Main characteristics of human stem cells.
Human endothelial progenitor cells (hEPCs) are adult stem cells, located in the bone marrow and peripheral blood. These cells can be differentiated into mature endothelial cells, which are involved in processes of angiogenesis and vessel regeneration. Different phenotypes and subtypes of endothelial progenitor cells (EPCs), such as early and late EPCs, have been described according to their functionality. Thus, it has been shown that early EPCs release cytokines that promote tissue regeneration and neovasculogenesis, whereas late EPC and endothelial colony forming cells (ECFCs) contribute to the formation of blood vessels and stimulate tube formation. It has been demonstrated that the number of circulating hEPC is decreased in individuals with hypercholesterolemia, hypertension, and/or diabetes. In addition, the number and the migratory activity of these cells are inversely correlated with risk factors such as hypertension, hypercholesterolemia, diabetes, and metabolic syndrome. On the other hand, the number of circulating hEPC is increased in hypoxia or acute myocardial infarction (AMI). hEPCs have been used for cell-based therapies due to their capacity to contribute in the re-endothelialization of injured blood vessels and neovascularization in ischemic tissues. This chapter provides an overview of the key role of hEPC in promoting angiogenesis and their potential use for cell therapy.
- stem cell
- endothelial progenitor cells
- vascular regeneration
- cell therapy
Stem cells are characterized by their ability to proliferate and self-renew in response to signals or stimuli generated by the microenvironment. These signals can also induce the differentiation of stem cells into diverse cell types with specialized features and functions [1, 2]. According to their differentiation potential, stem cells can be classified as either embryonic or adult. The characteristics of both cell populations are summarized in Table 1. In this chapter, we will focus on adult stem cell. This subtype of stem cells is present in several tissues and is thought to be a part of the natural tissue repair system (Figure 1). Adult stem cells can be present not only in tissues with high regeneration potential, such as the skin, intestinal epithelium , and vascular tissue  but also in tissues with lower cell turnover like the brain . They are responsible for tissue regeneration, and they can be classified as hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), and endothelial progenitor cells (EPCs).
|Characteristics||Embryonic stem cells||Adult stem cells|
|Complexity of isolation||+++||++|
2. Hematopoietic stem cells (HSCs)
HSCs are multipotent tissue-specific stem cells that give rise and maintain lifelong hematopoiesis . HSCs only comprise approximately 0.001–0.01% of total bone marrow cells in mice and approximately 0.01–0.2% of total bone marrow mononuclear cells in humans . Moreover, HSCs express cytokines receptors, allowing them to respond to signals from immune cells and to sense pathogens during inflammation or infection. This capacity allows them to adapt their cycling and differentiation behavior according to the requirements of the body .
3. Mesenchymal stem cells (MSCs)
MSCs are bone marrow–derived stem cells that have the capacity to form plastic-adherent colony forming unit-fibroblasts (CFU-f) . They exhibit a well-known phenotype (CD73+CD90+CD105+CD34−CD45−), and they have the capacity to differentiate into osteoblasts, adipocytes, and chondroblasts . Furthermore, they can be also differentiated into numerous cell types derived from all three embryonic layers, which include muscle, vascular, nervous, hematopoietic, and bone cells, among others. MSCs can be isolated from bone marrow, adipose tissue, synovium, skeletal muscle, dermis, pericytes, amniotic fluid, umbilical cord, and even human peripheral blood [10–13]. These cells are indeed promising candidates for tissue engineering and cell-based therapies not only because of their multipotent differentiation potential but also due to their low immunogenicity .
4. Human endothelial progenitor cells (hEPCs)
hEPCs are adult stem cells characterized by the capacity to proliferate , self-renew and repair endothelial tissue . They have been successfully isolated from peripheral blood , placenta, and bone marrow . Several cell surface markers have been described to identify hEPC, such as CD34 , vascular endothelial growth factor (VEGF) receptor-1 or Flt-1 [19, 20], CD133 or prominine-1 (surface glycoprotein), Tie-2 (endothelial receptor tyrosine kinase), Von Willebrand factor, Nanog, and Oct-4 (Octámer-4) .
The original description of hEPCs by Asahara et al. was based on (1) the ability of hEPC to adhere to fibronectin-coated surfaces and (2) the surface expression of both immature stem cells (CD34, CD45, VEGFR2, or Flk-1) and mature endothelial cell (EC) markers (CD31, E-selectin, and angiopoietin receptor Tie-2) . In addition, the expression of endothelial nitric oxide synthase (eNOS), the synthesis of nitric oxide (NO), and the ability to incorporate low-density lipoproteins (LDL) have been also associated with differentiation of hEPC toward endothelial cells .
4.1. Origin of hEPCs
To date, at least four cell sources of circulating hEPCs have been described: (1) HCSs (hemangioblast and myeloid cell), (2) bone marrow–derived MSCs, (3) hEPC not derived from bone marrow (fat and resident cells in tissues such as heart, liver, intestine, and nervous system), and (4) mature ECs migrating from the vascular wall [16, 23]. The best-characterized and most abundant hEPC are hematopoietic-derived hEPC, which can be isolated from peripheral blood mononuclear cells (PBMCs), umbilical cord, and placenta [16, 24]. Despite the fact that hematopoietic-derived hEPC are identified in different tissues, they have similar features, for example, hEPCs from umbilical cord exhibit the same surface markers (CD34, CD146, vWF, and VEGFR2) as hEPC from peripheral blood . Other similarities between hematopoietic-derived hEPC include the ability to uptake modified LDL and the capacity to form capillary type structures in matrigel . It has been shown that circulating monocytes have also the potential to differentiate into a variety of cell types (transdifferentiation), including EPCs . Schmeisser et al. showed that CD14+CD34− cells, isolated from PBMCs and cultured for 2–4 weeks on fibronectin-coated plates with VEGF supplemented medium, were able to express markers of ECs, such as von Willebrand factor (vWF) , vascular endothelial (VE)-cadherin, and eNOS . In addition, these CD14+ cells changed their phenotype toward endothelial morphology and were able to form capillary type structures on matrigel [29, 30]. The principal surface markers of hEPC are shown in Table 2.
|Hemangioblast||Early hEPC||Late hEPC||Endothelial cell|
|CD 34+||CD 34+||CD 34+||CD 34+|
|CD 133±||CD 133+||CD 31+||CD 31+|
Hematopoietic-derived hEPCs are maintained in a particular niche in the bone marrow, and they can be released into circulation by cytokines such as VEGF or stromal-derived factor 1 (SDF-1), synthesized by ischemic tissues and hormonal stimuli. Once in circulation, hEPCs are recruited to repair damaged endothelium and/or induce blood vessel formation. In target tissues, they can be differentiated into mature ECs to lead re-endothelialization processes and neovascularization .
Circulating hEPCs can be isolated and cultured from PBMCs by three different methods:
Cell-culture on fibronectin matrix in the presence of VEGF . Under these conditions, hEPCs are selected by their ability to bind fibronectin. After removing PBMCs in suspension, early hEPC can be identified after 3 days of culture, whereas late hEPCs are observed after 2 weeks of culture.
Successive cell-cultures on fibronectin matrix . This method takes into consideration a preliminary cell-culture of PBMCs in fibronectin-coated plates with medium without VEGF for 48 h. After that, cells in suspension are cultured for 5 days in a second fibronectin-coated plate to induce the adherence of hEPCs to the matrix and the generation of colony forming units of endothelial cells (CFU-ECs). Recent studies indicate that this technique selects a mixture of hematopoietic cells, including monocytes, lymphocytes, and progenitor cells .
