Repairing and rebuilding damaged tissue in diseased human subjects remains a daunting challenge for clinical medicine. Proper vascular formation that serves to deliver blood-borne nutrients and adequate levels of oxygen and to remove wastes is critical for successful tissue regeneration. Endothelial colony-forming cells (ECFC) represent a promising cell source for revascularization of damaged tissue. ECFCs are identified by displaying a hierarchy of clonal proliferative potential and by pronounced postnatal vascularization ability in vivo. In this review, we provide a brief overview of human ECFC isolation and characterization, a survey of a number of animal models of human disease in which ECFCs have been shown to have prominent roles in tissue repair, and a summary of current challenges that must be overcome before moving ECFC into human subjects as a cell therapy.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $64.85 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Tagin MA, Woolcott CG, Vincer MJ et al. Hypothermia for neonatal hypoxic ischemic encephalopathy: an updated systematic review and meta-analysis. Arch Pediatr Adolesc Med 2012;166:558–66.
Manley BJ, Owen LS, Hooper SB et al. Towards evidence-based resuscitation of the newborn infant. Lancet 2017;389:1639–48.
Owen LS, Manley BJ, Davis PG et al. The evolution of modern respiratory care for preterm infants. Lancet 2017;389:1649–59.
Neu J . Preterm infant nutrition, gut bacteria, and necrotizing enterocolitis. Curr Opin Clin Nutr Metab Care 2015;18:285–8.
Hartnett ME . Role of cytokines and treatment algorithms in retinopathy of prematurity. Curr Opin Ophthalmol 2017;28:282–8.
Tasev D, Koolwijk P, van Hinsbergh VW . Therapeutic potential of human-derived endothelial colony-forming cells in animal models. Tissue Eng Part B Rev 2016;22:371–82.
Medina RJ, Barber CL, Sabatier F et al. Endothelial progenitors: a consensus statement on nomenclature. Stem Cells Transl Med 2017;6:1316–20.
Basile DP, Yoder MC . Circulating and tissue resident endothelial progenitor cells. J Cell Physiol 2014;229:10–6.
Asahara T, Murohara T, Sullivan A et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997;275:964–7.
Estes ML, Mund JA, Ingram DA et al. Identification of endothelial cells and progenitor cell subsets in human peripheral blood. Curr Protoc Cytom 2010 Chapter 9;52:Unit 9 33 1-11.
Estes ML, Mund JA, Mead LE et al. Application of polychromatic flow cytometry to identify novel subsets of circulating cells with angiogenic potential. Cytometry A 2010;77:831–9.
Asahara T, Kawamoto A, Masuda H . Concise review: circulating endothelial progenitor cells for vascular medicine. Stem Cells 2011;29:1650–5.
Medina RJ, O'Neill CL, O'Doherty TM et al. Myeloid angiogenic cells act as alternative M2 macrophages and modulate angiogenesis through interleukin-8. Mol Med 2011;17:1045–55.
Purhonen S, Palm J, Rossi D et al. Bone marrow-derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth. Proc Natl Acad Sci USA 2008;105:6620–5.
Lin Y, Weisdorf DJ, Solovey A et al. Origins of circulating endothelial cells and endothelial outgrowth from blood. J Clin Invest 2000;105:71–77.
Medina RJ, O'Neill CL, Sweeney M et al. Molecular analysis of endothelial progenitor cell (EPC) subtypes reveals two distinct cell populations with different identities. BMC Med Genomics 2010;3:18.
Ingram DA, Mead LE, Moore DB et al. Vessel wall-derived endothelial cells rapidly proliferate because they contain a complete hierarchy of endothelial progenitor cells. Blood 2005;105:2783–6.
Hubert L, Darbousset R, Panicot-Dubois L et al. Neutrophils recruit and activate human endothelial colony-forming cells at the site of vessel injury via P-selectin glycoprotein ligand-1 and L-selectin. J Thromb Haemost 2014;12:1170–81.
Yoder MC . Is endothelium the origin of endothelial progenitor cells? Arterioscler Thromb Vasc Biol 2010;30:1094–103.
