The results of some preclinical and clinical experiment about treating diabetes type 1 & 2 by stem cell/IPCs transplantation.
Diabetes mellitus is an endocrine disorder characterised by inadequate production or use of insulin, resulting in abnormally high blood glucose levels. High blood glucose leads to the formation of reactive advanced glycation end-products (Feldman et al., 1997), which are responsible for complications such as blindness, kidney failure, cardiovascular disease, stroke, neuropathy and vascular dysfunction. Diabetes mellitus is classified as either type 1 or type 2. Type 1 diabetes mellitus (insulin-dependent diabetes mellitus) results from the autoimmune destruction of the pancreatic beta cells, whereas type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus) results from insulin resistance and impaired glucose tolerance.
Approximately 7.8% (23.6 million people) of the US population has been diagnosed with diabetes mellitus, and another 57 million people are likely to develop diabetes mellitus in the coming years (American Diabetes Association, 2007). The number of people with diabetes mellitus is set to continue to rapidly increase between now and 2030, especially in developing countries.
Over the last decade, a new form of treatment called islet transplantation therapy was thought to provide good patient outcomes; however, few islets are available for transplantation. Typically, the pooled islets isolated from two pancreases are enough to treat a single patient. Since the enormous potential of stem cells was discovered, it was hoped that they would provide the most effective treatment for diabetes mellitus. Over the past two decades, hundreds of studies have looked at the potential of stem cell therapy for treating diabetes mellitus. Successful stem cell therapy would eliminate the cause of the disease and lead to stable, long-term results; hence, the term “pancreatic regeneration” was coined. The hypothesis was that stem cells could regenerate the damaged pancreas. After careful consideration of the aetiology of diabetes mellitus, scientists have put forward two general treatment strategies: stem cell therapy to treat the autoimmune aspect of the disease, and stem cell therapy to treat the degenerative aspect of the disease. In this review, we focus on stem cell-based therapies aimed at islet regeneration through stem cell or insulin-producing cell (IPC) transplantation. We will also discuss the latest strategies for treating both type 1 and type 2 diabetes mellitus using stem cell therapy, along with the (initially promising) results.
2. Islet regeneration by cell replacement
2.1. Stem cell sources
Many different types of stem cells have been used in the research, testing and treatment of diabetes mellitus, including stem cells that can be used to regenerate pancreatic islets, e.g. embryonic stem cells, adult stem cells and infant stem cells (umbilical cord stem cells isolated from umbilical cord blood).
2.1.1. Embryonic stem cells
Human embryonic stem cells (ESCs) were first isolated at the University of Wisconsin-Madison in 1998 by James Thomson (Thomson et al., 1998). These cells were established as immortal pluripotent cell lines that are still in existence today. The ESCs were derived from blastocysts donated by couples undergoing treatment for infertility using methodology developed 17 years earlier to obtain mouse ESCs. Briefly, the trophectoderm is first removed from the blastocyst by immunosurgery and the inner cell mass is plated onto a feeder layer of mouse embryonic ﬁbroblasts (Trounson et al., 2001; 2002). However, cells can also be derived from early human embryos at the morula stage (Strelchenko et al. 2004) after the removal of the zona pellucida using an acidified solution, or by enzymatic digestion by pronase (Verlinsky et al., 2005). Nowadays, ESCs can be isolated from many different sources (Fig. 1).
ESCs are pluripotent, which means that they can differentiate into any of the functional cells derived from the three germ layers, including beta cells or insulin-producing cells (IPCs). The differentiation of ESCs into IPCs is prerequisite for their use as a diabetes mellitus treatment, and may occur either
In 2001, Assady et al. reported that IPCs could be generated by spontaneous differentiation of human ESCs. Although the IPC number and insulin content of these cells was low, this was the first proof-of-principle experiment indicating that human ESCs were a potential source of β-like cells. Recent reports from D'Amour et al. and Kroon et al. described the differentiation of pancreatic lineage cells from human ESCs
2.1.2. Induced pluripotent stem cells
First created by Takahashi et al. (2007) and Yu et al. (2007), induced pluripotent stem cells (IPSCs) are a new source of embryonic-like stem cells, and are considered a technical breakthrough in stem cell research. IPSCs have several advantages over ESCs. One major advantage is that IPSCs can be created from any cell-type; thus, creating patient-specific stem cells (Park et al., 2008; Dimos et al., 2008). Similar to ESCs, IPSCs can differentiate into many different cell types, including neurons (Dimos et al., 2008; Chambers et al., 2008), heart muscle cells (Zhang et al., 2009) and insulin-secreting cells (Tateishi et al., 2008; Zhang et al., 2009).
IPSCs can be created from many different cell types via a simple process. First-generation IPSCs are obtained by transferring four genes (
A recent study shows that IPSCs can be successfully created from adult fibroblasts derived from type 1 diabetic patients (Rene'Maehr et al., 2009). These cells were differentiated into IPCs and used to successfully treat diabetic rats (Alipio et al., 2010).
2.1.3. Pancreatic stem cells
A recent report by Harry Heimberg’s group (Heimberg et al., 2008) describes the existence of pancreatic stem cells in mice. In their most recent study, Heimberg's group ligated the ducts that secrete pancreatic enzymes in adult mice. The result was a doubling in the number of beta cells within two weeks. Also, the pancreases of the experimental animals began to produce more insulin; evidence that the newly generated beta cells were functional (Xu et al., 2008). Another research team showed that the production of new beta cells was dependent on the gene
Human pancreatic stem cells have also been successfully differentiated into IPCs (Noguchi et al., 2010). Islet cells were isolated from the pancreases of human donors using the Ricordi technique modified by the Edmonton protocol. The isolated cells were then cultured in media specifically designed for mouse or human pancreatic embryonic stem cell culture. The cells were differentiated for 2 weeks in induction media containing exendin-4, nicotinamide, keratinocyte growth factor, PDX-1 protein, or protein BETA2/NeuroD. However, according to Davani et al. (2007), human islet precursor cells derived from human pancreases exhibit the properties of mesenchymal stem cells (MSCs) in that they adhere to plastic, express CD73, CD90 and CD105, and differentiate
2.1.4. Mesenchymal stem cells
MSCs are multipotent stem cells that can differentiate into a variety of cell types, such as osteoblasts (bone cells), chondrocytes (cartilage cells) and adipocytes (fat cells) (Anna et al., 2008). This cell type was first discovered in 1924 by the cell morphologist Alexander A. Maximo, who described a type of cell within the mesenchyme that develops into various types of blood cell. Ernest A. McCulloch and James E. Till first revealed the clonal nature of marrow cells in 1963 (Becker et al., 1963; Siminovitch et al., 1963). Subsequently,
MSCs have been isolated from many different tissues, including bone marrow (Oyajobi et al.. 1999; Majumdar et al., 2000; Prockop et al., 2001; Smith et al., 2004; Titorencu et al., 2007; Wolfe et al., 2008; Gronthos and Zannettino et al., 2008; Phadnis et al., 2011; Bao et al., 2011), adipose tissue (Katz et al., 2005; Baptista et al., 2009; Caviggioli et al., 2009; Baer et al., 2010; Bruyn et al., 2010; Estes et al., 2010; Tucker, Bunnell, 2011), peripheral blood (Kassis et al., 2006), umbilical cord blood (Erices et al., 2000; Rosada et al., 2003; Hutson et al., 2005; Reinisch et al., 2007; Bieback and Klüter et al., 2007; Perdikogianni et al., 2008; Zhang et al., 2011), banked umbilical cord blood (Phuc et al., 2011), umbilical cords (Cutler et al., 2010; Farias et al., 2011), umbilical cord membranes (Deuse et al., 2010; Kita et al., 2010), umbilical cord veins (Santos et al., 2010), Wharton's jelly from the umbilical cord (Zeddou et al., 2010; Peng et al., 2011), placenta (Miao et al., 2006; Battula et al., 2007; Huang et al., 2009; Semenov et al., 2010; Pilz et al., 2011), decidua basalis (Macias et al., 2010; Lu et al., 2011), the ligamentum flavum (Chen et al., 2011), amniotic fluid (Feng et al., 2009; Choi et al., 2011, Shuang-Zhi et al., 2010), amniotic membrane (Chang et al., 2010; Marongiu et al., 2010), dental pulp (Agha-Hosseini et al., 2010; Karaöz et al., 2010; Yalvac et al., 2010; Spath et al., 2010), chorionic villi from human placenta (Poloni et al., 2008), foetal membranes (Soncini et al., 2007), menstrual blood (Meng et al., 2007; Hida et al., 2008; Musina et al., 2008; Kyurkchiev et al., 2010), and breast milk (Patki et al., 2010) (Fig. 2).