Cell-culture on collagen matrix. For this method, PBMCs are cultured in basal medium for 24 h in collagen-coated plates to induce the adherence of hEPCs to the collagen. hEPCs are then recovered and cultured again for 14 days to obtain mature ECs with high proliferative capacity called CFU-ECs . These cells were initially considered as “real” hEPCs because they do not express myeloid or hematopoietic markers and have the ability to form capillary-type structures similar to mature ECs. CFU-ECs express high levels of CD34 and KDR and low levels of CD45 on their cell membrane. The origin of the ECFCs has not been described yet, but it has been suggested that these cells could be derived from the vascular wall .
4.2. Quantification of circulating EPCs
Since EPCs can be identified from peripheral blood samples, their detection, quantification, and characterization may be considered as potential diagnostic and prognostic biomarkers and as a novel therapeutic option for cardiovascular disorders. The main methods to quantify EPCs in human studies can be divided into two approaches: flow cytometry and CFU assays; these are also the two most widely used methods for EPCs quantification. Flow cytometry offers the advantage of a multiparameter approach that allows the identification of both endothelial and stem cell markers. However, the gating strategies used to interpret the flow cytometric events are still highly variable and dependent on the criteria of each research group; therefore, a well-defined and uniform gating strategy to identify these cells has not been fully established yet.
The quantification of EPCs by flow cytometry requires a combination of antibodies that recognize antigens of both progenitor and endothelial cells. This technique has allowed to identify that
In terms of absolute quantification, it has been shown that peripheral blood samples from healthy donors (
The different absolute numbers obtained for circulating EPC quantification could be explained by the use of different gating strategies and phenotypes to identify EPC subpopulation.
4.3. Migration, recruitment, and differentiation toward EPCs
In healthy individuals, hEPC correspond to the 0.0001–0.01% of the total cells in blood circulation . The majority of these cells are located in the bone marrow as stem cells in a quiescent state. In this tissue, hEPCs are surrounded by stromal cells in a microenvironment characterized by low oxygen tension and high levels of chemoattractant molecules [29, 38]. Different factors such as hypoxia, trauma, physical exercise, estrogen, or cytokines can access to the bone marrow from circulation and induce the release of stem cells with the potential to differentiate toward hEPCs. Once released, stem cells migrate via circulatory system to the injury zone. How these cells reach the site of injury is not totally understood; however, it has been described that cells can be guided by the concentration gradient of different chemoattractant molecules .
It has been shown that hEPC migration and mobilization is related to the secretion of angiogenic growth factors such as VEGF-A, VEGF-B, stromal cell-derived factor 1 (SDF-1), and insulin-like growth factor-I (IGF-1) that attract cells to the site of injury . SDF-1 is a potent chemoattractant molecule released by platelets during endothelial damage , and its effects are dependent on the activation of the CXCR4 receptor. VEGF exerts its effect via tyrosine kinase receptors, VEGFR1 or VEGFR2, VEGFR3, which are mainly expressed in ECs from blood and lymph vessels. VEGF is produced by different cell types, such as ECs and smooth muscle cells, and is a potent angiogenic agent that regulates key steps in the process of angiogenesis, including proliferation and migration of ECs  and hEPC . Cytokines, such as tumor necrosis factor alpha (TNF-α), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-6, and IL-3, trigger the mobilization and recruitment of hEPC.
As mentioned, hEPCs migrate and home to specific sites following ischemic via growth factor and cytokine gradients. Some growth factors are unstable under acidic conditions of tissue ischemia; therefore, synthetic analogues stable at low pH may provide a more effective therapeutic approach for inducing hEPC mobilization and cerebral neovascularization after an ischemic stroke [46, 47].
Also, the release of hEPC from the stem cell niche in the bone marrow has been associated with the activation of proteinases such as elastase, cathepsin G, and matrix metalloproteinases (MMP) . It has been shown that stromal cells can maintain precursor stem cells or hEPCs in the bone marrow via the interaction of c-Kit ligand (cKitL), expressed on stromal cells and their receptors expressed on precursor hEPCs. The mechanism of this interaction is under investigation; however, it is known that stromal cells induce the synthesis of nitric oxide (NO) and MMP-9 in response to VEGF, SDF-1, and GM-CSF. The production of these two proteins has been associated with the cleavage of cKitL in stromal cells, allowing the release of hEPCs toward circulation [49–51].
4.4. EPCs and angiogenesis
Angiogenesis and re-endothelialization are required for the maintenance of vascular homeostasis. Initially, it was thought that these processes occurred exclusively by the migration and proliferation of mature ECs surrounding the endothelial injury. Nowadays, new vascular repair mechanisms involving precursor cells from bone marrow, such as hEPCs have been proposed [52–54].
All these studies have shown that hEPC are crucial for vascular repair, and it has been observed that the number and migratory activity of these cells in blood are inversely correlated with the presence of risk factors for coronary artery disease . Therefore, an adequate number and a correct functional state of hEPCs are required for the maintenance of the endothelium and vascular remodeling.
4.5. Mobilization mechanisms of EPCs in ischemia
One of the main transcription factors induced during acute and chronic ischemia in response to hypoxia is the hypoxia inducible factor 1 (HIF-1). In general, the activation of the HIF-1 pathway has been associated with protective responses during ischemia. The mechanism of activation of HIF-1 has been extensively described by Agani and Jiang . HIF-1 is a transcription complex formed by two subunits, alpha (Hif-1α) and beta (Hif-1β). While Hif-1β is constitutively expressed, Hif-1α levels are highly regulated by cellular oxygen partial pressure, thus Hif-1α-mediated cellular responses depend on oxygen levels . After Hif-1α induction, in response to low oxygen partial pressure, the ECs undergo prosurvival signals, which include the increased expression of VEGF and angiogenesis. HIF-1α is the main direct regulator of EC function and its upregulation in EPCs promoted differentiation, proliferation, and migration in a model of hindlimb ischemia .
HIF-1α-transfected EPCs exhibited higher revascularization potential, as increased capillary density was observed at the site of injury. This study suggests that siRNA-mediated downregulation of the HIF-1 α gene can effectively sensitize EPCs to hypoxic conditions. It can also significantly blunt early EPC growth and differentiation into ECs . The underlying mechanisms of the effect of HIF-1α in EPC have been well described [69–72].
It has been shown that hypoxia-induced HIF-1 is reduced in patients with chronic heart failure (CHF) ; however, it has been also observed that exercise transiently increases circulating hEPCs in CHF patients. This transient effect can be sustained for approximately 4 weeks when exercise is combined with statins and/or VEGF treatment [43, 63, 74, 75].
This evidence suggests that EPCs mobilization and recruitment could also be mediated by hypoxic conditions via HIF-1-induced expression of VEGF.
4.6. Cardiovascular risk factors and hEPC function
hEPCs number and functional status are important for their repair capacity; however, these parameters are greatly influenced by clinical condition and risk factors. Indeed, several studies have shown that patients with cardiovascular risk factors such as age, gender, smoking habits, hypertension, diabetes mellitus (DM), and dyslipidemia have reduced number and function of hEPCs in peripheral blood. In contrast, some cytokines, hormones, drugs, and physical activity can increase not only the circulating number of hEPC but also their function [30, 49, 74, 76] (Figure 4).