Ingram DA, Mead LE, Tanaka H et al. Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood. Blood 2004;104:2752–60.
Yoder MC, Mead LE, Prater D et al. Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood 2007;109:1801–9.
Melero-Martin JM, Khan ZA, Picard A et al. In vivo vasculogenic potential of human blood-derived endothelial progenitor cells. Blood 2007;109:4761–8.
Au P, Daheron LM, Duda DG et al. Differential in vivo potential of endothelial progenitor cells from human umbilical cord blood and adult peripheral blood to form functional long-lasting vessels. Blood 2008;111:1302–5.
Bompais H, Chagraoui J, Canron X et al. Human endothelial cells derived from circulating progenitors display specific functional properties compared with mature vessel wall endothelial cells. Blood 2004;103:2577–84.
Takahashi K, Yamanaka S . A decade of transcription factor-mediated reprogramming to pluripotency. Nat Rev Mol Cell Biol 2016;17:183–93.
Choi KD, Yu J, Smuga-Otto K et al. Hematopoietic and endothelial differentiation of human induced pluripotent stem cells. Stem Cells 2009;27:559–67.
James D, Nam HS, Seandel M et al. Expansion and maintenance of human embryonic stem cell-derived endothelial cells by TGFbeta inhibition is Id1 dependent. Nat Biotechnol 2010;28:161–6.
Goldman O, Feraud O, Boyer-Di Ponio J et al. A boost of BMP4 accelerates the commitment of human embryonic stem cells to the endothelial lineage. Stem Cells 2009;27:1750–9.
Sone M, Itoh H, Yamahara K et al. Pathway for differentiation of human embryonic stem cells to vascular cell components and their potential for vascular regeneration. Arterioscler Thromb Vasc Biol 2007;27:2127–34.
Prasain N, Lee MR, Vemula S et al. Differentiation of human pluripotent stem cells to cells similar to cord-blood endothelial colony-forming cells. Nat Biotechnol 2014;32:1151–7.
Kang KT, Coggins M, Xiao C et al. Human vasculogenic cells form functional blood vessels and mitigate adverse remodeling after ischemia reperfusion injury in rats. Angiogenesis 2013;16:773–84.
Schwarz TM, Leicht SF, Radic T et al. Vascular incorporation of endothelial colony-forming cells is essential for functional recovery of murine ischemic tissue following cell therapy. Arterioscler Thromb Vasc Biol 2012;32:e13–21.
Popernack ML, Gray N, Reuter-Rice K . Moderate-to-severe traumatic brain injury in children: complications and rehabilitation strategies. J Pediatr Health Care 2015;29:e1–7.
Zhang Y, Li Y, Wang S et al. Transplantation of expanded endothelial colony-forming cells improved outcomes of traumatic brain injury in a mouse model. J Surg Res 2013;185:441–9.
Huang XT, Zhang YQ, Li SJ et al. Intracerebroventricular transplantation of ex vivo expanded endothelial colony-forming cells restores blood-brain barrier integrity and promotes angiogenesis of mice with traumatic brain injury. J Neurotrauma 2013;30:2080–8.
Ding J, Zhao Z, Wang C et al. Bioluminescence imaging of transplanted human endothelial colony-forming cells in an ischemic mouse model. Brain Res 2016;1642:209–18.
Moubarik C, Guillet B, Youssef B et al. Transplanted late outgrowth endothelial progenitor cells as cell therapy product for stroke. Stem Cell Rev 2011;7:208–220.
Garrigue P, Hache G, Bennis Y et al. Erythropoietin pretreatment of transplanted endothelial colony-forming cells enhances recovery in a cerebral ischemia model by increasing their homing ability: a SPECT/CT study. J Nucl Med 2016;57:1798–804.
Baker CD, Ryan SL, Ingram DA et al. Endothelial colony-forming cells from preterm infants are increased and more susceptible to hyperoxia. Am J Respir Crit Care Med 2009;180:454–61.
Fujinaga H, Baker CD, Ryan SL et al. Hyperoxia disrupts vascular endothelial growth factor-nitric oxide signaling and decreases growth of endothelial colony-forming cells from preterm infants. Am J Physiol Lung Cell Mol Physiol 2009;297:L1160–9.
