;34(10):1323-1326.
Prichard HL, Reichert W, Klitzman B. IFATS collection: Adipose-derived stromal cells improve the foreign body response. Stem Cells. 2008;26(10):2691-2695.
Kilroy GE, Foster SJ, Wu X, Ruiz J, Sherwood S, Heifetz A, Ludlow JW, Stricker DM, Potiny S, Green P, Halvorsen YD, Cheatham B, Storms RW, Gimble JM. Cytokine profile of human adipose-derived stem cells: expression of angiogenic, hematopoietic, and pro-inflammatory factors. J Cell Physiol. 2007;212(3):702-709.
Wang M, Crisostomo PR, Herring C, Meldrum KK, Meldrum DR. Human progenitor cells from bone marrow or adipose tissue produce VEGF, HGF, and IGF-I in response to TNF by a p38 MAPK-dependent mechanism. Am J Physiol Regul Integr Comp Physiol. 2006;291(4):R880-884.
Rehman J, Traktuev D, Li J, Merfeld-Clauss S, Temm-Grove CJ, Bovenkerk JE, Pell CL, Johnstone BH, Considine RV, March KL. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation. 2004;109(10):1292-1298.
Kim Y, Kim H, Cho H, Bae Y, Suh K, Jung J. Direct comparison of human mesenchymal stem cells derived from adipose tissues and bone marrow in mediating neovascularization in response to vascular ischemia. Cell Physiol Biochem. 2007;20(6):867-876.
Takahashi M, Suzuki E, Oba S, Nishimatsu H, Kimura K, Nagano T, Nagai R, Hirata Y. Adipose tissue-derived stem cells inhibit neointimal formation in a paracrine fashion in rat femoral artery. Am J Physiol Heart Circ Physiol. 2010;298(2):H415-423.
Gao W, Qiao X, Ma S, Cui L. Adipose-derived stem cells accelerate neovascularization in ischaemic diabetic skin flap via expression of hypoxia-inducible factor-1alpha. J Cell Mol Med. 2010;15(12):2575-2585.
Dumont DJ, Fong GH, Puri MC, Gradwohl G, Alitalo K, Breitman ML. Vascularization of the mouse embryo: a study of flk-1, tek, tie, and vascular endothelial growth factor expression during development. Dev Dyn. 1995;203(1):80-92.
Jakeman LB, Armanini M, Phillips HS, Ferrara N. Developmental expression of binding sites and messenger ribonucleic acid for vascular endothelial growth factor suggests a role for this protein in vasculogenesis and angiogenesis. Endocrinology. 1993;133(2):848-859.
Tufro A, Norwood VF, Carey RM, Gomez RA. Vascular endothelial growth factor induces nephrogenesis and vasculogenesis. J Am Soc Nephrol. 1999;10(10):2125-2134.
Tse KH, Kingham PJ, Novikov LN, Wiberg M. Adipose tissue and bone marrow-derived stem cells react similarly in an ischaemia-like microenvironment. J Tissue Eng Regen Med. 2012;6(6):473-485.
Cai L, Johnstone BH, Cook TG, Liang Z, Traktuev D, Cornetta K, Ingram DA, Rosen ED, March KL. Suppression of hepatocyte growth factor production impairs the ability of adipose-derived stem cells to promote ischemic tissue revascularization. Stem Cells. 2007;25(12):3234-3243.
Sumi M, Sata M, Toya N, Yanaga K, Ohki T, Nagai R. Transplantation of adipose stromal cells, but not mature adipocytes, augments ischemia-induced angiogenesis. Life Sci. 2007;80(6):559-565.
Kondo K, Shintani S, Shibata R, Murakami H, Murakami R, Imaizumi M, Kitagawa Y, Murohara T. Implantation of adipose-derived regenerative cells enhances ischemia-induced angiogenesis. Arterioscler Thromb Vasc Biol. 2009;29(1):61-66.
Miranville A, Heeschen C, Sengenes C, Curat CA, Busse R, Bouloumie A. Improvement of postnatal neovascularization by human adipose tissue-derived stem cells. Circulation. 2004;110(3):349-355.
Koh YJ, Koh BI, Kim H, Joo HJ, Jin HK, Jeon J, Choi C, Lee DH, Chung JH, Cho CH, Park WS, Ryu JK, Suh JK, Koh GY. Stromal vascular fraction from adipose tissue forms profound vascular network through the dynamic reassembly of blood endothelial cells. Arterioscler Thromb Vasc Biol. 2011;31(5):1141-1150.
Kang Y, Park C, Kim D, Seong CM, Kwon K, Choi C. Unsorted human adipose tissue-derived stem cells promote angiogenesis and myogenesis in murine ischemic hindlimb model. Microvasc Res. 2010;80(3):310-316.
Bhang SH, Cho SW, La WG, Lee TJ, Yang HS, Sun AY, Baek SH, Rhie JW, Kim BS. Angiogenesis in ischemic tissue produced by spheroid grafting of human adipose-derived stromal cells. Biomaterials. 2011;32(11):2734-2747.
Kim WS, Park BS, Sung JH, Yang JM, Park SB, Kwak SJ, Park JS. Wound healing effect of adipose-derived stem cells: a critical role of secretory factors on human dermal fibroblasts. J Dermatol Sci. 2007;48(1):15-24.
Eltzschig HK, Carmeliet P. Hypoxia and inflammation. N Engl J Med. 2011;364(7):656-665.