Vasa et al. showed that the number of hEPC inversely correlates with cardiovascular risk factors (age and LDL cholesterol levels). According to these results, patients with higher cardiovascular risk factors have lower number of circulating hEPC compared with the control group . Studies by Hill et al. showed a positive correlation between hEPC colony numbers in culture and endothelium-dependent vasodilatation and a negative correlation between hEPC colony number and the Framingham index . Moreover, a negative correlation between the severity of atherosclerosis and hEPC levels has been described, showing decreased circulating hEPCs levels as an early risk factor of subclinical atherosclerosis . Furthermore, reduced number of circulating hEPCs has been found in patients with hypercholesterolemia, which correlates with the fact that increased plasma cholesterol levels have been linked with endothelial damage. In the same study, the number of hEPCs was negatively correlated with total cholesterol and low-density lipoprotein (LDL) cholesterol level . On the other hand, it has been also observed that the number of circulating hEPCs increases significantly after exercise  and in response to statins , antidiabetic (Pioglitazone, Sitagliptin) , and antihypertensive drugs (Ramipril and Enalapril) [82, 83].
4.7. Correlation of EPC and clinical conditions
In addition, lower numbers of circulating hEPCs have been observed in individuals with stable and unstable angina , erectile dysfunction , and atherosclerosis  compared with healthy volunteers. Patients with type 1 and 2 diabetes also show lower number and functionality of hEPC than healthy individuals . For instance, poor glycemic control, determined by HbA1c levels, appears to be associated with a reduction in the number of circulating EPCs, whereas an adequate control of glycemia seems to increase their numbers . Several mechanisms seem to be involved in that, including advanced glycation end products formation , reduced activity of silent information regulator 1 (SIRT1), and increased synthesis of platelet-activating factor (PAF) .
Patients with familial hypercholesterolemia and hypertension [91, 92] also showed lower number and function of circulating hEPC. However, this last effect was reversed when angiotensin-converting-enzyme inhibitor (ACE-inhibitor) was used, a phenomenon associated with reduction in the progress of vascular damage . Imanishi et al. have reported that hEPCs senescence is accelerated in both experimental hypertensive rats and in patients with essential hypertension, which may be related to telomerase inactivation [94, 95]. They also found that the hypertension-induced EPC senescence decreases vascular remodeling process .
Other conditions affecting the functionality of hEPC are ischemic heart disease and nonalcoholic fatty liver disease (NAFLD) . Also, in patients with stable coronary artery disease (CAD [66, 97]), heart failure deterioration has been correlated with low number of circulating hEPC.
Furthermore, EPCs play an important role in the development and regulation of vascularization in pregnancy. Luppi et al. reported a progressive increase of circulating CD133+/VEGFR-2+ cells from the first trimester onwards, with a significant rise of CD34+/VEGFR+ cells near-term . In preeclampsia for example, a pregnancy condition associated with hypertension, Matsubara et al. reported no difference in the number of circulating EPCs . In contrast, studies from Sugawara et al. and Lin et al. showed lower cell numbers of circulating hEPCs in this condition compared with normal pregnancies [100, 101].
|Conditions||Number hEPC||Function hEPC||Reference|
||Increased CD34+/CD133+/KDR+||Decreased migration||[129, 130]|
|Atherosclerosis/heart attacks||Increased colony forming units||Increased migration in patients|||
|Gestational diabetes 3rd trimester||Decrease in CD34+/CD133+||ND|||
|Diabetes mellitus type II||Increased in CD34+||Decreased vasculogenesis and adhesion capacity||[133, 134]|
|Erectile dysfunction||Decreased number of CD34+/KDR+||ND|||
|Exercising||Increased in CD34+ cells in vitro||Increased migration, proliferation|||
|Angiogenic capacity||[137, 138]|
|Erythropoietin||Increased CD34+||Increased migration||[139, 140]|
|Statins||Increase proliferation||Increased migration||[66, 74]|
|Estradiol||Increased CD34+||Increased mobilization|||
|Hyperhomocysteinemia||Increased CD34+ in vitro||Decreased proliferation,
migration, adhesion and vasculogenic capacity
|[76, 92, 142]|
|Acute myocardial infarct||Increased colony forming units||Increased migration and proliferation||[43, 75]|
|Low-density lipoprotein||CD34+/KDR+||Decreased migration||[31, 66]|
|Prostaglandin E||Increased CD34+||Increased migration and improves the function|||
|C-reactive protein||Decreased CD34+ in vitro||Decreased angiogenic capacity|||
Patients with obesity were reported to have reduced numbers of circulating hEPCs, and this was inversely associated with an increased intima-media thickness . Obesity was a more prominent predictor of the number of hEPC than any other cardiovascular risk factors, and weight loss was associated with an increased hEPC count and an improved brachial artery flow-mediated dilation. Similar evidence suggests that overweight is associated with reduced capacity to produce colony-forming units .
Altogether these studies support the idea that hEPCs play an important role in the maintenance of vasculature homeostasis. Thus, new therapeutic strategies should aim to increase their number and functionality in circulation. A summary of the main physiological and pathological conditions associated with functionality of hEPC is shown in Table 3.
4.8. Clinical translation of EPC therapy
Stem cell therapy holds great promise to restore damaged vessels. Researchers have made significant progress in cell transplantation in preclinical and clinical settings. For example, initial preclinical studies have reported favorable improvements in left ventricular function in a rat model of acute myocardial infarction (AMI) after intravenous injection of
In the human studies performed by Li et al.  and Lasala et al.  it has been shown that intracoronary infusion of hEPC in patients with AMI were associated with the migration and incorporation of hEPCs in the infarcted tissue, a reduction of infarct size, and secretion of angiogenic growth factors including VEGF, SDF-1, and IGF-1, which produced more capillarity and higher transdifferentiation of cells to cardiac progenitor cardiomyocytes [107, 108]. Moreover, these hEPCs also reduced apoptosis of endothelial cells and increased myocardial viability in the infarcted area [109, 110]. Studies from Dobert et al. described increased myocardial viability in patients receiving intracoronary infusion of peripheral blood bone marrow-derived hEPCs 4 days after myocardial infarction . In addition, other studies [112, 113] suggest that adhesion and differentiation of hEPC into mature ECs in infarcted tissue is partially modulated by fibrin, which in turn promotes angiogenesis. Similar studies have been conducted in patients with chronic critical limb ischemia of the lower extremities. In a Phase II clinical study, patients who received CD133+ cells, obtained from peripheral blood and mobilized with G-CSF, experienced limb salvage, symptomatic relief, appearance of blood flow, and significant functional improvement at the site of injury [114–116]. Similarly, treatment with autologous G-CSF-mobilized peripheral blood CD34+ cells in nonhealing diabetic foot patients have been promising .
Bone marrow-derived EPCs may be mobilized to stimulate angiogenesis and may attenuate tissue ischemia CAD and peripheral arterial disease (PAD). For instance, intramyocardial transplantation of autologous CD34+ cells improved survival in patients with cardiovascular diseases . In another study, patients with refractory angina who received autologous CD34+ cells showed a reduction of angina frequency and improvement of exercise tolerance .
In addition, hEPCs may contribute to liver repair and regeneration by promoting the secretion of supportive factors to induce host’s endogenous repair mechanisms . EPC treatment has been shown to halt the progression of liver fibrosis in rats by suppressing hepatic cell activation by increasing the MMP activity and regulating hepatocyte .