MSCs have been successfully differentiated into IPCs
2.1.5. Other sources
Recent reports suggest that pancreatic duct cells, liver cells, spleen cells, and other cell types have the ability to differentiate into islet cells. Although it is difficult to differentiate adult cells into insulin-producing pancreatic cells, some researchers have shown evidence of pancreatic duct regeneration in mouse models. When gastrin was injected into mice to induce acinar cells to differentiate into duct cells, these cells became a cellular substrate for the formation of new beta cells, similar to the effects seen in rats receiving glucose injections (Weir and Bonner-Weir et al., 2004).
Liver cells originating from the endothelium may also be candidates for this specialised insulin-secreting role (Meivar-Levy et al., 2006). Yang et al. (2002) reported that exposure to high glucose concentrations caused oval cells in the liver to differentiate into cells with a phenotype similar to that of pancreatic islet cells (Yang et al., 2002). Another strategy involves the
Fibroblasts are a relatively new source of islets and are easily isolated from skin. In a recent study, 61 single-cell-derived dermal fibroblast clones were established from human foreskin using a limiting dilution technique. These cells were able to differentiate into islet-like clusters when induced using pancreatic-inducing medium and several hormones, including insulin, glucagon and somatostatin, were detectable at both the mRNA and protein levels after induction. Moreover, transplantation of these islet-like clusters resulted in the release insulin in response to glucose
2.2. Stem cell transplantation strategies
2.2.1. Transplantation methods
Transplantation of stem cells/IPCs to treat diabetes mellitus has been investigated in both animal models and humans. Many different types of stem cells have been tested using different methods. Cells can be grafted underneath the kidney capsule (Rackham et al., 2011; Figliuzzi et al., 2009; Ito et al., 2010; Lin et al., 2009; Kodama et al., 2009; Kodama et al., 2008; Zhang et al., 2010; Ohmura et al., 2010; Xiao et al., 2008; Berman et al., 2010), delivered via intra-peritoneal injection (Boroujeni et al., 2011; Chandra et al., 2009; Koya et al., 2008; Shao et al., 2011; Kadam et al., 2010; Phuc et al., 2011; Lin et al., 2009) or intra-portally (Shyu et al., 2011; Trivedi et al., 2008; Li et al., 2010; Wu et al., 2007; Longoni et al., 2010; Itakura et al., 2007), grafted into the liver (Chao et al., 2008; Zhu et al., 2009; Xu et al., 2007; Chen et al., 2009; Wang et al., 2010) or injected into the tail vein (Dinarvand et al., 2010; Koblas et al., 2009; Kajiyama et al., 2010; Jurewicz et al., 2010) (Fig. 3). However, there is little research comparing the efficiency of these methods. Chen et al. (2009) showed that transplantation of stem cells into the liver produces better results than transplantation into the renal capsule. Although diabetes mellitus is caused by destruction of the beta cells within the pancreatic islets, no studies have attempted transplantation directly into the pancreas. This is because the pancreas is very sensitive organ and is vulnerable to mechanical intervention.
2.2.2. Stem cell transplantation
Unlike IPC transplantation, the mechanisms underlying islet regeneration and the reductions in blood glucose levels seen in diabetic patients require further study. The main questions that need to be answered are: 1) what role do grafted stem cells play in the regeneration of pancreatic islets? 2) How will stem cells behave when grafted into the body rather than the pancreas?
One type of stem cell that has been used to treat diabetes mellitus and investigated extensively in animal models is MSCs. Almost all research on MSC transplantation shows that
Another study showed that MSCs display immunomodulatory functions. MSCs prevented beta-cell destruction and development of diabetes mellitus by inducing regulatory T cells (Madec et al., 2009). Thus, MSC transplantation may prevent islet cell destruction by the immune system seen in type 1 diabetes mellitus and the pancreatic islets can be gradually restored. The result was a decrease in blood sugar levels and weight gain. While in a more recent study, it is said that MSCs protected islets from hypoxia/reoxygenation (H/R)-induced injury by decreasing apoptosis and increasing the expression of HIF-1α, HO-1, and COX-2 mRNA. The MSCs induced the expression of anti-apoptotic genes, thereby enhancing resistance to H/R-induced apoptosis and dysfunction (Lu et al., 2010).
The use of ESCs for treating diabetes mellitus is limited because of high levels of tumour formation. So there were a few researches using the ESCs for treating diabetes mellitus. In one study, pancreatic cell ontogeny within ESCs transplanted into the renal capsule of STZ-induced mice resulted in pancreatogenesis
2.2.3. Transplantation of differentiated stem cells
Based on the successful transplantation of beta cells, or pancreatic islets, for the treatment of diabetes mellitus (Ris et al., 2011; Wahoff et al., 1995; 1996), transplantation of IPCs differentiated from stem cells is seen as a promising therapy for diabetic patients, particularly in light of the lack of tissue donors and the many side effects of insulin injections. Unlike stem cells, transplanted IPCs produce insulin directly. IPC transplantation using different grafting methods has been studied in mouse models. Routes of administration include the portal vein, intra-peritoneal injection, the liver, the tail vein, and the kidney capsule. IPCs, differentiated from bone marrow-derived MSCs, were successfully allografted into the portal vein in a rat model of diabetes mellitus. After transplantation, the IPCs migrated into the liver where they expressed islet hormones, resulting in reduced glucose levels between Days 6 and 20 post-injection (Wu et al., 2007). Xenotransplantation of IPCs derived from fresh or banked human umbilical cord blood into diabetic mice also showed positive results. These IPCs, transplanted via the portal vein (Wang et al., 2010) or intraperitoneally (Phuc et al., 2011), reduced the blood glucose levels in diabetic mice. When IPCs were grafted into the portal vein, human C-peptides were detected in the mouse livers by immunohistochemistry (Wang et al., 2010). Similar to these results, xenotransplantation of IPCs differentiated from the Wharton’s jelly from human umbilical cords restored normoglycaemia, body weight and a normal glucose tolerance test, indicating that the cells are functional when grafted via the portal vein (Kadam et al., 2010) or liver (Chao et al., 2008).
Zhang et al. (2010) injected IPCs differentiated from human islet-derived progenitor cells under the renal capsule of immunodeficient mice. One month later, 19/28 mice transplanted with progenitor cells and 4/14 mice transplanted with IPCs produced human C-peptide that was detectable in the blood. This indicates that the
ESCs were also differentiated into IPCs and used to treat diabetes mellitus in animal models. After transplantation, these cells did not induce teratoma formation in STZ-induced mice and treatment reduced blood glucose levels to almost normal levels (Kim et al., 2003). Another study indicated that ESCs could differentiate into IPCs; however, transplantation of these pancreatic progenitor clusters into STZ-induced mice failed to reverse the hyperglycaemic state. This indicates that ESCs can differentiate into pancreatic progenitor cells and commit to a pancreatic islet cell fate, but are unable to perform the normal functions of beta cells (Chen et al., 2008). While most studies have focused on experimental treatments using IPC transplantation, another study used liver cells (rather than IPCs) to treat diabetes mellitus. Hepatic cells were differentiated from bone marrow-derived MSCs. Transplantation of syngeneic hepatic cells into STZ-induced mice cured their diabetes mellitus. Treatment of mice with hyperglycaemia and islet cell destruction resulted in repair of the pancreatic islets. Blood glucose levels, intra-peritoneal glucose tolerance tests, and serum insulin levels recovered significantly in the treated group. In addition, both body weight and the number of islets were significantly increased (Dinarvand et al., 2010).