Reichenberger MA, Heimer S, Schaefer A, Lass U, Gebhard MM, Germann G, Leimer U, Kollensperger E, Mueller W. Adipose derived stem cells protect skin flaps against ischemia-reperfusion injury. Stem Cell Rev. 2012;8(3):854-862.
Mazo M, Hernandez S, Gavira JJ, Abizanda G, Arana M, Lopez-Martinez T, Moreno C, Merino J, Martino-Rodriguez A, Uixeira A, de Jalon JA, Pastrana J, Martinez-Caro D, Prosper F. Treatment of reperfused ischemia with adipose-derived stem cells in a preclinical swine model of myocardial infarction. Cell Transplant. 2011.
Sun CK, Yen CH, Lin YC, Tsai TH, Chang LT, Kao YH, Chua S, Fu M, Ko SF, Leu S, Yip HK. Autologous transplantation of adipose-derived mesenchymal stem cells markedly reduced acute ischemia-reperfusion lung injury in a rodent model. J Transl Med. 2011;9:118.
Froehlich H, Gulati R, Boilson B, Witt T, Harbuzariu A, Kleppe L, Dietz AB, Lerman A, Simari RD. Carotid repair using autologous adipose-derived endothelial cells. Stroke. 2009;40(5):1886-1891.
Malis CD, Bonventre JV. Susceptibility of mitochondrial membranes to calcium and reactive oxygen species: implications for ischemic and toxic tissue damage. Prog Clin Biol Res. 1988;282:235-259.
Clark IA, Cowden WB, Hunt NH. Free radical-induced pathology. Med Res Rev. 1985;5(3):297-332.
Kloner RA, Przyklenk K, Whittaker P. Deleterious effects of oxygen radicals in ischemia/reperfusion. Resolved and unresolved issues. Circulation. 1989;80(5):1115-1127.
Thompson JA, Hess ML. The oxygen free radical system: a fundamental mechanism in the production of myocardial necrosis. Prog Cardiovasc Dis. 1986;28(6):449-462.
Kim WS, Park BS, Kim HK, Park JS, Kim KJ, Choi JS, Chung SJ, Kim DD, Sung JH. Evidence supporting antioxidant action of adipose-derived stem cells: protection of human dermal fibroblasts from oxidative stress. J Dermatol Sci. 2008;49(2):133-142.
Chen YT, Sun CK, Lin YC, Chang LT, Chen YL, Tsai TH, Chung SY, Chua S, Kao YH, Yen CH, Shao PL, Chang KC, Leu S, Yip HK. Adipose-derived mesenchymal stem cell protects kidneys against ischemia-reperfusion injury through suppressing oxidative stress and inflammatory reaction. J Transl Med. 2011;9:51.
Sun CK, Chang CL, Lin YC, Kao YH, Chang LT, Yen CH, Shao PL, Chen CH, Leu S, Yip HK. Systemic administration of autologous adipose-derived mesenchymal stem cells alleviates hepatic ischemia-reperfusion injury in rats. Crit Care Med. 2011;40(4):1279-1290.
Suga H, Eto H, Aoi N, Kato H, Araki J, Doi K, Higashino T, Yoshimura K. Adipose tissue remodeling under ischemia: death of adipocytes and activation of stem/progenitor cells. Plast Reconstr Surg. 2010;126(6):1911-1923.
Chan RK, Zamora DO, Wrice NL, Baer DG, Renz EM, Christy RJ, Natesan S. Development of a vascularized skin construct using adipose-derived stem cells from debrided burned skin. Stem Cells Int. 2012;2012:841203.
Zografou A, Tsigris C, Papadopoulos O, Kavantzas N, Patsouris E, Donta I, Perrea D. Improvement of skin-graft survival after autologous transplantation of adipose-derived stem cells in rats. J Plast Reconstr Aesthet Surg. 2011;64(12):1647-1656.
Lim JS, Yoo G. Effects of adipose-derived stromal cells and of their extract on wound healing in a mouse model. J Korean Med Sci. 2010;25(5):746-751.
Lee SH, Jin SY, Song JS, Seo KK, Cho KH. Paracrine effects of adipose-derived stem cells on keratinocytes and dermal fibroblasts. Ann Dermatol. 2012;24(2):136-143.
Song SY, Jung JE, Jeon YR, Tark KC, Lew DH. Determination of adipose-derived stem cell application on photo-aged fibroblasts, based on paracrine function. Cytotherapy. 2012;13(3):378-384.
Jung H, Kim HH, Lee DH, Hwang YS, Yang HC, Park JC. Transforming growth factor-beta 1 in adipose derived stem cells conditioned medium is a dominant paracrine mediator determines hyaluronic acid and collagen expression profile. Cytotechnology. 2011;63(1):57-66.
Reichenberger MA, Mueller W, Schafer A, Heimer S, Leimer U, Lass U, Germann G, Kollensperger E. Fibrin-embedded adipose derived stem cells enhance skin flap survival. Stem Cell Rev. 2012;8(3):844-853.
Song SH, Lee MO, Lee JS, Jeong HC, Kim HG, Kim WS, Hur M, Cha HJ. Genetic modification of human adipose-derived stem cells for promoting wound healing. J Dermatol Sci. 2012;66(2):98-107.
Altman AM, Yan Y, Matthias N, Bai X, Rios C, Mathur AB, Song YH, Alt EU. IFATS collection: Human adipose-derived stem cells seeded on a silk fibroin-chitosan scaffold enhance wound repair in a murine soft tissue injury model. Stem Cells. 2009;27(1):250-258.