Similar evidence has suggested that hEPCs are involved in the recovery after deep vein thrombosis (DVT). DVT is characterized by a fibrotic vein injury with loss of venous compliance and subsequent venous hypertension . In this disease, hEPCs were involved in blood vessel recanalization in organized venous thrombi . Human studies suggest that children with idiopathic pulmonary arterial hypertension (IPAH) had no severe adverse events after hEPCs infusion and improved pulmonary functions [124, 125]. In animal models, Baker et al. (2013) described the use of autologous bone marrow-derived EPCs in a rat model of pulmonary arterial hypertension (PAH) . They found that EPCs reduced the hemodynamics and ventricular weight, at the same time that they increased connexin, eNOS expression and activity, Bcl-2 expression, and the number of alveolar sacs and small lung arterioles.
5. Concluding remarks
Vascular regeneration is a dynamic area of research showing remarkable medical advances, both in basic science and in the clinical application field. The preclinical and clinical studies reviewed here strongly support a therapeutic potential use of EPCs in the treatment of cardiovascular diseases; however, the very low number of these cells limits their use for cell-based therapies. The number of EPCs needed for therapy in human adults is relatively large, that is, about 3 × 108 to 6 × 108 cells, which means that 8.5–120 L of peripheral blood are required to isolate an adequate number of EPCs. Therefore, protocols aimed to expand EPCs will be needed for future therapies. However, EPCs can be used in the present as a biomarker to identify the state of diverse diseases.
The mechanisms by which EPCs mediate vessel growth and repair could potentially be ascribed to a variety of angiogenic factors produced by EPCs. However, optimal quality/quantity of EPCs is essential to set up a successful therapeutic EPC-based approach. In order to get this, it is important to improve the isolation, characterization, and expansion methods to obtain the optimal numbers and functionality of EPCs. In addition, it is also relevant to improve the administration of these cells and the cellular application techniques such as quantification of EPC. Finally, a positive clinical outcome will be the main indicative to demonstrate whether these are able to repair the disease-based dysfunction by the different mechanism already mentioned in this chapter.
Pomerantz J, Blau HM. Nuclear reprogramming: a key to stem cell function in regenerative medicine. Nature Cell Biology. 2004;6(9):810–6.
McCulloch EA, Till JE. Perspectives on the properties of stem cells. Nature Medicine. 2005;11(10):1026–8.
Chia LA, Kuo CJ. The intestinal stem cell. Progress in Molecular Biology and Translational Science. 2010;96:157–73.
Gage FH. Mammalian neural stem cells. Science. 2000;287(5457):1433–8.
Kondo M, Wagers AJ, Manz MG, Prohaska SS, Scherer DC, Beilhack GF, et al. Biology of hematopoietic stem cells and progenitors: implications for clinical application. Annual Review of Immunology. 2003;21:759–806.
Oguro H, Ding L, Morrison SJ. SLAM family markers resolve functionally distinct subpopulations of hematopoietic stem cells and multipotent progenitors. Cell Stem Cell. 2013;13(1):102–16.
Riether C, Schurch CM, Ochsenbein AF. Regulation of hematopoietic and leukemic stem cells by the immune system. Cell Death and Differentiation. 2015;22(2):187–98.
Friedenstein AJ, Chailakhyan RK, Latsinik NV, Panasyuk AF, Keiliss-Borok IV. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation. 1974;17(4):331–40.
Halfon S, Abramov N, Grinblat B, Ginis I. Markers distinguishing mesenchymal stem cells from fibroblasts are downregulated with passaging. Stem Cells and Development. 2011;20(1):53–66.
Mitrano TI, Grob MS, Carrion F, Nova-Lamperti E, Luz PA, Fierro FS, et al. Culture and characterization of mesenchymal stem cells from human gingival tissue. Journal of Periodontology. 2010;81(6):917–25.
Salvolini E, Lucarini G, Zizzi A, Orciani M, Di Benedetto G, Di Primio R. Human skin-derived mesenchymal stem cells as a source of VEGF and nitric oxide. Archives of Dermatological Research. 2010;302(5):367–74.
Battula VL, Bareiss PM, Treml S, Conrad S, Albert I, Hojak S, et al. Human placenta and bone marrow derived MSC cultured in serum-free, b-FGF-containing medium express cell surface frizzled-9 and SSEA-4 and give rise to multilineage differentiation. Differentiation; Research in Biological Diversity. 2007;75(4):279–91.
Aguilera V, Briceno L, Contreras H, Lamperti L, Sepulveda E, Diaz-Perez F, et al. Endothelium trans differentiated from Wharton’s jelly mesenchymal cells promote tissue regeneration: potential role of soluble pro-angiogenic factors. PLoS One. 2014;9(11):e111025.
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143–7.
Schmidt A, Brixius K, Bloch W. Endothelial precursor cell migration during vasculogenesis. Circulation Research. 2007;101(2):125–36.
Mayr M, Niederseer D, Niebauer J. From bench to bedside: what physicians need to know about endothelial progenitor cells. The American Journal of Medicine. 2011;124(6):489–97.
Levesque JP, Winkler IG, Larsen SR, Rasko JE. Mobilization of bone marrow-derived progenitors. Handbook of Experimental Pharmacology. 2007(180):3–36.
Sipos PI, Crocker IP, Hubel CA, Baker PN. Endothelial progenitor cells: their potential in the placental vasculature and related complications. Placenta. 2010;31(1):1–10.
Timmermans F, Van Hauwermeiren F, De Smedt M, Raedt R, Plasschaert F, De Buyzere ML, et al. Endothelial outgrowth cells are not derived from CD133+ cells or CD45+ hematopoietic precursors. Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27(7):1572–9.
Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275(5302):964–7.
Romagnani P, Annunziato F, Liotta F, Lazzeri E, Mazzinghi B, Frosali F, et al. CD14 + CD34 low cells with stem cell phenotypic and functional features are the major source of circulating endothelial progenitors. Circulation Research. 2005;97(4):314–22.
Diaz-Perez F, Radojkovic C, Aguilera V, Veas C, Gonzalez M, Lamperti L, et al. L-arginine transport and nitric oxide synthesis in human endothelial progenitor cells. Journal of Cardiovascular Pharmacology. 2012;60(5):439–49.
Alexandru N, Popov D, Dragan E, Andrei E, Georgescu A. Circulating endothelial progenitor cell and platelet microparticle impact on platelet activation in hypertension associated with hypercholesterolemia. PLoS One. 2013;8(1):e52058.
Kim J, Jeon YJ, Kim HE, Shin JM, Chung HM, Chae JI. Comparative proteomic analysis of endothelial cells progenitor cells derived from cord blood- and peripheral blood for cell therapy. Biomaterials. 2013;34(6):1669–85.
Sudchada S, Kheolamai P, Y UP, Chayosumrit M, Supokawej A, Manochantr S, et al. CD14-/CD34+ is the founding population of umbilical cord blood-derived endothelial progenitor cells and angiogenin1 is an important factor promoting the colony formation. Annals of Hematology. 2012;91(3):321–9.
Shin JW, Lee DW, Kim MJ, Song KS, Kim HS, Kim HO. Isolation of endothelial progenitor cells from cord blood and induction of differentiation by ex vivo expansion. Yonsei Medical Journal. 2005;46(2):260–7.
O’Neill TJt, Wamhoff BR, Owens GK, Skalak TC. Mobilization of bone marrow-derived cells enhances the angiogenic response to hypoxia without transdifferentiation into endothelial cells. Circulation Research. 2005;97(10):1027–35.
Schmeisser A, Garlichs CD, Zhang H, Eskafi S, Graffy C, Ludwig J, et al. Monocytes coexpress endothelial and macrophagocytic lineage markers and form cord-like structures in Matrigel under angiogenic conditions. Cardiovascular Research. 2001;49(3):671–80.