Baker CD, Balasubramaniam V, Mourani PM et al. Cord blood angiogenic progenitor cells are decreased in bronchopulmonary dysplasia. Eur Respir J 2012;40:1516–22.
Borghesi A, Massa M, Campanelli R et al. Circulating endothelial progenitor cells in preterm infants with bronchopulmonary dysplasia. Am J Respir Crit Care Med 2009;180:540–6.
Alphonse RS, Vadivel A, Fung M et al. Existence, functional impairment, and lung repair potential of endothelial colony-forming cells in oxygen-induced arrested alveolar growth. Circulation 2014;129:2144–57.
Alphonse RS, Vadivel A, Zhong S et al. The isolation and culture of endothelial colony-forming cells from human and rat lungs. Nat Protoc 2015;10:1697–708.
Baker CD, Seedorf GJ, Wisniewski BL et al. Endothelial colony-forming cell conditioned media promote angiogenesis in vitro and prevent pulmonary hypertension in experimental bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 2013;305:L73–81.
Connor KM, Krah NM, Dennison RJ et al. Quantification of oxygen-induced retinopathy in the mouse: a model of vessel loss, vessel regrowth and pathological angiogenesis. Nat Protoc 2009;4:1565–73.
Medina RJ, O'Neill CL, Humphreys MW et al. Outgrowth endothelial cells: characterization and their potential for reversing ischemic retinopathy. Invest Ophthalmol Vis Sci 2010;51:5906–13.
Sakimoto S, Marchetti V, Aguilar E et al. CD44 expression in endothelial colony-forming cells regulates neurovascular trophic effect. JCI Insight 2017;2:e89906.
Bonventre JV, Yang L . Cellular pathophysiology of ischemic acute kidney injury. J Clin Invest 2011;121:4210–21.
Brodsky SV, Yamamoto T, Tada T et al. Endothelial dysfunction in ischemic acute renal failure: rescue by transplanted endothelial cells. Am J Physiol Renal Physiol 2002;282:F1140–9.
Burger D, Vinas JL, Akbari S et al. Human endothelial colony-forming cells protect against acute kidney injury: role of exosomes. Am J Pathol 2015;185:2309–2323.
Collett JA, Mehrotra P, Crone A et al. Endothelial colony forming cells ameliorate endothelial dysfunction via secreted factors following ischemia-reperfusion injury. Am J Physiol Renal Physiol 2016;312:F897–907.
Sradnick J, Rong S, Luedemann A et al. Extrarenal progenitor cells do not contribute to renal endothelial repair. J Am Soc Nephrol 2016;27:1714–26.
Vinas JL, Burger D, Zimpelmann J et al. Transfer of microRNA-486-5p from human endothelial colony forming cell-derived exosomes reduces ischemic kidney injury. Kidney Int 2016;90:1238–50.
Hanahan D, Weinberg RA . Hallmarks of cancer: the next generation. Cell 2011;144:646–74.
Naito H, Wakabayashi T, Kidoya H et al. Endothelial side population cells contribute to tumor angiogenesis and antiangiogenic drug resistance. Cancer Res 2016;76:3200–10.
Naito H, Kidoya H, Sakimoto S et al. Identification and characterization of a resident vascular stem/progenitor cell population in preexisting blood vessels. EMBO J 2012;31:842–55.
Bieback K, Vinci M, Elvers-Hornung S et al. Recruitment of human cord blood-derived endothelial colony-forming cells to sites of tumor angiogenesis. Cytotherapy 2013;15:726–39.
Laurenzana A, Biagioni A, D'Alessio S et al. Melanoma cell therapy: endothelial progenitor cells as shuttle of the MMP12 uPAR-degrading enzyme. Oncotarget 2014;5:3711–27.
Margheri G, Zoppi A, Olmi R et al. Tumor-tropic endothelial colony forming cells (ECFCs) loaded with near-infrared sensitive Au nanoparticles: a "cellular stove" approach to the photoablation of melanoma. Oncotarget 2016;7:39846–60.