Fotuhi P, Song YH, Alt E. Electrophysiological consequence of adipose-derived stem cell transplantation in infarcted porcine myocardium. Europace. 2007;9(12):1218-1221.
Zhang DZ, Gai LY, Liu HW, Jin QH, Huang JH, Zhu XY. Transplantation of autologous adipose-derived stem cells ameliorates cardiac function in rabbits with myocardial infarction. Chin Med J (Engl). 2007;120(4):300-307.
Kamihata H, Matsubara H, Nishiue T, Fujiyama S, Tsutsumi Y, Ozono R, Masaki H, Mori Y, Iba O, Tateishi E, Kosaki A, Shintani S, Murohara T, Imaizumi T, Iwasaka T. Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation. 2001;104(9):1046-1052.
Leobon B, Roncalli J, Joffre C, Mazo M, Boisson M, Barreau C, Calise D, Arnaud E, Andre M, Puceat M, Penicaud L, Prosper F, Planat-Benard V, Casteilla L. Adipose-derived cardiomyogenic cells: in vitro expansion and functional improvement in a mouse model of myocardial infarction. Cardiovasc Res. 2009;83(4):757-767.
Mazo M, Planat-Benard V, Abizanda G, Pelacho B, Leobon B, Gavira JJ, Penuelas I, Cemborain A, Penicaud L, Laharrague P, Joffre C, Boisson M, Ecay M, Collantes M, Barba J, Casteilla L, Prosper F. Transplantation of adipose derived stromal cells is associated with functional improvement in a rat model of chronic myocardial infarction. Eur J Heart Fail. 2008;10(5):454-462.
Zhang X, Wang H, Ma X, Adila A, Wang B, Liu F, Chen B, Wang C, Ma Y. Preservation of the cardiac function in infarcted rat hearts by the transplantation of adipose-derived stem cells with injectable fibrin scaffolds. Exp Biol Med (Maywood). 2010;235(12):1505-1515.
Cai L, Johnstone BH, Cook TG, Tan J, Fishbein MC, Chen PS, March KL. IFATS collection: Human adipose tissue-derived stem cells induce angiogenesis and nerve sprouting following myocardial infarction, in conjunction with potent preservation of cardiac function. Stem Cells. 2009;27(1):230-237.
Beitnes JO, Oie E, Shahdadfar A, Karlsen T, Muller RM, Aakhus S, Reinholt FP, Brinchmann JE. Intramyocardial injections of human mesenchymal stem cells following acute myocardial infarction modulate scar formation and improve left ventricular function. Cell Transplant. 2012; in press.
Ma T, Liu H, Chen W, Xia X, Bai X, Liang L, Zhang Y, Liang T. Implanted adipose-derived stem cells attenuate small-for-size liver graft injury by secretion of VEGF in rats. Am J Transplant. 2012;12(3):620-629.
Matsumoto D, Sato K, Gonda K, Takaki Y, Shigeura T, Sato T, Aiba-Kojima E, Iizuka F, Inoue K, Suga H, Yoshimura K. Cell-assisted lipotransfer: supportive use of human adipose-derived cells for soft tissue augmentation with lipoinjection. Tissue Eng. 2006;12(12):3375-3382.
Yang YC, Liu BS, Shen CC, Lin CH, Chiao MT, Cheng HC. Transplantation of adipose tissue-derived stem cells for treatment of focal cerebral ischemia. Curr Neurovasc Res. 2011;8(1):1-13.
Kang SK, Lee DH, Bae YC, Kim HK, Baik SY, Jung JS. Improvement of neurological deficits by intracerebral transplantation of human adipose tissue-derived stromal cells after cerebral ischemia in rats. Exp Neurol. 2003;183(2):355-366.
Leu S, Lin YC, Yuen CM, Yen CH, Kao YH, Sun CK, Yip HK. Adipose-derived mesenchymal stem cells markedly attenuate brain infarct size and improve neurological function in rats. J Transl Med. 2010;8:63.
Ryu HH, Lim JH, Byeon YE, Park JR, Seo MS, Lee YW, Kim WH, Kang KS, Kweon OK. Functional recovery and neural differentiation after transplantation of allogenic adipose-derived stem cells in a canine model of acute spinal cord injury. J Vet Sci. 2009;10(4):273-284.
Wang Y, Zhao Z, Ren Z, Zhao B, Zhang L, Chen J, Xu W, Lu S, Zhao Q, Peng J. Recellularized nerve allografts with differentiated mesenchymal stem cells promote peripheral nerve regeneration. Neurosci Lett. 2012;514(1):96-101.
Santiago LY, Clavijo-Alvarez J, Brayfield C, Rubin JP, Marra KG. Delivery of adipose-derived precursor cells for peripheral nerve repair. Cell Transplant. 2009;18(2):145-158.
Zhang HT, Cheng HY, Cai YQ, Ma X, Liu WP, Yan ZJ, Jiang XD, Xu RX. Comparison of adult neurospheres derived from different origins for treatment of rat spinal cord injury. Neurosci Lett. 2009;458(3):116-121.
Nakada A, Fukuda S, Ichihara S, Sato T, Itoi S, Inada Y, Endo K, Nakamura T. Regeneration of central nervous tissue using a collagen scaffold and adipose-derived stromal cells. Cells Tissues Organs. 2009;190(6):326-335.
Zhao LR, Duan, W.M., Reyes, M., Keene, C.D., Verfaillie, C.M., Low, W.C. Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats. Exp. Neurol. 2002;174:11-20.