Du F, Zhou J, Gong R, Huang X, Pansuria M, Virtue A, et al. Endothelial progenitor cells in atherosclerosis. Frontiers in Bioscience. 2012;17:2327–49.
Fadini GP, Losordo D, Dimmeler S. Critical reevaluation of endothelial progenitor cell phenotypes for therapeutic and diagnostic use. Circulation Research. 2012;110(4):624–37.
Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. The New England Journal of Medicine. 2003;348(7):593–600.
Van Craenenbroeck EM, Van Craenenbroeck AH, van Ierssel S, Bruyndonckx L, Hoymans VY, Vrints CJ, et al. Quantification of circulating CD34+/KDR+/CD45dim endothelial progenitor cells: analytical considerations. International Journal of Cardiology. 2013;167(5):1688–95.
Van Craenenbroeck EM, Conraads VM, Van Bockstaele DR, Haine SE, Vermeulen K, Van Tendeloo VF, et al. Quantification of circulating endothelial progenitor cells: a methodological comparison of six flow cytometric approaches. Journal of Immunological Methods. 2008;332(1–2):31–40.
Redondo S, Hristov M, Gordillo-Moscoso AA, Ruiz E, Weber C, Tejerina T. High-reproducible flow cytometric endothelial progenitor cell determination in human peripheral blood as CD34+/CD144+/CD3– lymphocyte sub-population. Journal of Immunological Methods. 2008;335(1–2):21–7.
Hristov M, Schmitz S, Nauwelaers F, Weber C. A flow cytometric protocol for enumeration of endothelial progenitor cells and monocyte subsets in human blood. Journal of Immunological Methods. 2012;381(1–2):9–13.
Duda DG, Cohen KS, Scadden DT, Jain RK. A protocol for phenotypic detection and enumeration of circulating endothelial cells and circulating progenitor cells in human blood. Nature Protocols. 2007;2(4):805–10.
Khan SS, Solomon MA, McCoy JP, Jr. Detection of circulating endothelial cells and endothelial progenitor cells by flow cytometry. Cytometry Part B, Clinical Cytometry. 2005;64(1):1–8.
Miller-Kasprzak E, Jagodzinski PP. Endothelial progenitor cells as a new agent contributing to vascular repair. Archivum Immunologiae et Therapiae Experimentalis. 2007;55(4):247–59.
Dong C, Goldschmidt-Clermont PJ. Endothelial progenitor cells: a promising therapeutic alternative for cardiovascular disease. Journal of Interventional Cardiology. 2007;20(2):93–9.
Urbich C, Aicher A, Heeschen C, Dernbach E, Hofmann WK, Zeiher AM, et al. Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells. Journal of Molecular and Cellular Cardiology. 2005;39(5):733–42.
De Falco E, Avitabile D, Totta P, Straino S, Spallotta F, Cencioni C, et al. Altered SDF-1-mediated differentiation of bone marrow-derived endothelial progenitor cells in diabetes mellitus. Journal of Cellular and Molecular Medicine. 2009;13(9B):3405–14.
Li B, Sharpe EE, Maupin AB, Teleron AA, Pyle AL, Carmeliet P, et al. VEGF and PlGF promote adult vasculogenesis by enhancing EPC recruitment and vessel formation at the site of tumor neovascularization. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology. 2006;20(9):1495–7.
Shintani S, Murohara T, Ikeda H, Ueno T, Honma T, Katoh A, et al. Mobilization of endothelial progenitor cells in patients with acute myocardial infarction. Circulation. 2001;103(23):2776–9.
Jin DK, Shido K, Kopp HG, Petit I, Shmelkov SV, Young LM, et al. Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes. Nature Medicine. 2006;12(5):557–67.
Langer H, May AE, Daub K, Heinzmann U, Lang P, Schumm M, et al. Adherent platelets recruit and induce differentiation of murine embryonic endothelial progenitor cells to mature endothelial cells in vitro. Circulation Research. 2006;98(2):e2–10.
Rouhl RP, van Oostenbrugge RJ, Damoiseaux J, Tervaert JW, Lodder J. Endothelial progenitor cell research in stroke: a potential shift in pathophysiological and therapeutical concepts. Stroke; A Journal of Cerebral Circulation. 2008;39(7):2158–65.
Chen J, Chen S, Chen Y, Zhang C, Wang J, Zhang W, et al. Circulating endothelial progenitor cells and cellular membrane microparticles in db/db diabetic mouse: possible implications in cerebral ischemic damage. American Journal of Physiology Endocrinology and Metabolism. 2011;301(1):E62–71.
Zhang S, Zhao L, Shen L, Xu D, Huang B, Wang Q, et al. Comparison of various niches for endothelial progenitor cell therapy on ischemic myocardial repair: coexistence of host collateralization and Akt-mediated angiogenesis produces a superior microenvironment. Arteriosclerosis, Thrombosis, and Vascular Biology. 2012;32(4):910–23.
Capobianco S, Chennamaneni V, Mittal M, Zhang N, Zhang C. Endothelial progenitor cells as factors in neovascularization and endothelial repair. World Journal of Cardiology. 2010;2(12):411–20.
Matsumoto T, Mifune Y, Kawamoto A, Kuroda R, Shoji T, Iwasaki H, et al. Fracture induced mobilization and incorporation of bone marrow-derived endothelial progenitor cells for bone healing. Journal of Cellular Physiology. 2008;215(1):234–42.
Yang Z, von Ballmoos MW, Faessler D, Voelzmann J, Ortmann J, Diehm N, et al. Paracrine factors secreted by endothelial progenitor cells prevent oxidative stress-induced apoptosis of mature endothelial cells. Atherosclerosis. 2010;211(1):103–9.
Jang IH, Heo SC, Kwon YW, Choi EJ, Kim JH. Role of formyl peptide receptor 2 in homing of endothelial progenitor cells and therapeutic angiogenesis. Advances in Biological Regulation. 2015;57:162–72.
Pearson JD. Endothelial progenitor cells—an evolving story. Microvascular Research. 2010;79(3):162–8.
Yoder MC. Endothelial progenitor cell: a blood cell by many other names may serve similar functions. Journal of Molecular Medicine. 2013;91(3):285–95.
Finkenzeller G, Graner S, Kirkpatrick CJ, Fuchs S, Stark GB. Impaired in vivo vasculogenic potential of endothelial progenitor cells in comparison to human umbilical vein endothelial cells in a spheroid-based implantation model. Cell Proliferation. 2009;42(4):498–505.
Hur J, Yoon CH, Kim HS, Choi JH, Kang HJ, Hwang KK, et al. Characterization of two types of endothelial progenitor cells and their different contributions to neovasculogenesis. Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24(2):288–93.
Shumiya T, Shibata R, Shimizu Y, Ishii M, Kubota R, Shintani S, et al. Evidence for the therapeutic potential of ex vivo expanded human endothelial progenitor cells using autologous serum. Circulation Journal: Official Journal of the Japanese Circulation Society. 2010;74(5):1006–13.
Krankel N, Luscher TF, Landmesser U. “Endothelial progenitor cells” as a therapeutic strategy in cardiovascular disease. Current Vascular Pharmacology. 2012;10(1):107–24.
Cui B, Huang L, Fang Y, Guo R, Yin Y, Zhao X. Transplantation of endothelial progenitor cells overexpressing endothelial nitric oxide synthase enhances inhibition of neointimal hyperplasia and restores endothelium-dependent vasodilatation. Microvascular Research. 2011;81(1):143–50.