2.2.4. Stem cell gene therapy
Due to their properties of self-renewal and capacity for multipotent differentiation, stem cells are thought to be the best vector for delivering genes and therapeutic gene-coded proteins into the body. Gene transfer experiments that cause stem cells to differentiate into beta cells, or that transfer specific genes coding for insulin, have also been conducted in recent years. There are several possible reasons why the use of stem cell gene therapies can be used to treat diabetes mellitus. However, no study has compared the difference between IPCs produced by chemical induction and those derived from gene transfer. Some researchers hypothesise that the key is the genetic transfer of the signalling pathways related to differentiation from stem cells into IPCs, which will create IPCs more similar to stem cells
2.2.5. Transplantation of immuno-isolated IPCs
Transplantation IPCs offers a potential cell replacement therapy for patients with type 1 diabetes mellitus. However, because of the inadequate number of cells obtained from donors, other stem cell sources have drawn significant attention from many research groups. The efficacy of these approaches is limited because they typically necessitate the administration of immunosuppressive agents to prevent rejection of transplanted cells. The use immunosuppressive drugs can have deleterious side effects, such as increased susceptibility to infection, liver and kidney damage, and an increased risk of cancer. In addition, immunosuppressive drugs may have unexpected effects on the transplanted tissues. For example, some reports have shown that cyclosporine can inhibit insulin secretion by pancreatic cells.
Immuno-isolation is a promising technique that protects the implanted tissues from rejection. One of the most common immuno-isolation techniques is to encapsulate cells within a semi-permeable membrane, such as alginate, that physically protects the grafts from the host’s immune cells while simultaneously allowing nutrients and metabolic products to diffuse into or out of the capsule. To achieve this, the cells are encapsulated within a hydrogel or alginate membrane using gravity, electrostatic forces, or coaxial airflow to form the capsule. Allogeneic and xenogeneic transplantation of encapsulated islets of Langerhans restores normal blood glucose levels in mice (Dufrane et al., 2006; Fan et al., 1990; Omer et al., 2003), dogs (Soon-Shiong et al., 1992a,b; 1993) and non-human primates (Sun et al., 1996) with diabetes mellitus induced by autoimmune diseases or chemical injury, without on the need for immunosuppressive agents. In most of these studies, transplantation was via intraperitoneal injection of islet cells. However, Dufrane et al. (2006) recently reported the generation of encapsulated porcine islets using a Ca-alginate material. These capsules were implanted under the kidney capsule of nondiabetic
In another study, transplantation of alginate-encapsulated IPCs from an embryo-derived mouse embryo progenitor-derived insulin-producing-1 (MEPI-1) cell line lowered hyperglycaemia in immuno-competent, allogeneic diabetic mice. After transplantation, hyperglycaemia was reversed and was followed by a 2.5-month period of normal to moderate hypoglycaemia before relapse. Relapse occurred within 2 weeks in mice transplanted with non-encapsulated MEPI-1 cells. Blood glucose levels, insulin levels, and the results of an oral glucose tolerance test all correlated directly with the number of viable cells remaining in the capsules in the transplanted animals (Shao et al., 2011). Moreover, encapsulation of IPCs differentiated from amnion-derived MSCs, or adipose tissue-derived MSCs in polyurethane-polyvinyl pyrrolidone macrocapsules, or IPCs in calcium alginate, resulted in the restoration of normoglycaemia without immunorejection (Chandra et al., 2009; Kadam et al., 2010) in diabetic rats
2.2.6. Co-transplantation of stem cells and IPCs
Allogeneic islet/IPC transplantation is an efficient method for maintaining normal glucose levels and for the treatment of diabetes mellitus. However, limited sources of islets/IPCs, high rates of islet/IPC graft failure and the need for long-term immunosuppression are major obstacles to the widespread application of these therapies. To overcome these problems, co-transplantation of pancreatic islets/IPCs and adult stem cells is considered as a potential target for the near future. In fact, new results suggest that co-transplantation of stem/precursor cells, particularly MSCs, and islets/IPCs promotes tissue engraftment and beta cell/IPC survival. This theory proposes that stem cells also act as "feeder" cells for the islets, supporting graft protection, tissue revascularisation, and immune acceptance (Sordi et al., 2010).
Overcoming the loss of islet mass is important for successful islet transplantation. Adipose tissue-derived stem cells (ADSCs; referred to as MSCs by some authors) have angiogenic and anti-inflammatory properties. Co-transplantation of ADSCs and islets into mice promotes survival, improves insulin secretion by the graft, and reduces the islet mass required for treatment (Ohmura et al., 2010). In another study, MSCs derived from adipose tissue were differentiated into IPCs and co-transplanted with cultured bone marrow cells into 11 diabetic patients (7 male, 4 female; disease duration, 1–24 years; age range, 13–43 years). Their mean exogenous insulin requirements were 1.14 units/kg BW/day, the mean glycosylated haemoglobin (Hb1Ac) level was 8.47%, and the mean c-peptide level was 0.1 ng/mL. All the patients received successful transplants and the mean follow-up period was 23 months. The results showed a decreased mean exogenous insulin requirement of 0.63 units/kgBW/day, a reduced Hb1Ac of 7.39%, and raised serum c-peptide levels (0.38 ng/mL). The patients reported no diabetic ketoacidosis events and a mean weight gain of 2.5 kg on a normal vegetarian diet and physical activity (Vanikar et al., 2010). However, a previous report indicated that similar results were obtained with undifferentiated MSC-derived adipose tissue co-transplanted with cultured bone marrow. In this study, human adipose tissue-derived MSCs were transfused along with unfractionated cultured bone marrow into five insulinopenic diabetic patients (2 male, 3 female; age range, 14–28 years; disease duration, 0.6 to 10 years) being treated with human insulin (14–70 U/d). The patients had postprandial blood sugar levels between 156 and 470 mg%, Hb1Ac levels of 6.8% to 9.9%, and c-peptide levels of 0.02 to 0.2 ng/mL. After successful transplantation, all patients showed a 30% to 50% reduction in their insulin requirements along with a 4–26-fold increase in serum c-peptide levels during a mean follow-up period of 2.9 months (Trivedi et al., 2008).
After transplantation, MSCs appear to play an immunomodulatory role, thereby promoting graft acceptance. In a cynomolgus monkey model, allogeneic MSCs were co-transplanted with islets intra-portally on postoperative Day 0 and intravenously with donor marrow on postoperative Days 5 and 11. Increased co-transplantation efficiency was associated with increased numbers of regulatory T-cells in the peripheral blood, indicating that co-transplantation of MSCs and islets may be an important method of enhancing islet engraftment and, thereby, decreasing the number of islets required (Berman et al., 2010). Co-transplantation may also downregulate the production of pro-inflammatory cytokines. These results also suggest that MSCs may prevent acute rejection and improve graft function after portal vein pancreatic islet transplantation (Longoni et al., 2010), or that they may induce haematopoietic chimerism and subsequent immune tolerance without causing graft-versus-host disease (Itakura et al., 2007). Moreover, MSC-stimulated graft vascularisation and improved islet graft function are both associated with co-transplanted islets (Figliuzzi et al. 2009; Ito et al. 2010). In addition, interleukin (IL)-6, IL-8, vascular endothelial growth factor-A, hepatocyte growth factor, and transforming growth factor-beta were detected at significant levels in MSC culture medium. These are trophic factors secreted by human MSCs that enhance the survival and function of the islets after transplantation (Park et al., 2010).
3. Islet regeneration by immune correction
There is increasing evidence suggesting that both autoimmune and autoinflammatory mechanisms are involved in the development of type 1 and type-2 diabetes mellitus. Type 1 diabetes mellitus is currently treated with anti-inflammatory drugs and immunosuppressive and immunomodulatory agents. However, despite their profound effects on immune responses, these drugs do not induce clinically significant remission in certain patients. In recent years, stem cells have come to be regarded as the best treatment for autoimmune disorders, including type 1 diabetes mellitus.
In a phase 1/2 study of autologous non-myeloablative haematopoietic stem cell (HSC) transplantation, C-peptide levels were detected in 23 type 1 diabetes mellitus patients (age range, 13–31 years). During a 7–58 month follow-up (mean, 29.8 months; median, 30 months), 20/23 patients with no previous history of ketoacidosis and not receiving corticosteroids were found to be insulin free. Twelve patients maintained normal blood glucose levels for up to 31 months (range, 14–52 months). Eight patients suffered a relapse and resumed insulin injections at a lower dose (0.1–0.3 IU/kg). No mortality was reported. Thus, C-peptide levels increased significantly and the majority of patients achieved insulin independence with good glycemic control (Couri et al., 2009).