Croft AP, Przyborski SA. Mesenchymal stem cells expressing neural antigens instruct a neurogenic cell fate on neural stem cells. Exp Neurol. 2009;216(2):329-341.
Wislet-Gendebien S, Bruyere F, Hans G, Leprince P, Moonen G, Rogister B. Nestin-positive mesenchymal stem cells favour the astroglial lineage in neural progenitors and stem cells by releasing active BMP4. BMC Neurosci. 2004;5:33.
Lopatina T, Kalinina N, Karagyaur M, Stambolsky D, Rubina K, Revischin A, Pavlova G, Parfyonova Y, Tkachuk V. Adipose-derived stem cells stimulate regeneration of peripheral nerves: BDNF secreted by these cells promotes nerve healing and axon growth de novo. PLoS One. 2011;6(3):e17899.
Reid AJ, Sun M, Wiberg M, Downes S, Terenghi G, Kingham PJ. Nerve repair with adipose-derived stem cells protects dorsal root ganglia neurons from apoptosis. Neuroscience. 2011;199:515-522.
Wei X, Du Z, Zhao L, Feng D, Wei G, He Y, Tan J, Lee WH, Hampel H, Dodel R, Johnstone BH, March KL, Farlow MR, Du Y. IFATS collection: The conditioned media of adipose stromal cells protect against hypoxia-ischemia-induced brain damage in neonatal rats. Stem Cells. 2009;27(2):478-488.
Cho YJ, Song HS, Bhang S, Lee S, Kang BG, Lee JC, An J, Cha CI, Nam DH, Kim BS, Joo KM. Therapeutic effects of human adipose stem cell-conditioned medium on stroke. J Neurosci Res. 2012;90(9):1794-1802.
Park SS, Lee YJ, Lee SH, Lee D, Choi K, Kim WH, Kweon OK, Han HJ. Functional recovery after spinal cord injury in dogs treated with a combination of Matrigel and neural-induced adipose-derived mesenchymal Stem cells. Cytotherapy. 2012;14(5):584-597.
Chung JY, Kim W, Im W, Yoo DY, Choi JH, Hwang IK, Won MH, Chang IB, Cho BM, Hwang HS, Moon SM. Neuroprotective effects of adipose-derived stem cells against ischemic neuronal damage in the rabbit spinal cord. J Neurol Sci. 2012;317(1-2):40-46.
Zhang Y, Luo H, Zhang Z, Lu Y, Huang X, Yang L, Xu J, Yang W, Fan X, Du B, Gao P, Hu G, Jin Y. A nerve graft constructed with xenogeneic acellular nerve matrix and autologous adipose-derived mesenchymal stem cells. Biomaterials. 2010;31(20):5312-5324.
Hasharoni A, Zilberman Y, Turgeman G, Helm GA, Liebergall M, Gazit D. Murine spinal fusion induced by engineered mesenchymal stem cells that conditionally express bone morphogenetic protein-2. J Neurosurg Spine. 2005;3(1):47-52.
Chang SC, Chuang H, Chen YR, Yang LC, Chen JK, Mardini S, Chung HY, Lu YL, Ma WC, Lou J. Cranial repair using BMP-2 gene engineered bone marrow stromal cells. J Surg Res. 2004;119(1):85-91.
Guo X, Zheng Q, Kulbatski I, Yuan Q, Yang S, Shao Z, Wang H, Xiao B, Pan Z, Tang S. Bone regeneration with active angiogenesis by basic fibroblast growth factor gene transfected mesenchymal stem cells seeded on porous beta-TCP ceramic scaffolds. Biomed Mater. 2006;1(3):93-99.
Studeny M, Marini FC, Champlin RE, Zompetta C, Fidler IJ, Andreeff M. Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. Cancer Res. 2002;62(13):3603-3608.
Chen XC, Wang R, Zhao X, Wei YQ, Hu M, Wang YS, Zhang XW, Zhang R, Zhang L, Yao B, Wang L, Jia YQ, Zeng TT, Yang JL, Tian L, Kan B, Lin XJ, Lei S, Deng HX, Wen YJ, Mao YQ, Li J. Prophylaxis against carcinogenesis in three kinds of unestablished tumor models via IL12-gene-engineered MSCs. Carcinogenesis. 2006;27(12):2434-2441.
Lin L, Fu X, Zhang X, Chen LX, Zhang JY, Yu CL, Ma KT, Zhou CY. Rat adipose-derived stromal cells expressing BMP4 induce ectopic bone formation in vitro and in vivo. Acta Pharmacol Sin. 2006;27(12):1608-1615.
Dragoo JL, Choi JY, Lieberman JR, Huang J, Zuk PA, Zhang J, Hedrick MH, Benhaim P. Bone induction by BMP-2 transduced stem cells derived from human fat. J Orthop Res. 2003;21(4):622-629.
Hsu WK, Wang JC, Liu NQ, Krenek L, Zuk PA, Hedrick MH, Benhaim P, Lieberman JR. Stem cells from human fat as cellular delivery vehicles in an athymic rat posterolateral spine fusion model. J Bone Joint Surg Am. 2008;90(5):1043-1052.
Diekman BO, Estes BT, Guilak F. The effects of BMP6 overexpression on adipose stem cell chondrogenesis: Interactions with dexamethasone and exogenous growth factors. J Biomed Mater Res A. 2010;93(3):994-1003.