Edelberg JM, Tang L, Hattori K, Lyden D, Rafii S. Young adult bone marrow-derived endothelial precursor cells restore aging-impaired cardiac angiogenic function. Circulation Research. 2002;90(10):E89–93.
Feng Y, Gordts SC, Chen F, Hu Y, Van Craeyveld E, Jacobs F, et al. Topical HDL administration reduces vein graft atherosclerosis in apo E deficient mice. Atherosclerosis. 2011;214(2):271–8.
Feng Y, van Eck M, Van Craeyveld E, Jacobs F, Carlier V, Van Linthout S, et al. Critical role of scavenger receptor-BI-expressing bone marrow-derived endothelial progenitor cells in the attenuation of allograft vasculopathy after human apo A-I transfer. Blood. 2009;113(3):755–64.
Kalka C, Masuda H, Takahashi T, Gordon R, Tepper O, Gravereaux E, et al. Vascular endothelial growth factor(165) gene transfer augments circulating endothelial progenitor cells in human subjects. Circulation Research. 2000;86(12):1198–202.
Friedrich EB, Walenta K, Scharlau J, Nickenig G, Werner N. CD34-/CD133+/VEGFR-2+ endothelial progenitor cell subpopulation with potent vasoregenerative capacities. Circulation Research. 2006;98(3):e20–5.
Kawamoto A, Gwon HC, Iwaguro H, Yamaguchi JI, Uchida S, Masuda H, et al. Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia. Circulation. 2001;103(5):634–7.
Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H, et al. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circulation Research. 2001;89(1):E1–7.
Agani F, Jiang BH. Oxygen-independent regulation of HIF-1: novel involvement of PI3K/AKT/mTOR pathway in cancer. Current Cancer Drug Targets. 2013;13(3):245–51.
Brocato J, Chervona Y, Costa M. Molecular responses to hypoxia-inducible factor 1alpha and beyond. Molecular Pharmacology. 2014;85(5):651–7.
Zan T, Li H, Du Z, Gu B, Liu K, Li Q. Enhanced endothelial progenitor cell mobilization and function through direct manipulation of hypoxia inducible factor-1alpha. Cell Biochemistry and Function. 2015;33(3):143–9.
Jiang M, Wang B, Wang C, He B, Fan H, Guo TB, et al. Inhibition of hypoxia-inducible factor-1alpha and endothelial progenitor cell differentiation by adenoviral transfer of small interfering RNA in vitro. Journal of Vascular Research. 2006;43(6):511–21.
Hoenig MR, Bianchi C, Sellke FW. Hypoxia inducible factor-1 alpha, endothelial progenitor cells, monocytes, cardiovascular risk, wound healing, cobalt and hydralazine: a unifying hypothesis. Current Drug Targets. 2008;9(5):422–35.
Kutscher C, Lampert FM, Kunze M, Markfeld-Erol F, Stark GB, Finkenzeller G. Overexpression of hypoxia-inducible factor-1 alpha improves vasculogenesis-related functions of endothelial progenitor cells. Microvascular Research. 2016;105:85–92.
Van Craenenbroeck EM, Bruyndonckx L, Van Berckelaer C, Hoymans VY, Vrints CJ, Conraads VM. The effect of acute exercise on endothelial progenitor cells is attenuated in chronic heart failure. European Journal of Applied Physiology. 2011;111(9):2375–9.
Dimmeler S, Aicher A, Vasa M, Mildner-Rihm C, Adler K, Tiemann M, et al. HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. The Journal of Clinical Investigation. 2001;108(3):391–7.
Ghani U, Shuaib A, Salam A, Nasir A, Shuaib U, Jeerakathil T, et al. Endothelial progenitor cells during cerebrovascular disease. Stroke; A Journal of Cerebral Circulation. 2005;36(1):151–3.
Chen JZ, Zhang FR, Tao QM, Wang XX, Zhu JH, Zhu JH. Number and activity of endothelial progenitor cells from peripheral blood in patients with hypercholesterolaemia. Clinical Science. 2004;107(3):273–80.
Castejon R, Jimenez-Ortiz C, Valero-Gonzalez S, Rosado S, Mellor S, Yebra-Bango M. Decreased circulating endothelial progenitor cells as an early risk factor of subclinical atherosclerosis in systemic lupus erythematosus. Rheumatology. 2014;53(4):631–8.
Veas C, Jara C, Willis ND, Perez-Contreras K, Gutierrez N, Toledo J, et al. Overexpression of LOXIN protects endothelial progenitor cells from apoptosis induced by oxidized low density lipoprotein. Journal of Cardiovascular Pharmacology. 2016;67(4):326–35.
Adams V, Lenk K, Linke A, Lenz D, Erbs S, Sandri M, et al. Increase of circulating endothelial progenitor cells in patients with coronary artery disease after exercise-induced ischemia. Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24(4):684–90.
Hibbert B, Simard T, Ramirez FD, Pourdjabbar A, Raizman JE, Maze R, et al. The effect of statins on circulating endothelial progenitor cells in humans: a systematic review. Journal of Cardiovascular Pharmacology. 2013;62(5):491–6.
Sakatani Y, Miyoshi T, Oe H, Noda Y, Ohno Y, Nakamura K, et al. Pioglitazone prevents the endothelial dysfunction induced by ischemia and reperfusion in healthy subjects. Journal of Cardiovascular Pharmacology. 2014;64(4):326–31.
Raptis AE, Markakis KP, Mazioti MC, Ikonomidis I, Maratou EP, Vlahakos DV, et al. Effect of aliskiren on circulating endothelial progenitor cells and vascular function in patients with type 2 diabetes and essential hypertension. American Journal of Hypertension. 2015;28(1):22–9.
Suzuki R, Fukuda N, Katakawa M, Tsunemi A, Tahira Y, Matsumoto T, et al. Effects of an angiotensin II receptor blocker on the impaired function of endothelial progenitor cells in patients with essential hypertension. American Journal of Hypertension. 2014;27(5):695–701.
George J, Goldstein E, Abashidze S, Deutsch V, Shmilovich H, Finkelstein A, et al. Circulating endothelial progenitor cells in patients with unstable angina: association with systemic inflammation. European Heart Journal. 2004;25(12):1003–8.
Foresta C, Caretta N, Lana A, Cabrelle A, Palu G, Ferlin A. Circulating endothelial progenitor cells in subjects with erectile dysfunction. International Journal of Impotence Research. 2005;17(3):288–90.
Taguchi A, Matsuyama T, Moriwaki H, Hayashi T, Hayashida K, Nagatsuka K, et al. Circulating CD34-positive cells provide an index of cerebrovascular function. Circulation. 2004;109(24):2972–5.
Jiraritthamrong C, Kheolamai P, Y UP, Chayosumrit M, Supokawej A, Manochantr S, et al. In vitro vessel-forming capacity of endothelial progenitor cells in high glucose conditions. Annals of Hematology. 2012;91(3):311–20.
Oikonomou D, Kopf S, von Bauer R, Djuric Z, Cebola R, Sander A, et al. Influence of insulin and glargine on outgrowth and number of circulating endothelial progenitor cells in type 2 diabetes patients: a partially double-blind, randomized, three-arm unicenter study. Cardiovascular Diabetology. 2014;13:137.
Li H, Zhang X, Guan X, Cui X, Wang Y, Chu H, et al. Advanced glycation end products impair the migration, adhesion and secretion potentials of late endothelial progenitor cells. Cardiovascular Diabetology. 2012;11:46.