In another study, bone marrow from
The initial results of some studies investigating the treatment of type 2 diabetes mellitus show that transplantation of stem cells produces good results. Intra-bone marrow-bone marrow transplantation plus thymus transplantation can be used to treat type 2 diabetes mellitus by normalising the T cell imbalance. Recipient
The results from some preclinical or clinical trials to treat type 1 and type 2 diabetes were summarized in Table 1.
Taking into account all the currently available results (Table 1), we can expect that diabetes mellitus will be successfully treated using stem cell therapy in the near future. However, questions regarding the survival of the cells after grafting and improvements in the vitality and maintenance of cellular function after transplantation remain to be answered. On the basis of evidence supporting the many advantages of bone marrow transplantation, umbilical cord blood transplantation, and HSC therapy for blood-related diseases, the strategy of HSC/BM/UCB may produce several positive results in the coming years and become the treatment of choice for both type 1 and type 2 diabetes mellitus. Although more difficult, ESCs or adult stem cell-derived IPC transplantation are also important treatments for diabetes mellitus, especially when HSCs are in short supply.
Agha-Hosseini F. Jahani M. A. Jahani M. Mirzaii-Dizgah I. Ali-Moghaddam K. 2010In vitro isolation of stem cells derived from human dental pulp,
Alipio Z. Liao W. Roemer E. J. Waner M. Fink L. M. Ward D. C. Ma Y. 2010Reversal of hyperglycemia in diabetic mouse models using induced-pluripotent stem (iPS)-derived pancreatic beta-like cells,
American Diabetes Association 2007Economic costs of diabetes in the U.S.
Anna M. Wobus 2008
Assady S. Maor G. Amit M. Itskovitz-Eldor J. Skorecki K. L. Tzukerman M. 2001Insulin production by human embryonic stem cells.
Aviv V. Meivar-Levy I. Rachmut I. H. Rubinek T. Mor E. Ferber S. 2009Exendin-4 promotes liver cell proliferation and enhances the PDX-1-induced liver to pancreas transdifferentiation process,
Baer P. C. Griesche N. Luttmann W. Schubert R. Luttmann A. Geiger H. 2010Human adipose-derived mesenchymal stem cells in vitro: evaluation of an optimal expansion medium preserving stemness,
Bao X. Wei J. Feng M. Lu S. Li G. Dou W. Ma W. Ma S. An Y. Qin C. 2011Zhao RC, Wang R. Transplantation of human bone marrow-derived mesenchymal stem cells promotes behavioral recovery and endogenous neurogenesis after cerebral ischemia in rats,
Baptista L. S. do Amaral R. J. Carias R. B. Aniceto M. Claudio-da-Silva C. Borojevic R. 2009An alternative method for the isolation of mesenchymal stromal cells derived from lipoaspirate samples, Cytotherapy, (2009), 11 6 706 715
Battula V. L. Treml S. Abele H. Bühring H. J. 2008Prospective isolation and characterization of mesenchymal stem cells from human placenta using a frizzled-9-specific monoclonal antibody,
Becker A. J. Mc Culloch E. A. Till J. E. 1963Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells,
Berman D. M. Willman M. A. Han D. Kleiner G. Kenyon N. M. Cabrera O. Karl J. A. Wiseman R. W. O’Connor D. H. Bartholomew A. M. Kenyon N. S. 2010Mesenchymal stem cells enhance allogeneic islet engraftment in nonhuman primates,
Bi D. Chen F. G. Zhang W. J. Zhou G. D. Cui L. Liu W. Cao Y. 2010Differentiation of human multipotent dermal fibroblasts into islet-like cell clusters,
Bieback K. Klüter H. 2007Mesenchymal stromal cells from umbilical cord blood,
Blyszczuk P. Czyz J. Kania G. 2003Expression of Pax4 in embryonic stem cells promotes differentiation of nestin-positive progenitor and insulin-producing cells,
Boroujeni N. B. Hashemi S. M. Khaki Z. Soleimani M. 2011The reversal of hyperglycemia after transplantation of mouse embryonic stem cells induced into early hepatocyte-like cells in streptozotocin-induced diabetic mice,
Caviggioli F. Vinci V. Salval A. Klinger M. 2009Human adipose-derived stem cells: isolation, characterization and applications in surgery,
Chamson-Reig A. Arany E. J. Hill D. J. 2010Lineage tracing and resulting phenotype of haemopoietic-derived cells in the pancreas during beta cell regeneration,
Chandra V. G. S. Phadnis S. Nair P. D. Bhonde R. R. 2009Generation of pancreatic hormone-expressing islet-like cell aggregates from murine adipose tissue-derived stem cells,
Chang C. F. Hsu K. H. Chiou S. H. Ho L. L. Fu Y. S. Hung S. C. 2008Fibronectin and pellet suspension culture promote differentiation of human mesenchymal stem cells into insulin producing cells,
Chang Y. J. Hwang S. M. Tseng C. P. Cheng F. C. Huang S. H. Hsu L. F. Hsu L. W. Tsai M. S. 2010Isolation of mesenchymal stem cells with neurogenic potential from the mesoderm of the amniotic membrane,
Chao K. C. Chao K. F. Fu Y. S. Liu S. H. 2008Islet-like clusters derived from mesenchymal stem cells in Wharton’s Jelly of the human umbilical cord for transplantation to control type 1 diabetes,
Chen B. Zhou L. Wang L. Hu S. Wang R. 2009Better induction and differentiation strategy for rat pancreatic stem cells: transplant in liver niche,
Chen C. Zhang Y. Sheng X. Huang C. Zang Y. Q. 2008Differentiation of embryonic stem cells towards pancreatic progenitor cells and their transplantation into streptozotocin-induced diabetic mice,
Chen Y. T. Wei J. D. Wang J. P. Lee H. H. Chiang E. R. Lai H. C. Chen L. L. Lee Y. T. Tsai C. C. Liu C. L. Hung S. C. 2011Isolation of mesenchymal stem cells from human ligamentum flavum: implicating etiology of ligamentum flavum hypertrophy,
Choi S. A. Lee J. H. Kim K. J. Kim E. Y. Park K. S. Park Y. B. Li X. Ha Y. N. Park J. Y. Kim M. K. 2011Isoaltion and characterization of mesenchymal stem cells derived from human amniotic fluid,
Couri C. E. Oliveira M. C. Stracieri A. B. Moraes D. A. Pieroni F. Barros G. M. Madeira M. I. Malmegrim K. C. Foss-Freitas M. C. Simões B. P. Martinez E. Z. Foss M. C. Burt R. K. Voltarelli J. C. 2009C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus,
Cutler A. J. Limbani V. Girdlestone J. Navarrete C. V. 2010Umbilical cord-derived mesenchymal stromal cells modulate monocyte function to suppress T cell proliferation,
D’Amour K. A. Bang A. G. Eliazer S. Kelly O. G. Agulnick A. D. Smart N. G. Moorman M. A. Kroon E. Carpenter M. K. Baetge E. E. 2006Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells,
Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2, Danwei Huangfu. Kenji Osafune. René Maehr. Wenjun Guo. Astrid Eijkelenboom. Shuibing Chen. Whitney Muhlestein. Douglas A. Melton
Davani B. Ikonomou L. Raaka B. M. Geras-Raaka E. Morton R. A. Marcus-Samuels B. Gershengorn M. C. 2007Human islet-derived precursor cells are mesenchymal stromal cells that differentiate and mature to hormone-expressing cells in vivo,
Deuse T. Stubbendorff M. Tang-Quan K. Phillips N. Kay M. A. Eiermann T. Phan T. T. Volk H. D. Reichenspurner H. Robbins R. C. Schrepfer S. 2010Immunogenicity and immunomodulatory properties of umbilical cord lining mesenchymal stem cells,
Dimos J. T. Rodolfa K. T. Niakan K. K. 2008Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons,
Dinarvand P. Hashemi S. M. Soleimani M. 2010Effect of transplantation of mesenchymal stem cells induced into early hepatic cells in streptozotocin-induced diabetic mice,
Dong Q. Y. Chen L. Gao G. Q. Wang L. Song J. Chen B. Xu Y. X. Sun L. 2008Allogeneic diabetic mesenchymal stem cells transplantation in streptozotocin-induced diabetic rat,
Dufrane D. Steenberghe M. Goebbels R. M. Saliez A. Guiot Y. Gianello P. 2006The influence of implantation site on the biocompatibility and survival of alginate encapsulated pig islets in rats,
Erices A. Conget P. Minguell J. J. 2000Mesenchymal progenitor cells in human umbilical cord blood,
Estes B. T. Diekman B. O. Gimble J. M. Guilak F. 2010Isolation of adipose-derived stem cells and their induction to a chondrogenic phenotype,
Evans M. J. Kaufman M. H. 1981Establishment in culture of pluripotent cells from mouse embryos.