Jin XB, Sun YS, Zhang K, Wang J, Shi TP, Ju XD, Lou SQ. Tissue engineered cartilage from hTGF beta2 transduced human adipose derived stem cells seeded in PLGA/alginate compound in vitro and in vivo. J Biomed Mater Res A. 2008;86(4):1077-1087.
Jabbarzadeh E, Starnes T, Khan YM, Jiang T, Wirtel AJ, Deng M, Lv Q, Nair LS, Doty SB, Laurencin CT. Induction of angiogenesis in tissue-engineered scaffolds designed for bone repair: a combined gene therapy-cell transplantation approach. Proc Natl Acad Sci U S A. 2008;105(32):11099-11104.
Lu F, Li J, Gao J, Ogawa R, Ou C, Yang B, Fu B. Improvement of the survival of human autologous fat transplantation by using VEGF-transfected adipose-derived stem cells. Plast Reconstr Surg. 2009;124(5):1437-1446.
Kucerova L, Altanerova V, Matuskova M, Tyciakova S, Altaner C. Adipose tissue-derived human mesenchymal stem cells mediated prodrug cancer gene therapy. Cancer Res. 2007;67(13):6304-6313.
Josiah DT, Zhu D, Dreher F, Olson J, McFadden G, Caldas H. Adipose-derived stem cells as therapeutic delivery vehicles of an oncolytic virus for glioblastoma. Mol Ther. 2009;18(2):377-385.
Grisendi G, Bussolari R, Cafarelli L, Petak I, Rasini V, Veronesi E, De Santis G, Spano C, Tagliazzucchi M, Barti-Juhasz H, Scarabelli L, Bambi F, Frassoldati A, Rossi G, Casali C, Morandi U, Horwitz EM, Paolucci P, Conte P, Dominici M. Adipose-derived mesenchymal stem cells as stable source of tumor necrosis factor-related apoptosis-inducing ligand delivery for cancer therapy. Cancer Res. 2010;70(9):3718-3729.
De Ugarte DA, Morizono, K., Elbarbary, A., Alfonso, Z.C., Zuk, P.A., Zhu, M., Dragoo, J.L., Ashjian, P.H., Thomas, B., Benhaim, P., Chen, I., Fraser, J.K., Hedrick, M.H. Comparison of multi-lineage cells from human adipose tissue and bone marrow. Cells Tissues Organs. 2003;174:101-109.
Pittenger MF, Mackay, A. M., Beck, S. C., Jaiswal, R. K., Douglas, R., Mosca, J. D., Moorman, M. A., Simonetti, D. W., Craig, S., and Marshak, D. R. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143-147.
Aust L, Devlin B, Foster SJ, Halvorsen YD, Hicok K, du Laney T, Sen A, Willingmyre GD, Gimble JM. Yield of human adipose-derived adult stem cells from liposuction aspirates. Cytotherapy. 2004;6(1):7-14.
Zhu Y, Liu T, Song K, Fan X, Ma X, Cui Z. Adipose-derived stem cell: a better stem cell than BMSC. Cell Biochem Funct. 2008;26(6):664-675.
Oedayrajsingh-Varma MJ, van Ham SM, Knippenberg M, Helder MN, Klein-Nulend J, Schouten TE, Ritt MJ, van Milligen FJ. Adipose tissue-derived mesenchymal stem cell yield and growth characteristics are affected by the tissue-harvesting procedure. Cytotherapy. 2006;8(2):166-177.
Lendeckel S, Jodicke A, Christophis P, Heidinger K, Wolff J, Fraser JK, Hedrick MH, Berthold L, Howaldt HP. Autologous stem cells (adipose) and fibrin glue used to treat widespread traumatic calvarial defects: case report. J Craniomaxillofac Surg. 2004;32(6):370-373.
Rigotti G, Marchi A, Galie M, Baroni G, Benati D, Krampera M, Pasini A, Sbarbati A. Clinical treatment of radiotherapy tissue damage by lipoaspirate transplant: a healing process mediated by adipose-derived adult stem cells. Plast Reconstr Surg. 2007;119(5):1409-1422; discussion 1423-1404.
Casteilla L, Planat-Benard V, Laharrague P, Cousin B. Adipose-derived stromal cells: Their identity and uses in clinical trials, an update. World J Stem Cells. 2011;3(4):25-33.
Yoshimura K, Sato K, Aoi N, Kurita M, Hirohi T, Harii K. Cell-assisted lipotransfer for cosmetic breast augmentation: supportive use of adipose-derived stem/stromal cells. Aesthetic Plast Surg. 2008;32(1):48-55; discussion 56-47.
Lee HC, An SG, Lee HW, Park JS, Cha KS, Hong TJ, Park JH, Lee SY, Kim SP, Kim YD, Chung SW, Bae YC, Shin YB, Kim JI, Jung JS. Safety and effect of adipose tissue-derived stem cell implantation in patients with critical limb ischemia. Circ J. 2012;76(7):1750-1760.
Akita S, Akino K, Hirano A, Ohtsuru A, Yamashita S. Mesenchymal stem cell therapy for cutaneous radiation syndrome. Health Phys. 2010;98(6):858-862.
Mesimaki K, Lindroos B, Tornwall J, Mauno J, Lindqvist C, Kontio R, Miettinen S, Suuronen R. Novel maxillary reconstruction with ectopic bone formation by GMP adipose stem cells. Int J Oral Maxillofac Surg. 2009;38(3):201-209.