Balestrieri ML, Servillo L, Esposito A, D’Onofrio N, Giovane A, Casale R, et al. Poor glycemic control in type 2 diabetes patients reduces endothelial progenitor cell number by influencing SIRT1 signalling via platelet-activating factor receptor activation. Diabetologia. 2013;56(1):162–72.
Fabbri-Arrigoni FI, Clarke L, Wang G, Charakida M, Ellins E, Halliday N, et al. Levels of circulating endothelial cells and colony-forming units are influenced by age and dyslipidemia. Pediatric Research. 2012;72(3):299–304.
Zhu XY, Urbieta Caceres VH, Favreau FD, Krier JD, Lerman A, Lerman LO. Enhanced endothelial progenitor cell angiogenic potency, present in early experimental renovascular hypertension, deteriorates with disease duration. Journal of Hypertension. 2011;29(10):1972–9.
Cacciatore F, Bruzzese G, Vitale DF, Liguori A, de Nigris F, Fiorito C, et al. Effects of ACE inhibition on circulating endothelial progenitor cells, vascular damage, and oxidative stress in hypertensive patients. European Journal of Clinical Pharmacology. 2011;67(9):877–83.
Imanishi T, Hano T, Sawamura T, Nishio I. Oxidized low-density lipoprotein induces endothelial progenitor cell senescence, leading to cellular dysfunction. Clinical and Experimental Pharmacology & Physiology. 2004;31(7):407–13.
Imanishi T, Moriwaki C, Hano T, Nishio I. Endothelial progenitor cell senescence is accelerated in both experimental hypertensive rats and patients with essential hypertension. Journal of Hypertension. 2005;23(10):1831–7.
Bozdag-Turan I, Turan RG, Paranskaya L, Arsoy NS, Turan CH, Akin I, et al. Correlation between the functional impairment of bone marrow-derived circulating progenitor cells and the extend of coronary artery disease. Journal of Translational Medicine. 2012;10:143.
Werner N, Wassmann S, Ahlers P, Schiegl T, Kosiol S, Link A, et al. Endothelial progenitor cells correlate with endothelial function in patients with coronary artery disease. Basic Research in Cardiology. 2007;102(6):565–71.
Luppi P, Powers RW, Verma V, Edmunds L, Plymire D, Hubel CA. Maternal circulating CD34 + VEGFR-2+ and CD133 + VEGFR-2+ progenitor cells increase during normal pregnancy but are reduced in women with preeclampsia. Reproductive Sciences. 2010;17(7):643–52.
Matsubara K, Abe E, Matsubara Y, Kameda K, Ito M. Circulating endothelial progenitor cells during normal pregnancy and pre-eclampsia. American Journal of Reproductive Immunology. 2006;56(2):79–85.
Lin C, Rajakumar A, Plymire DA, Verma V, Markovic N, Hubel CA. Maternal endothelial progenitor colony-forming units with macrophage characteristics are reduced in preeclampsia. American journal of hypertension. 2009;22(9):1014–9.
Sugawara J, Mitsui-Saito M, Hayashi C, Hoshiai T, Senoo M, Chisaka H, et al. Decrease and senescence of endothelial progenitor cells in patients with preeclampsia. The Journal of Clinical Endocrinology and Metabolism. 2005;90(9):5329–32.
Muller-Ehmsen J, Braun D, Schneider T, Pfister R, Worm N, Wielckens K, et al. Decreased number of circulating progenitor cells in obesity: beneficial effects of weight reduction. European Heart Journal. 2008;29(12):1560–8.
MacEneaney OJ, Kushner EJ, Van Guilder GP, Greiner JJ, Stauffer BL, DeSouza CA. Endothelial progenitor cell number and colony-forming capacity in overweight and obese adults. International Journal of Obesity. 2009;33(2):219–25.
Ott I, Keller U, Knoedler M, Gotze KS, Doss K, Fischer P, et al. Endothelial-like cells expanded from CD34+ blood cells improve left ventricular function after experimental myocardial infarction. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology. 2005;19(8):992–4.
Mao M, Xu X, Zhang Y, Zhang B, Fu ZH. Endothelial progenitor cells: the promise of cell-based therapies for acute lung injury. Inflammation Research: Official Journal of the European Histamine Research Society. 2013;62(1):3–8.
Xu JY, Lee YK, Wang Y, Tse HF. Therapeutic application of endothelial progenitor cells for treatment of cardiovascular diseases. Current Stem Cell Research & Therapy. 2014;9(5):401–14.
Lasala GP, Silva JA, Kusnick BA, Minguell JJ. Combination stem cell therapy for the treatment of medically refractory coronary ischemia: a Phase I study. Cardiovascular Revascularization Medicine: Including Molecular Interventions. 2011;12(1):29–34.
Li CJ, Gaol RL, Yang YJ, Hu FH, Yang WX, You SJ, et al. Effect of intracoronary infusion of bone marrow mononuclear cells or peripheral endothelial progenitor cells on myocardial ischemia-reperfusion injury in mini-swine. Chinese Medical Sciences Journal 2010;25(3):176–81.
Assmus B, Schachinger V, Teupe C, Britten M, Lehmann R, Dobert N, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI). Circulation. 2002;106(24):3009–17.
Sharif F, Bartunek J, Vanderheyden M. Adult stem cells in the treatment of acute myocardial infarction. Catheterization and Cardiovascular Interventions: Official Journal of the Society for Cardiac Angiography & Interventions. 2011;77(1):72–83.
Dobert N, Britten M, Assmus B, Berner U, Menzel C, Lehmann R, et al. Transplantation of progenitor cells after reperfused acute myocardial infarction: evaluation of perfusion and myocardial viability with FDG-PET and thallium SPECT. European Journal of Nuclear Medicine and Molecular Imaging. 2004;31(8):1146–51.
Barsotti MC, Magera A, Armani C, Chiellini F, Felice F, Dinucci D, et al. Fibrin acts as biomimetic niche inducing both differentiation and stem cell marker expression of early human endothelial progenitor cells. Cell Proliferation. 2011;44(1):33–48.
Caiado F, Carvalho T, Silva F, Castro C, Clode N, Dye JF, et al. The role of fibrin E on the modulation of endothelial progenitors adhesion, differentiation and angiogenic growth factor production and the promotion of wound healing. Biomaterials. 2011;32(29):7096–105.
Canizo MC, Lozano F, Gonzalez-Porras JR, Barros M, Lopez-Holgado N, Briz E, et al. Peripheral endothelial progenitor cells (CD133 +) for therapeutic vasculogenesis in a patient with critical limb ischemia. One-year follow-up. Cytotherapy. 2007;9(1):99–102.
Karakoyun R, Koksoy C, Yilmaz TU, Altun H, Banli O, Albayrak A, et al. The angiogenic effects of ischemic conditioning in experimental critical limb ischemia. European Journal of Vascular and Endovascular Surgery: The Official Journal of the European Society for Vascular Surgery. 2014;47(2):172–9.
Lara-Hernandez R, Lozano-Vilardell P, Blanes P, Torreguitart-Mirada N, Galmes A, Besalduch J. Safety and efficacy of therapeutic angiogenesis as a novel treatment in patients with critical limb ischemia. Annals of Vascular Surgery. 2010;24(2):287–94.
Tanaka R, Masuda H, Kato S, Imagawa K, Kanabuchi K, Nakashioya C, et al. Autologous G-CSF-mobilized peripheral blood CD34+ cell therapy for diabetic patients with chronic nonhealing ulcer. Cell Transplantation. 2014;23(2):167–79.