Fan M. Y. Lum Z. P. Fu X. W. Levesque L. Tai I. T. Sun A. M. 1990Reversal of diabetes in BB rats by transplantation of encapsulated pancreatic islets,
Farias V. A. Linares-Fernández J. L. Peñalver J. L. Payá Colmenero. J. A. Ferrón G. O. Duran E. L. Fernández R. M. Olivares E. G. O’Valle F. Puertas A. Oliver F. J. Ruiz de Almodóvar. J. M. 2011Human umbilical cord stromal stem cell express CD10 and exert contractile properties,
Feldman E. L. Stevens M. J. Greene D. A. 1997Pathogenesis of diabetic neuropathy,
Feng J. X. La X. L. Ma Y. Bi X. J. Wen H. 2009Isolation of human pluripotent mesenchymal stem cells from second-trimester amniotic fluid using two kinds of culture protocol and their differentiation into neuron-like cells,
Figliuzzi M. Cornolti R. Perico N. Rota C. Morigi M. Remuzzi G. Remuzzi A. Benigni A. 2009Bone marrow-derived mesenchymal stem cells improve islet graft function in diabetic rats,
Friedenstein A. J. Deriglasova U. F. Kulagina N. N. Panasuk A. F. Rudakowa S. F. Luria E. A. Ruadkow I. A. 1974Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method,
Friedenstein A. J. Gorskaja J. F. Kulagina N. N. 1976Fibroblast precursors in normal and irradiated mouse hematopoietic organs,
Gao F. Wu D. Q. Hu Y. H. Jin G. X. 2008Extracellular matrix gel is necessary for in vitro cultivation of insulin producing cells from human umbilical cord blood derived mesenchymal stem cells,
Gao F. Wu D. Q. Hu Y. H. Jin G. X. Li G. D. Sun T. W. Li F. J. 2008In vitro cultivation of islet-like cell clusters from human umbilical cord blood-derived mesenchymal stem cells,
Gao X. Song L. Shen K. Wang H. Niu W. Qin X. 2008Transplantation of bone marrow derived cells promotes pancreatic islet repair in diabetic mice,
Gefen-Halevi S. Rachmut I. H. Molakandov K. Berneman D. Mor E. Meivar-Levy I. Ferber S. 2010NKX6.1 promotes PDX-1-induced liver to pancreatic β-cells reprogramming,
Gronthos S. Zannettino A. C. 2008A method to isolate and purify human bone marrow stromal stem cells,
Hansson M. Tonning A. Frandsen U. 2004Artifactual insulin release from differentiated embryonic stem cells.
Hasegawa Y. Ogihara T. Yamada T. Ishigaki Y. Imai J. Uno K. Gao J. Kaneko K. Ishihara H. Sasano H. Nakauchi H. Oka Y. Katagiri H. 2007Bone marrow (BM) transplantation promotes beta-cell regeneration after acute injury through BM cell mobilization,
Hida N. Nishiyama N. Miyoshi S. Kira S. Segawa K. Uyama T. Mori T. Miyado K. Ikegami Y. Cui C. Kiyono T. Kyo S. Shimizu T. Okano T. Sakamoto M. Ogawa S. Umezawa A. 2008Novel cardiac precursor-like cells from human menstrual blood-derived mesenchymal cells,
Hisanaga E. Park K. Y. Yamada S. Hashimoto H. Takeuchi T. Mori M. Seno M. Umezawa K. Takei I. Kojima I. 2008A simple method to induce differentiation of murine bone marrow mesenchymal cells to insulin-producing cells using conophylline and betacellulin-delta4,
Hori Y. Rulifson I. C. Tsai B. C. Heit J. J. Cahoy J. D. Kim S. K. 2002Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells,
Huang Y. Kucia M. Hussain L. R. Wen Y. Xu H. Yan J. Ratajczak M. Z. Ildstad S. T. 2010Bone marrow transplantation temporarily improves pancreatic function in streptozotocin-induced diabetes: potential involvement of very small embryonic-like cells,
Huang Y. C. Yang Z. M. Chen X. H. Tan M. Y. Wang J. Li X. Q. Xie H. Q. Deng L. 2009Isolation of mesenchymal stem cells from human placental decidua basalis and resistance to hypoxia and serum deprivation.
Hutson E. L. Boyer S. Genever P. G. 2005Rapid isolation, expansion, and differentiation of osteoprogenitors from full-term umbilical cord blood,
Itakura S. Asari S. Rawson J. Ito T. Todorov I. Liu C. P. Sasaki N. Kandeel F. Mullen Y. 2007Mesenchymal stem cells facilitate the induction of mixed hematopoietic chimerism and islet allograft tolerance without GVHD in the rat,
Ito T. Itakura S. Todorov I. Rawson J. Asari S. Shintaku J. Nair I. Ferreri K. Kandeel F. Mullen Y. 2010Mesenchymal stem cell and islet co-transplantation promotes graft revascularization and function,
Jiang J. Au M. Lu K. Eshpeter A. Korbutt G. Fisk G. Majumdar A. S. 2007Generation of insulin-producing islet-like clusters from human embryonic stem cells,
Jiang W. Shi Y. Zhao D. Chen S. Yong J. Zhang J. Qing T. Sun X. Zhang P. Ding M. Li D. Deng H. 2007In vitro derivation of functional insulin-producing cells from human embryonic stem cells,
Jurewicz M. Yang S. Augello A. Godwin J. G. Moore R. F. Azzi J. Fiorina P. Atkinson M. Sayegh M. H. Abdi R. 2010Congenic mesenchymal stem cell therapy reverses hyperglycemia in experimental type 1 diabetes,
Kadam S. Muthyala S. Nair P. Bhonde R. 2010Human placenta-derived mesenchymal stem cells and islet-like cell clusters generated from these cells as a novel source for stem cell therapy in diabetes,
Kadam S. S. Bhonde R. R. 2010Islet neogenesis from the constitutively nestin expressing human umbilical cord matrix derived mesenchymal stem cells,
Kadam S. S. Sudhakar M. Nair P. D. Bhonde R. R. 2010Reversal of experimental diabetes in mice by transplantation of neo-islets generated from human amnion-derived mesenchymal stromal cells using immuno-isolatory macrocapsules,
Kajiyama H. Hamazaki T. S. Tokuhara M. Masui S. Okabayashi K. Ohnuma K. Yabe S. Yasuda K. Ishiura S. Okochi H. Asashima M. 2010Pdx1-transfected adipose tissue-derived stem cells differentiate into insulin-producing cells in vivo and reduce hyperglycemia in diabetic mice,
Karaöz E. Doğan B. N. Aksoy A. Gacar G. Akyüz S. Ayhan S. Genç Z. S. Yürüker S. Duruksu G. Demircan P. C. Sariboyaci A. E. 2010Isolation and in vitro characterisation of dental pulp stem cells from natal teeth,
Karnieli O. Izhar-Prato Y. Bulvik S. Efrat S. 2007Generation of insulin-producing cells from human bone marrow mesenchymal stem cells by genetic manipulation,
Kassis I. Zangi L. Rivkin R. Levdansky L. Samuel S. Marx G. Gorodetsky R. 2006Isolation of mesenchymal stem cells from G-CSF-mobilized human peripheral blood using fibrin microbeads,
Katz A. J. Tholpady A. Tholpady S. S. Shang H. Ogle R. C. 2005Cell surface and transcriptional characterization of human adipose-derived adherent stromal (hADAS) cells,
Kim D. Gu Y. Ishii M. Fujimiya M. Qi M. Nakamura N. Yoshikawa T. Sumi S. Inoue K. 2003In vivo functioning and transplantable mature pancreatic islet-like cell clusters differentiated from embryonic stem cell,
Kita K. Gauglitz G. G. Phan T. T. Herndon D. N. Jeschke M. G. 2010Isolation and characterization of mesenchymal stem cells from the sub-amniotic human umbilical cord lining membrane,
Koblas T. Zacharovová K. Berková Z. Leontovic I. Dovolilová E. Zámecník L. Saudek F. 2009In vivo differentiation of human umbilical cord blood-derived cells into insulin-producing beta cells,
Kodama M. Takeshita F. Kanegasaki S. Ochiya T. Quinn G. 2008Pancreatic endocrine and exocrine cell ontogeny from renal capsule transplanted embryonic stem cells in streptozocin-injured mice,