Peterson B, Zhang J, Iglesias R, Kabo M, Hedrick M, Benhaim P, Lieberman JR. Healing of critically sized femoral defects, using genetically modified mesenchymal stem cells from human adipose tissue. Tissue Eng. 2005;11(1-2):120-129.
Dudas JR, Marra KG, Cooper GM, Penascino VM, Mooney MP, Jiang S, Rubin JP, Losee JE. The osteogenic potential of adipose-derived stem cells for the repair of rabbit calvarial defects. Ann Plast Surg. 2006;56(5):543-548.
Chen Q, Yang Z, Sun S, Huang H, Sun X, Wang Z, Zhang Y, Zhang B. Adipose-derived stem cells modified genetically in vivo promote reconstruction of bone defects. Cytotherapy. 2010;12(6):831-840.
Sheyn D, Kallai I, Tawackoli W, Cohn Yakubovich D, Oh A, Su S, Da X, Lavi A, Kimelman-Bleich N, Zilberman Y, Li N, Bae H, Gazit Z, Pelled G, Gazit D. Gene-modified adult stem cells regenerate vertebral bone defect in a rat model. Mol Pharm. 2011;8(5):1592-1601.
Yang M, Ma QJ, Dang GT, Ma K, Chen P, Zhou CY. In vitro and in vivo induction of bone formation based on ex vivo gene therapy using rat adipose-derived adult stem cells expressing BMP-7. Cytotherapy. 2005;7(3):273-281.
Chou Y-F, Zuk PA, Chang T-L, Benhaim P, Wu BM. Adipose-Derived Stem Cells and BMP2: Part 1 eated Adipose-Derived Stem Cells Do Not Improve Repair of Segmental Femoral Defects. Conn. Tiss. Res. 2011; 52(2):119-132
Keibl C, Fugl A, Zanoni G, Tangl S, Wolbank S, Redl H, van Griensven M. Human adipose derived stem cells reduce callus volume upon BMP-2 administration in bone regeneration. Injury. 2011;42(8):814-820.
Ra JC, Shin IS, Kim SH, Kang SK, Kang BC, Lee HY, Kim YJ, Jo JY, Yoon EJ, Choi HJ, Kwon E. Safety of intravenous infusion of human adipose tissue-derived mesenchymal stem cells in animals and humans. Stem Cells Dev. 2011;20(8):1297-1308.
Garcia-Olmo D, Garcia-Arranz M, Garcia LG, Cuellar ES, Blanco IF, Prianes LA, Montes JA, Pinto FL, Marcos DH, Garcia-Sancho L. Autologous stem cell transplantation for treatment of rectovaginal fistula in perianal Crohn's disease: a new cell-based therapy. Int J Colorectal Dis. 2003;18(5):451-454.
Garcia-Olmo D, Garcia-Arranz M, Herreros D, Pascual I, Peiro C, Rodriguez-Montes JA. A phase I clinical trial of the treatment of Crohn's fistula by adipose mesenchymal stem cell transplantation. Dis Colon Rectum. 2005;48(7):1416-1423.
Garcia-Olmo D, Herreros D, De-La-Quintana P, Guadalajara H, Trebol J, Georgiev-Hristov T, Garcia-Arranz M. Adipose-derived stem cells in Crohn's rectovaginal fistula. Case Report Med. 2010;2010:961758.
Garcia-Olmo D, Herreros D, Pascual M, Pascual I, De-La-Quintana P, Trebol J, Garcia-Arranz M. Treatment of enterocutaneous fistula in Crohn's Disease with adipose-derived stem cells: a comparison of protocols with and without cell expansion. Int J Colorectal Dis. 2009;24(1):27-30.
Guadalajara H, Herreros D, De-La-Quintana P, Trebol J, Garcia-Arranz M, Garcia-Olmo D. Long-term follow-up of patients undergoing adipose-derived adult stem cell administration to treat complex perianal fistulas. Int J Colorectal Dis. 2012;27(5):595-600.
Song KH. New techniques for treating an anal fistula. J Korean Soc Coloproctol. 2012;28(1):7-12.
Garcia-Olmo D, Herreros D, Pascual I, Pascual JA, Del-Valle E, Zorrilla J, De-La-Quintana P, Garcia-Arranz M, Pascual M. Expanded adipose-derived stem cells for the treatment of complex perianal fistula: a phase II clinical trial. Dis Colon Rectum. 2009;52(1):79-86.
Herreros MD, Garcia-Arranz M, Guadalajara H, De-La-Quintana P, Garcia-Olmo D. Autologous expanded adipose-derived stem cells for the treatment of complex cryptoglandular perianal fistulas: a phase III randomized clinical trial (FATT 1: fistula Advanced Therapy Trial 1) and long-term evaluation. Dis Colon Rectum. 2012;55(7):762-772.
Riordan NH, Ichim TE, Min WP, Wang H, Solano F, Lara F, Alfaro M, Rodriguez JP, Harman RJ, Patel AN, Murphy MP, Lee RR, Minev B. Non-expanded adipose stromal vascular fraction cell therapy for multiple sclerosis. J Transl Med. 2009;7:29.
Ra JC, Kang SK, Shin IS, Park HG, Joo SA, Kim JG, Kang BC, Lee YS, Nakama K, Piao M, Sohl B, Kurtz A. Stem cell treatment for patients with autoimmune disease by systemic infusion of culture-expanded autologous adipose tissue derived mesenchymal stem cells. J Transl Med. 2011;9:181.