Holmen C, Elsheikh E, Stenvinkel P, Qureshi AR, Pettersson E, Jalkanen S, et al. Circulating inflammatory endothelial cells contribute to endothelial progenitor cell dysfunction in patients with vasculitis and kidney involvement. Journal of the American Society of Nephrology: JASN. 2005;16(10):3110–20.
Premer C, Hare JM. Can endothelial progenitor cells treat patients with refractory angina? Circulation Research. 2014;115(11):904–7.
Gutierrez-Grobe Y, Gavilanes-Espinar JG, Masso-Rojas FA, Sanchez-Valle V, Paez-Arenas A, Ponciano-Rodriguez G, et al. Metabolic syndrome and nonalcoholic fatty liver disease. The role of endothelial progenitor cells. Annals of Hepatology. 2013;12(6):908–14.
Liu F, Liu ZD, Wu N, Wang JH, Zhang HH, Fei R, et al. In vitro interactions between rat bone marrow-derived endothelial progenitor cells and hepatic stellate cells: interaction between EPCs and HSCs. In Vitro Cellular & Developmental Biology Animal. 2013;49(7):537–47.
Laser A, Elfline M, Luke C, Slack D, Shah A, Sood V, et al. Deletion of cysteine-cysteine receptor 7 promotes fibrotic injury in experimental post-thrombotic vein wall remodeling. Arteriosclerosis, Thrombosis, and Vascular Biology. 2014;34(2):377–85.
Alessio AM, Beltrame MP, Nascimento MC, Vicente CP, de Godoy JA, Silva JC, et al. Circulating progenitor and mature endothelial cells in deep vein thrombosis. International Journal of Medical Sciences. 2013;10(12):1746–54.
Ikutomi M, Sahara M, Nakajima T, Minami Y, Morita T, Hirata Y, et al. Diverse contribution of bone marrow-derived late-outgrowth endothelial progenitor cells to vascular repair under pulmonary arterial hypertension and arterial neointimal formation. Journal of Molecular and Cellular Cardiology. 2015;86:121–35.
Xia L, Fu GS, Yang JX, Zhang FR, Wang XX. Endothelial progenitor cells may inhibit apoptosis of pulmonary microvascular endothelial cells: new insights into cell therapy for pulmonary arterial hypertension. Cytotherapy. 2009;11(4):492–502.
Baker CD, Seedorf GJ, Wisniewski BL, Black CP, Ryan SL, Balasubramaniam V, et al. Endothelial colony-forming cell conditioned media promote angiogenesis in vitro and prevent pulmonary hypertension in experimental bronchopulmonary dysplasia. American Journal of Physiology, Lung Cellular and Molecular Physiology. 2013;305(1):L73–81.
Smart N, Riley PR. The stem cell movement. Circulation Research. 2008;102(10):1155–68.
Adams V, Challen GA, Zuba-Surma E, Ulrich H, Vereb G, Tarnok A. Where new approaches can stem from: focus on stem cell identification. Cytometry Part A: The Journal of the International Society for Analytical Cytology. 2009;75(1):1–3.
Egan CG, Caporali F, Garcia-Gonzalez E, Galeazzi M, Sorrentino V. Endothelial progenitor cells and colony-forming units in rheumatoid arthritis: association with clinical characteristics. Rheumatology. 2008;47(10):1484–8.
Szekanecz Z, Koch AE. Vasculogenesis in rheumatoid arthritis. Arthritis Research & Therapy. 2010;12(2):110.
Jung C, Fischer N, Fritzenwanger M, Thude H, Ferrari M, Fabris M, et al. Endothelial progenitor cells in adolescents: impact of overweight, age, smoking, sport and cytokines in younger age. Clinical Research in Cardiology: Official Journal of the German Cardiac Society. 2009;98(3):179–88.
Acosta JC, Haas DM, Saha CK, Dimeglio LA. Ingram DA, Haneline LS. Gestational diabetes mellitus alters maternal and neonatal circulating endothelial progenitor cell subsets. American Journal of Obstetrics and Gynecology. 2011;204(3):254 e8–e15.
Mieno S, Boodhwani M, Robich MP, Clements RT, Sodha NR, Sellke FW. Effects of diabetes mellitus on VEGF-induced proliferation response in bone marrow derived endothelial progenitor cells. Journal of Cardiac Surgery. 2010;25(5):618–25.
Pistrosch F, Herbrig K, Oelschlaegel U, Richter S, Passauer J, Fischer S, et al. PPARgamma-agonist rosiglitazone increases number and migratory activity of cultured endothelial progenitor cells. Atherosclerosis. 2005;183(1):163–7.
Esposito K, Ciotola M, Maiorino MI, Giugliano F, Autorino R, De Sio M, et al. Circulating CD34+ KDR+ endothelial progenitor cells correlate with erectile function and endothelial function in overweight men. The Journal of Sexual Medicine. 2009;6(1):107–14.
Han JK, Lee HS, Yang HM, Hur J, Jun SI, Kim JY, et al. Peroxisome proliferator-activated receptor-delta agonist enhances vasculogenesis by regulating endothelial progenitor cells through genomic and nongenomic activations of the phosphatidylinositol 3-kinase/Akt pathway. Circulation. 2008;118(10):1021–33.
Laufs U, Urhausen A, Werner N, Scharhag J, Heitz A, Kissner G, et al. Running exercise of different duration and intensity: effect on endothelial progenitor cells in healthy subjects. European Journal of Cardiovascular Prevention and Rehabilitation: Official Journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology. 2005;12(4):407–14.
Laufs U, Werner N, Link A, Endres M, Wassmann S, Jurgens K, et al. Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis. Circulation. 2004;109(2):220–6.
Aydin Z, Duijs J, Bajema IM, van Zonneveld AJ, Rabelink TJ. Erythropoietin, progenitors, and repair. Kidney International Supplement. 2007(107):S16–20.
Urao N, Okigaki M, Yamada H, Aadachi Y, Matsuno K, Matsui A, et al. Erythropoietin-mobilized endothelial progenitors enhance reendothelialization via Akt-endothelial nitric oxide synthase activation and prevent neointimal hyperplasia. Circulation Research. 2006;98(11):1405–13.
Iwakura A, Luedemann C, Shastry S, Hanley A, Kearney M, Aikawa R, et al. Estrogen-mediated, endothelial nitric oxide synthase-dependent mobilization of bone marrow-derived endothelial progenitor cells contributes to reendothelialization after arterial injury. Circulation. 2003;108(25):3115–21.
Alam MM, Mohammad AA, Shuaib U, Wang C, Ghani U, Schwindt B, et al. Homocysteine reduces endothelial progenitor cells in stroke patients through apoptosis. Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism. 2009;29(1):157–65.
Chen DD, Dong YG, Yuan H, Chen AF. Endothelin 1 activation of endothelin A receptor/NADPH oxidase pathway and diminished antioxidants critically contribute to endothelial progenitor cell reduction and dysfunction in salt-sensitive hypertension. Hypertension. 2012;59(5):1037–43.
Herrler T, Leicht SF, Huber S, Hermann PC, Schwarz TM, Kopp R, et al. Prostaglandin E positively modulates endothelial progenitor cell homeostasis: an advanced treatment modality for autologous cell therapy. Journal of Vascular Research. 2009;46(4):333–46.
Verma S, Kuliszewski MA, Li SH, Szmitko PE, Zucco L, Wang CH, et al. C-reactive protein attenuates endothelial progenitor cell survival, differentiation, and function: further evidence of a mechanistic link between C-reactive protein and cardiovascular disease. Circulation. 2004;109(17):2058–67.