Kodama M. Tsukamoto K. Yoshida K. Aoki K. Kanegasaki S. Quinn G. 2009Embryonic stem cell transplantation correlates with endogenous neurogenin 3 expression and pancreas regeneration in streptozotocin-injured mice,
Kojima H. Fujimiya M. Matsumura K. Younan P. Imaeda H. Maeda M. Chan L. 2003NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice,
Koya V. Lu S. Sun Y. P. Purich D. L. Atkinson M. A. Li S. W. Yang L. J. 2008Reversal of streptozotocin-induced diabetes in mice by cellular transduction with recombinant pancreatic transcription factor pancreatic duodenal homeobox-1: a novel protein transduction domain-based therapy,
Kroon E. Martinson L. A. Kadoya K. Bang A. G. Kelly O. G. Eliazer S. Young H. Richardson M. Smart N. G. Cunningham J. Agulnick A. D. D’Amour K. A. Carpenter M. K. Baetge E. E. 2008Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo,
Kyurkchiev S. Shterev A. Dimitrov R. 2010Assessment of presence and characteristics of multipotent stromal cells in human endometrium and decidua,
Leon-Quinto T. Jones J. Skoudy A. Burcin M. Soria B. 2004In vitro directed differentiation of mouse embryonic stem cells into insulin-producing cells,
Li H. Y. Chen Y. J. Chen S. J. Kao C. L. Tseng L. M. Lo W. L. Chang C. M. Yang D. M. Ku H. H. Twu N. F. Liao C. Y. Chiou S. H. Chang Y. L. 2010Induction of insulin-producing cells derived from endometrial mesenchymal stem-like cells,
Li L. Li F. Qi H. Feng G. Yuanm K. Deng H. Zhou H. 2008Coexpression of Pdx1 and betacellulin in mesenchymal stem cells could promote the differentiation of nestin-positive epithelium-like progenitors and pancreatic islet-like spheroids,
Li M. Abraham N. G. Vanella L. Zhang Y. Inaba M. Hosaka N. Hoshino S. Shi M. Ambrosini Y. M. Gershwin M. E. Ikehara S. 2010Successful modulation of type 2 diabetes in db/db mice with intra-bone marrow--bone marrow transplantation plus concurrent thymic transplantation,
Li Y. Zhang R. Qiao H. Zhang H. Wang Y. Yuan H. Liu Q. Liu D. Chen L. Pei X. 2007Generation of insulin-producing cells from PDX-1 gene-modified human mesenchymal stem cells,
Limbert C. Seufert J. 2009In vitro (re)programming of human bone marrow stromal cells toward insulin-producing phenotypes,
Lin G. Wang G. Liu G. Yang L. J. Chang L. J. Lue T. F. Lin C. S. 2009Treatment of type 1 diabetes with adipose tissue-derived stem cells expressing pancreatic duodenal homeobox 1,
Lin H. Y. Tsai C. C. Chen L. L. Chiou S. H. Wang Y. J. Hung S. C. 2010Fibronectin and laminin promote differentiation of human mesenchymal stem cells into insulin producing cells through activating Akt and ERK,
Lin P. Chen L. Yang N. Sun Y. Xu Y. X. 2009Evaluation of stem cell differentiation in diabetic rats transplanted with bone marrow mesenchymal stem cells,
Longoni B. Szilagyi E. Quaranta P. Paoli G. T. Tripodi S. Urbani S. Mazzanti B. Rossi B. Fanci R. Demontis G. C. Marzola P. Saccardi R. Cintorino M. Mosca F. 2010Mesenchymal stem cells prevent acute rejection and prolong graft function in pancreatic islet transplantation,
Lu D. R. 2010Implantation of bFGF-treated islet progenitor cells ameliorates streptozotocin-induced diabetes in rats,
Lu G. H. Zhang S. Z. Chen Q. Wang X. F. Lu F. F. Liu J. Li M. Li Z. Y. 2011Isolation and multipotent differentiation of human decidua basalis-derived mesenchymal stem cells,
Lu Y. Jin X. Chen Y. Li S. Yuan Y. Mai G. Tian B. Long D. Zhang J. Zeng L. Li Y. Cheng J. 2010Mesenchymal stem cells protect islets from hypoxia/reoxygenation-induced injury,
Lumelsky N. Blondel O. Laeng P. Velasco I. Ravin R. Mc Kay R. 2001Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets,
Macias M. I. Grande J. Moreno A. Domínguez I. Bornstein R. Flores A. I. 2010Isolation and characterization of true mesenchymal stem cells derived from human term decidua capable of multilineage differentiation into all 3 embryonic layers,
Madec A. M. Mallone R. Afonso G. Abou Mrad. E. Mesnier A. Eljaafari A. Thivolet C. 2009Mesenchymal stem cells protect NOD mice from diabetes by inducing regulatory T cells,
Majumdar M. K. Banks V. Peluso D. P. Morris E. A. 2000Isolation, characterization, and chondrogenic potential of human bone marrow-derived multipotential stromal cells,
Mao G. H. Chen G. A. Bai H. Y. Song T. R. Wang Y. X. 2009The reversal of hyperglycaemia in diabetic mice using PLGA scaffolds seeded with islet-like cells derived from human embryonic stem cells,
Marongiu F. Gramignoli R. Sun Q. Tahan V. Miki T. Dorko K. Ellis E. Strom S. C. 2010Isolation of amniotic mesenchymal stem cells,
Meivar-Levy I. Ferber S. 2006Regenerative medicine: using liver to generate pancreas for treating diabetes,
Meivar-Levy I. Ferber S. 2010Adult cell fate reprogramming: converting liver to pancreas,
Meng X. Ichim T. E. Zhong J. Rogers A. Yin Z. Jackson J. Wang H. Ge W. Bogin V. Chan K. W. Thébaud B. Riordan N. H. 2007Endometrial regenerative cells: a novel stem cell population,
Miao Z. Jin J. Chen L. Zhu J. Huang W. Zhao J. Qian H. Zhang X. 2006Isolation of mesenchymal stem cells from human placenta: comparison with human bone marrow mesenchymal stem cells,
Moriscot C. de Fraipont F. Richard M. J. Marchand M. Savatier P. Bosco D. Favrot M. Benhamou P. Y. 2005Human bone marrow mesenchymal stem cells can express insulin and key transcription factors of the endocrine pancreas developmental pathway upon genetic and/or microenvironmental manipulation in vitro,
Musina R. A. Belyavski A. V. Tarusova O. V. Solovyova E. V. Sukhikh G. T. 2008Endometrial mesenchymal stem cells isolated from the menstrual blood,
Nakagawa M. Koyanagi M. Tanabe K. Takahashi K. Ichisaka T. Aoi T. Okita K. Mochiduki Y. Takizawa N. Yamanaka S. 2007Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts,
Naujok O. Francini F. Picton S. Bailey C. J. Lenzen S. Jörns A. 2009Changes in gene expression and morphology of mouse embryonic stem cells on differentiation into insulin-producing cells in vitro and in vivo,
Noguchi H. Matsumoto S. Ueda M. Hayashi S. Kobayashi N. Jackson A. Naziruddin B. Levy M. F. 2008Method for isolation of mouse pancreatic stem cells,
Noguchi H. Naziruddin B. Shimoda M. Fujita Y. Chujo D. Takita M. Peng H. Sugimoto K. Itoh T. Tamura Y. Olsen G. S. Kobayashi N. Onaca N. Hayashi S. Levy M. F. Matsumoto S. 2010Induction of insulin-producing cells from human pancreatic progenitor cells,
Noguchi H. Oishi K. Ueda M. Yukawa H. Hayashi S. Kobayashi N. Levy M. F. Matusmoto S. 2009Establishment of mouse pancreatic stem cell line,
Ohmura Y. Tanemura M. Kawaguchi N. Machida T. Tanida T. Deguchi T. Wada H. Kobayashi S. Marubashi S. Eguchi H. Takeda Y. Matsuura N. Ito T. Nagano H. Doki Y. Mori M. 2010Combined transplantation of pancreatic islets and adipose tissue-derived stem cells enhances the survival and insulin function of islet grafts in diabetic mice,