Fang B, Song Y, Liao L, Zhang Y, Zhao RC. Favorable response to human adipose tissue-derived mesenchymal stem cells in steroid-refractory acute graft-versus-host disease. Transplant Proc. 2007;39(10):3358-3362.
Fang B, Song Y, Lin Q, Zhang Y, Cao Y, Zhao RC, Ma Y. Human adipose tissue-derived mesenchymal stromal cells as salvage therapy for treatment of severe refractory acute graft-vs.-host disease in two children. Pediatr Transplant. 2007;11(7):814-817.
Fang B, Song YP, Liao LM, Han Q, Zhao RC. Treatment of severe therapy-resistant acute graft-versus-host disease with human adipose tissue-derived mesenchymal stem cells. Bone Marrow Transplant. 2006;38(5):389-390.
Yanez R, Lamana ML, Garcia-Castro J, Colmenero I, Ramirez M, Bueren JA. Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease. Stem Cells. 2006;24(11):2582-2591.
Yoshimura K, Sato K, Aoi N, Kurita M, Inoue K, Suga H, Eto H, Kato H, Hirohi T, Harii K. Cell-assisted lipotransfer for facial lipoatrophy: efficacy of clinical use of adipose-derived stem cells. Dermatol Surg. 2008;34(9):1178-1185.
Wang L, Lu Y, Luo X, Fu MG, Hu X, Dong H, Fan ZH. [Cell-assissted lipotransfer for breast augmentation: a report of 18 patients]. Zhonghua Zheng Xing Wai Ke Za Zhi. 2012;28(1):1-6.
Fierro FA, Sierralta WD, Epunan MJ, Minguell JJ. Marrow-derived mesenchymal stem cells: role in epithelial tumor cell determination. Clin Exp Metastasis. 2004;21(4):313-319.
Zhu W, Xu W, Jiang R, Qian H, Chen M, Hu J, Cao W, Han C, Chen Y. Mesenchymal stem cells derived from bone marrow favor tumor cell growth in vivo. Exp Mol Pathol. 2006;80(3):267-274.
Zimmerlin L, Donnenberg AD, Rubin JP, Basse P, Landreneau RJ, Donnenberg VS. Regenerative therapy and cancer: in vitro and in vivo studies of the interaction between adipose-derived stem cells and breast cancer cells from clinical isolates. Tissue Eng Part A. 2011;17(1-2):93-106.
Vona-Davis L, Rose DP. Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression. Endocr Relat Cancer. 2007;14(2):189-206.
Sasser AK, Sullivan NJ, Studebaker AW, Hendey LF, Axel AE, Hall BM. Interleukin-6 is a potent growth factor for ER-alpha-positive human breast cancer. FASEB J. 2007;21(13):3763-3770.
Razmkhah M, Jaberipour M, Erfani N, Habibagahi M, Talei AR, Ghaderi A. Adipose derived stem cells (ASCs) isolated from breast cancer tissue express IL-4, IL-10 and TGF-beta1 and upregulate expression of regulatory molecules on T cells: do they protect breast cancer cells from the immune response? Cell Immunol. 2011;266(2):116-122.
Liang W, Xia H, Li J, Zhao RC. Human adipose tissue derived mesenchymal stem cells are resistant to several chemotherapeutic agents. Cytotechnology. 2011;63(5):523-530.
Fantuzzi G. Adiponectin and inflammation: consensus and controversy. J Allergy Clin Immunol. 2008;121(2):326-330.
Lago F, Gomez R, Gomez-Reino JJ, Dieguez C, Gualillo O. Adipokines as novel modulators of lipid metabolism. Trends Biochem Sci. 2009;34(10):500-510.
Zeyda M, Farmer D, Todoric J, Aszmann O, Speiser M, Gyori G, Zlabinger GJ, Stulnig TM. Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production. Int J Obes (Lond). 2007;31(9):1420-1428.
Deng Y, Scherer PE. Adipokines as novel biomarkers and regulators of the metabolic syndrome. Ann N Y Acad Sci. 2010;1212:E1-E19.
Maury E, Ehala-Aleksejev K, Guiot Y, Detry R, Vandenhooft A, Brichard SM. Adipokines oversecreted by omental adipose tissue in human obesity. Am J Physiol Endocrinol Metab. 2007;293(3):E656-665.
Cancello R, Clement K. Is obesity an inflammatory illness? Role of low-grade inflammation and macrophage infiltration in human white adipose tissue. BJOG. 2006;113(10):1141-1147.
Balistreri CR, Caruso C, Candore G. The role of adipose tissue and adipokines in obesity-related inflammatory diseases. Mediators Inflamm. 2010;2010:802078.
Fain JN. Release of inflammatory mediators by human adipose tissue is enhanced in obesity and primarily by the nonfat cells: a review. Mediators Inflamm. 2010;2010:513948.
Codoner-Franch P, Valls-Belles V, Arilla-Codoner A, Alonso-Iglesias E. Oxidant mechanisms in childhood obesity: the link between inflammation and oxidative stress. Transl Res. 2011;158(6):369-384.
Zhang K, Kaufman RJ. Identification and characterization of endoplasmic reticulum stress-induced apoptosis in vivo. Methods Enzymol. 2008;442(395-419.
Gao CL, Zhu C, Zhao YP, Chen XH, Ji CB, Zhang CM, Zhu JG, Xia ZK, Tong ML, Guo XR. Mitochondrial dysfunction is induced by high levels of glucose and free fatty acids in 3T3-L1 adipocytes. Mol Cell Endocrinol. 2010;320(1-2):25-33.
Malhotra JD, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid Redox Signal. 2007;9(12):2277-2293.
Bulua AC, Simon A, Maddipati R, Pelletier M, Park H, Kim KY, Sack MN, Kastner DL, Siegel RM. Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). J Exp Med. 2011;208(3):519-533.
Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007;117(1):175-184.
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW, Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112(12):1796-1808.
Harman-Boehm I, Bluher M, Redel H, Sion-Vardy N, Ovadia S, Avinoach E, Shai I, Kloting N, Stumvoll M, Bashan N, Rudich A. Macrophage infiltration into omental versus subcutaneous fat across different populations: effect of regional adiposity and the comorbidities of obesity. J Clin Endocrinol Metab. 2007;92(6):2240-2247.
Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, Fortier M, Greenberg AS, Obin MS. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res. 2005;46(11):2347-2355.
Lumeng CN, Deyoung SM, Bodzin JL, Saltiel AR. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity. Diabetes. 2007;56(1):16-23.
Subramanian V, Ferrante AW, Jr. Obesity, inflammation, and macrophages. Nestle Nutr Workshop Ser Pediatr Program. 2009;63:151-159; discussion 159-162, 259-168.
Wozniak SE, Gee LL, Wachtel MS, Frezza EE. Adipose tissue: the new endocrine organ? A review article. Dig Dis Sci. 2009;54(9):1847-1856.
Ye J, Gimble JM. Regulation of stem cell differentiation in adipose tissue by chronic inflammation. Clin Exp Pharmacol Physiol. 2011;38(12):872-878.
Dercum FX. Three cases of a hitherto unclassified affection resembling in its grosser aspects obesity, but associated with special nervous symptoms - adiposis dolorosa. Am J Med Sci. 1892;civ:521.
Madelung O. Uber den Fetthals. Langenbecks Arch Chir. 1888;37:106.
Fife CE, Maus EA, Carter MJ. Lipedema: a frequently misdiagnosed and misunderstood fatty deposition syndrome. Adv Skin Wound Care. 2010;23(2):81-92; quiz 93-84.
Herbst KL. Rare adipose disorders (RADs) masquerading as obesity. Acta Pharmacol Sin. 2012;33(2):155-172.
Langendoen SI, Habbema L, Nijsten TE, Neumann HA. Lipoedema: from clinical presentation to therapy. A review of the literature. Br J Dermatol. 2009;161(5):980-986.
Curri SB, Merlen JF. [Microvascular disorders of adipose tissue]. J Mal Vasc. 1986;11(3):303-309.
Foldi E, Foldi M. Foldi's Textbook of Lymphology. Munich: Elsevier; 2006.
Kim JH, Lee YM, Ahn EM, Kim KW, Yu YS. Decursin inhibits retinal neovascularization via suppression of VEGFR-2 activation. Mol Vis. 2009;15:1868-1875.
Frank RN. Vascular endothelial growth factor--its role in retinal vascular proliferation. N Engl J Med. 1994;331(22):1519-1520.
Cao R, Brakenhielm E, Wahlestedt C, Thyberg J, Cao Y. Leptin induces vascular permeability and synergistically stimulates angiogenesis with FGF-2 and VEGF. Proc Natl Acad Sci U S A. 2001;98(11):6390-6395.
Siems W, Grune T, Voss P, Brenke R. Anti-fibrosclerotic effects of shock wave therapy in lipedema and cellulite. Biofactors. 2005;24(1-4):275-282.
Partsch H, Stoberl C, Urbanek A, Wenzel-Hora BI. Clinical use of indirect lymphography in different forms of leg edema. Lymphology. 1988;21(3):152-160.
Schneider M, Conway EM, Carmeliet P. Lymph makes you fat. Nat Genet. 2005;37(10):1023-1024.
Nougues J, Reyne Y, Dulor JP. Differentiation of rabbit adipocyte precursors in primary culture. Int J Obes. 1988;12(4):321-333.
Bagheri S, Ohlin K, Olsson G, Brorson H. Tissue tonometry before and after liposuction of arm lymphedema following breast cancer. Lymphat Res Biol. 2005;3(2):66-80.
Wigle JT, Harvey N, Detmar M, Lagutina I, Grosveld G, Gunn MD, Jackson DG, Oliver G. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J. 2002;21(7):1505-1513.
Harvey NL, Srinivasan RS, Dillard ME, Johnson NC, Witte MH, Boyd K, Sleeman MW, Oliver G. Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity. Nat Genet. 2005;37(10):1072-1081.
Wigle JT, Oliver G. Prox1 function is required for the development of the murine lymphatic system. Cell. 1999;98(6):769-778.
Blaber SP, Webster RA, Hill CJ, Breen EJ, Kuah D, Vesey G, Herbert BR. Analysis of in vitro secretion profiles from adipose-derived cell populations. J Transl Med. 2012;10(1):172.
Hsiao ST, Asgari A, Lokmic Z, Sinclair R, Dusting GJ, Lim SY, Dilley RJ. Comparative analysis of paracrine factor expression in human adult mesenchymal stem cells derived from bone marrow, adipose, and dermal tissue. Stem Cells Dev. 2012;21(12):2189-2203.
Banas A, Teratani T, Yamamoto Y, Tokuhara M, Takeshita F, Osaki M, Kawamata M, Kato T, Okochi H, Ochiya T. IFATS collection: in vivo therapeutic potential of human adipose tissue mesenchymal stem cells after transplantation into mice with liver injury. Stem Cells. 2008;26(10):2705-2712.