Omer A. Keegan M. Czismadia E. De Vos P. Van Rooijen N. Bonner-Weir S. Weir G. C. 2003Macrophage depletion improves survival of porcine neonatal pancreatic cell clusters contained in alginate macrocapsules transplanted into rats,
Oyajobi B. O. Lomri A. Hott M. Marie P. J. 1999Isolation and characterization of human clonogenic osteoblast progenitors immunoselected from fetal bone marrow stroma using STRO-1 monoclonal antibody,
Parekh V. S. Joglekar M. V. Hardikar A. A. 2009Differentiation of human umbilical cord blood-derived mononuclear cells to endocrine pancreatic lineage,
Park I. H. Arora N. Huo H. 2008Disease-specific induced pluripotent stem cells,
Park K. S. Kim Y. S. Kim J. H. Choi B. Kim S. H. Tan A. H. Lee M. S. Lee M. K. Kwon C. H. Joh J. W. Kim S. J. Kim K. W. 2010Trophic molecules derived from human mesenchymal stem cells enhance survival, function, and angiogenesis of isolated islets after transplantation,
Patki S. Kadam S. Chandra V. Bhonde R. 2010Human breast milk is a rich source of multipotent mesenchymal stem cells,
Paz A. H. Salton G. D. Ayala-Lugo A. Gomes C. Terraciano P. Scalco R. Laurino C. C. Passos E. P. Schneider M. R. Meurer L. Cirne-Lima E. 2011Betacellulin overexpression in mesenchymal stem cells induces insulin secretion in vitro and ameliorates streptozotocin-induced hyperglycemia in rats,
Peng J. Wang Y. Zhang L. Zhao B. Zhao Z. Chen J. Guo Q. Liu S. Sui X. Xu W. Lu S. 2011Humanumbilical cord Wharton’s jelly-derived mesenchymal stem cells differentiate into a Schwann-cell phenotype and promote neurite outgrowth in vitro,
Perdikogianni C. Dimitriou H. Stiakaki E. Martimianaki G. Kalmanti M. 2008Could cord blood be a source of mesenchymal stromal cells for clinical use?
Phadnis S. M. Joglekar M. V. Dalvi M. P. Muthyala S. Nair P. D. Ghaskadbi S. M. Bhonde R. R. Hardikar A. A. 2011Human bone marrow-derived mesenchymal cells differentiate and mature into endocrine pancreatic lineage in vivo,
Phuc P. V. Nhung T. H. Loan D. T. Chung D. C. Ngoc P. K. 2010Differentiating of banked human umbilical cord blood-derived mesenchymal stem cells into insulin-secreting cells,
Pilz G. A. Ulrich C. Ruh M. Abele H. Schäfer R. Kluba T. Bühring H. J. Rolauffs B. Aicher W. K. 2010Human Term Placenta-Derived Mesenchymal Stromal Cells Are Less Prone to Osteogenic Differentiation Than Bone Marrow-Derived Mesenchymal Stromal Cells,
Poloni A. Rosini V. Mondini E. Maurizi G. Mancini S. Discepoli G. Biasio S. Battaglini G. Berardinelli E. Serrani F. Leoni P. 2008Characterization and expansion of mesenchymal progenitor cells from first-trimester chorionic villi of human placenta,
Prockop D. J. Sekiya I. Colter D. C. 2001Isolation and characterization of rapidly self-renewing stem cells from cultures of human marrow stromal cells,
Rackham C. L. Chagastelles P. C. Nardi N. B. Hauge-Evans A. C. Jones P. M. King A. J. 2011Co-transplantation of mesenchymal stem cells maintains islet organisation and morphology in mice,
Rajagopal J. Anderson W. J. Kume S. Martinez O. I. Melton D. A. 2003Insulin staining of ES cell progeny from insulin uptake,
Reinisch A. Bartmann C. Rohde E. Schallmoser K. Bjelic-Radisic V. Lanzer G. Linkesch W. Strunk D. 2007Humanized system to propagate cord blood-derived multipotent mesenchymal stromal cells for clinical application,
Rene ´. Maehra Shuibing. Chena Melinda. Snitowa Thomas. Ludwigb Lisa. Yagasaki a. Robin Golandc. Rudolph L. Leibel Douglas A. Meltona 2009Generation of pluripotent stem cells from patients with type 1 diabetes,
Ris F. Niclauss N. Morel P. Demuylder-Mischler S. Muller Y. Meier R. Genevay M. Bosco D. Berney T. 2011Islet Autotransplantation After Extended Pancreatectomy for Focal Benign Disease of the Pancreas,
Rosada C. Justesen J. Melsvik D. Ebbesen P. Kassem M. 2003The human umbilical cord blood: a potential source for osteoblast progenitor cells,
Santos T. M. Percegona L. S. González P. Calil A. Corradi Perini. C. Faucz F. R. Câmara N. O. Aita C. A. 2010Expression of pancreatic endocrine markers by mesenchymal stem cells from human umbilical cord vein,
Sapir T. Shternhall K. Meivar-Levy I. Blumenfeld T. Cohen H. Skutelsky E. Eventov-Friedman S. Barshack I. Goldberg I. Pri-Chen S. Ben-Dor L. Polak-Charcon S. Karasik A. Shimon I. Mor E. Ferber S. 2005Cell-replacement therapy for diabetes: Generating functional insulin-producing tissue from adult human liver cells,
Schroeder I. S. Rolletschek A. Blyszczuk P. Kania G. Wobus A. M. 2006Differentiation of mouse embryonic stem cells to insulin-producing cells,
Semenov O. V. Koestenbauer S. Riegel M. Zech N. Zimmermann R. Zisch A. H. Malek A. 2010Multipotent mesenchymal stem cells from human placenta: critical parameters for isolation and maintenance of stemness after isolation,
Shao S. Gao Y. Xie B. Xie F. Lim S. K. Li G. 2011Correction of hyperglycemia in type 1 diabetic models by transplantation of encapsulated insulin-producing cells derived from mouse embryo progenitor,
Shi Y. Hou L. Tang F. 2005Inducing embryonic stem cells to differentiate into pancreatic β cells by a novel three-step approach with activin a and all-trans retinoic acid,
Shternhall-Ron K. Quintana F. J. Perl S. Meivar-Levy I. Barshack I. Cohen I. R. Ferber S. 2007Ectopic PDX-1 expression in liver ameliorates type 1 diabetes,
Shuang-Zhi H. Ping S. Xi-Ning P. 2010Culture and identification of human amniotic mesenchymal stem cells,
Shyu J. F. Wang H. S. Shyr Y. M. Wang S. E. Chen C. H. Tan J. S. Lin M. F. Hsieh P. S. Sytwu H. K. Chen T. H. 2011Alleviation of hyperglycemia in diabetic rats by intraportal injection of insulin-producing cells generated from surgically resected human pancreatic tissue,
Siminovitch L. Mc Culloch E. A. Till J. E. 1963The distribution of colony-forming cells among spleen colonies,
Sipione S. Eshpeter A. Lyon J. G. Korbutt G. S. Bleackley R. C. 2004Insulin expressing cells from differentiated embryonic stem cells are not beta cells,
Smith J. R. Pochampally R. Perry A. Hsu S. C. Prockop D. J. 2004Isolation of a highly clonogenic and multipotential subfraction of adult stem cells from bone marrow stroma,
Soncini M. Vertua E. Gibelli L. Zorzi F. Denegri M. Albertini A. Wengler G. S. Parolini O. 2007Isolation and characterization of mesenchymal cells from human fetal membranes,
Soon-Shiong P. Feldman E. Nelson R. Heintz R. Merideth N. Sandford P. Zheng T. Komtebedde J. 1992Long-term reversal of diabetes in the large animal model by encapsulated islet transplantation,
Soon-Shiong P. Feldman E. Nelson R. Komtebedde J. Smidsrod O. Skjak-Braek G. Espevik T. Heintz R. Lee M. 1992Successful reversal of spontaneous diabetes in dogs by intraperitoneal microencapsulated islets,
Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets. Sordi V. Malosio M. L. Marchesi F. Mercalli A. Melzi R. Giordano T. Belmonte N. Ferrari G. Leone B. E. Bertuzzi F. Zerbini G. Allavena P. Bonifacio E. Piemonti L.
Sordi V. Piemonti L. 2010Mesenchymal stem cells as feeder cells for pancreatic islet transplants,
Sordi V. 2009Mesenchymal stem cell homing capacity,
Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice, Soria B. Roche E. Berna G. Leon-Quinto T. Reig J. A. Martin F.
Spath L. Rotilio V. Alessandrini M. Gambara G. De Angelis L. Mancini M. Mitsiadis T. A. Vivarelli E. Naro F. Filippini A. Papaccio G. 2010Explant-derived human dental pulp stem cells enhance differentiation and proliferation potentials,
Strelchenko N. Verlinsky O. Kukharenko V. Verlinsky Y. 2004Morula-derived human embryonic stem cells,
Sun Y. Chen L. Hou X. G. Hou W. K. Dong J. J. Sun L. Tang K. X. Wang B. Song J. Li H. Wang K. X. 2007Differentiation of bone marrow-derived mesenchymal stem cells from diabetic patients into insulin-producing cells in vitro,
Sun Y. Ma X. Zhou D. Vacek I. Sun A. M. 1996Normalization of diabetes in spontaneously diabetic cynomologus monkeys by xenografts of microencapsulated porcine islets without immunosuppression,
Takahashi K. Yamanaka S. 2006Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors,
Takahashi K. Tanabe K. Ohnuki M. 2007Induction of pluripotent stem cells from adult human fibroblasts by defined factors,
Titorencu I. Jinga V. V. Constantinescu E. Gafencu A. V. Ciohodaru C. Manolescu I. Zaharia C. Simionescu M. 2007Proliferation, differentiation and characterization of osteoblasts from human BM mesenchymal cells,
Trivedi H. L. Vanikar A. V. Thakker U. Firoze A. Dave S. D. Patel C. N. Patel J. V. Bhargava A. B. Shankar V. 2008Human adipose tissue-derived mesenchymal stem cells combined with hematopoietic stem cell transplantation synthesize insulin,
Trounson A. 2002Human embryonic stem cells: mother of all cell and tissues,
Trovato L. De Fazio R. Annunziata M. Sdei S. Favaro E. Ponti R. Marozio L. Ghigo E. Benedetto C. Granata R. 2009Pluripotent stem cells isolated from human amniotic fluid and differentiation into pancreatic beta-cells,
Tucker H. A. Bunnell B. A. 2011Characterization of human adipose-derived stem cells using flow cytometry,
Vanikar A. V. Dave S. D. Thakkar U. G. Trivedi H. L. 2010Cotransplantation of adipose tissue-derived insulin-secreting mesenchymal stem cells and hematopoietic stem cells: a novel therapy for insulin-dependent diabetes mellitus,
Human embryonic stem cell lines with genetic disorders, Verlinsky Y. Strelchenko N. Kukharenko V. Rechitsky S. Verlinsky O. Galat V. Kuliev A.
Wahoff D. C. Papalois B. E. Najarian J. S. Kendall D. M. Farney A. C. Leone J. P. Jessurun J. Dunn D. L. Robertson R. P. Sutherland D. E. 1995Autologous islet transplantation to prevent diabetes after pancreatic resection,
Wahoff D. C. Paplois B. E. Najarian J. S. Farney A. C. Leonard A. S. Kendall D. M. Roberston R. R. Sutherland D. E. 1996Islet Autotransplantation after total pancreatectomy in a child,
Wang H. S. Shyu J. F. Shen W. S. Hsu H. C. Chi T. C. Chen C. P. Huang S. W. Shyr Y. M. Tang K. T. Chen T. H. 2010Transplantation of insulin producing cells derived from umbilical cord stromal mesenchymal stem cells to treat NOD mice,
Weir G. C. Bonner-Weir S. 2004Beta-cell precursors--a work in progress,
Wolfe M. Pochampally R. Swaney W. Reger R. L. 2008Isolation and culture of bone marrow-derived human multipotent stromal cells (hMSCs),
Wu L. F. Wang N. N. Liu Y. S. Wei X. 2009Differentiation of Wharton’s jelly primitive stromal cells into insulin-producing cells in comparison with bone marrow mesenchymal stem cells,
Wu X. H. Liu C. P. Xu K. F. Mao X. D. Zhu J. Jiang J. J. Cui D. Zhang M. Xu Y. Liu C. 2007Reversal of hyperglycemia in diabetic rats by portal vein transplantation of islet-like cells generated from bone marrow mesenchymal stem cells,
Xiao M. An L. Yang X. Ge X. Qiao H. Zhao T. Ma X. Fan J. Zhu M. Dou Z. 2008Establishing a human pancreatic stem cell line and transplanting induced pancreatic islets to reverse experimental diabetes in rats,
Xie Q. P. Huang H. Xu B. Dong X. Gao S. L. Zhang B. Wu Y. L. 2009Human bone marrow mesenchymal stem cells differentiate into insulin-producing cells upon microenvironmental manipulation in vitro,
Xu J. Lu Y. Ding F. Zhan X. Zhu M. Wang Z. 2007Reversal of diabetes in mice by intrahepatic injection of bone-derived GFP-murine mesenchymal stem cells infected with the recombinant retrovirus-carrying human insulin gene,
Xu X. D’Hoker J. Stangé G. Bonné S. De Leu N. Xiao X. Van de Casteele M. Mellitzer G. Ling Z. Pipeleers D. Bouwens L. Scharfmann R. Gradwohl G. Heimberg H. 2008Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas,
Yalvac M. E. Ramazanoglu M. Rizvanov A. A. Sahin F. Bayrak O. F. Salli U. Palotás A. Kose G. T. 2010Isolation and characterization of stem cells derived from human third molar tooth germs of young adults: implications in neo-vascularization, osteo-, adipo- and neurogenesis,
Yang L. Li S. Hatch H. Ahrens K. Cornelius J. G. Petersen B. E. Peck A. B. 2002In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormone-producing cells,
Yu J. Vodyanik M. A. Smuga-Otto K. 2007Induced pluripotent stem cell lines derived from human somatic cells,
Yuan H. Li J. Xin N. Zhao Z. Qin G. 2010Expression of Pdx1 mediates differentiation from mesenchymal stem cells into insulin-producing cells,
Zalzman M. Anker-Kitai L. Efrat S. 2010Differentiation of human liver-derived, insulin-producing cells toward the beta-cell phenotype,
Zeddou M. Briquet A. Relic B. Josse C. Malaise M. G. Gothot A. Lechanteur C. Beguin Y. 2010The umbilical cord matrix is a better source of mesenchymal stem cells (MSC) than the umbilical cord blood,
Zhang X. Hirai M. Cantero S. Ciubotariu R. Dobrila L. Hirsh A. Igura K. Satoh H. Yokomi I. Nishimura T. Takahashi T. A. 2011Isolation and characterization of mesenchymal stem cells from human umbilical cord blood: Reevaluation of critical factors for successful isolation and high ability to proliferate and differentiate to chondrocytes as compared to mesenchymal stem cells from bone marrow and adipose tissue,
Zhang Y. Ren Z. Zou C. Wang S. Luo B. Li F. Liu S. Zhang Y. A. 2010Insulin-producing cells from human pancreatic islet-derived progenitor cells following transplantation in mice,
Zhu S. Lu Y. Zhu J. Xu J. Huang H. Zhu M. Chen Y. Zhou Y. Fan X. Wang Z. 2009Effects of Intrahepatic Bone-Derived Mesenchymal Stem Cells Autotransplantation on the Diabetic Beagle Dogs,