Kang KT, Lin RZ, Kuppermann D et al. Endothelial colony forming cells and mesenchymal progenitor cells form blood vessels and increase blood flow in ischemic muscle. Sci Rep 2017;7:770.
Liu Y, Teoh SH, Chong MS et al. Vasculogenic and osteogenesis-enhancing potential of human umbilical cord blood endothelial colony-forming cells. Stem Cells 2012;30:1911–24.
Lin RZ, Moreno-Luna R, Zhou B et al. Equal modulation of endothelial cell function by four distinct tissue-specific mesenchymal stem cells. Angiogenesis 2012;15:443–55.
Souidi N, Stolk M, Rudeck J et al. stromal cells act as guardians for endothelial progenitors by reducing their immunogenicity after co-transplantation. Stem Cells 2017;35:1233–45.
Shafiee A, Patel J, Wong HY et al. Priming of endothelial colony-forming cells in a mesenchymal niche improves engraftment and vasculogenic potential by initiating mesenchymal transition orchestrated by NOTCH signaling. FASEB J 2017;31:610–24.
Buno KP, Chen X, Weibel JA et al. In vitro multitissue interface model supports rapid vasculogenesis and mechanistic study of vascularization across tissue compartments. ACS Appl Mater Interfaces 2016;8:21848–60.
Melero-Martin JM, De Obaldia ME, Allen P et al. Host myeloid cells are necessary for creating bioengineered human vascular networks in vivo. Tissue Eng Part A 2010;16:2457–66.
Bennis Y, Sarlon-Bartoli G, Guillet B et al. Priming of late endothelial progenitor cells with erythropoietin before transplantation requires the CD131 receptor subunit and enhances their angiogenic potential. J Thromb Haemost 2012;10:1914–28.
Lee JH, Lee SH, Choi SH et al. The sulfated polysaccharide fucoidan rescues senescence of endothelial colony-forming cells for ischemic repair. Stem Cells 2015;33:1939–51.
Sarlon G, Zemani F, David L et al. Therapeutic effect of fucoidan-stimulated endothelial colony-forming cells in peripheral ischemia. J Thromb Haemost 2012;10:38–48.
Heo SC, Kwon YW, Jang IH et al. WKYMVm-induced activation of formyl peptide receptor 2 stimulates ischemic neovasculogenesis by promoting homing of endothelial colony-forming cells. Stem Cells 2014;32:779–90.
Stalin J, Harhouri K, Hubert L et al. Soluble CD146 boosts therapeutic effect of endothelial progenitors through proteolytic processing of short CD146 isoform. Cardiovasc Res 2016;111:240–51.
Green LA, Njoku V, Mund J et al. Endogenous transmembrane TNF-alpha protects against premature senescence in endothelial colony forming cells. Circ Res 2016;118:1512–24.
Kim H, Prasain N, Vemula S et al. Human platelet lysate improves human cord blood derived ECFC survival and vasculogenesis in three dimensional (3D) collagen matrices. Microvasc Res 2015;101:72–81.
Allen P, Kang KT, Bischoff J . Rapid onset of perfused blood vessels after implantation of ECFCs and MPCs in collagen, PuraMatrix and fibrin provisional matrices. J Tissue Eng Regen Med 2015;9:632–636.
Critser PJ, Kreger ST, Voytik-Harbin SL et al. Collagen matrix physical properties modulate endothelial colony forming cell-derived vessels in vivo. Microvasc Res 2010;80:23–30.
Blue EK, DiGiuseppe R, Derr-Yellin E et al. Gestational diabetes induces alterations in the function of neonatal endothelial colony-forming cells. Pediatr Res 2014;75:266–72.
Jarajapu YP, Hazra S, Segal M et al. Vasoreparative dysfunction of CD34+ cells in diabetic individuals involves hypoxic desensitization and impaired autocrine/paracrine mechanisms. PLoS ONE 2014;9:e93965.
Nakatsuji N, Nakajima F, Tokunaga K . HLA-haplotype banking and iPS cells. Nat Biotechnol 2008;26:739–40.
Zimmermann A, Preynat-Seauve O, Tiercy JM et al. Haplotype-based banking of human pluripotent stem cells for transplantation: potential and limitations. Stem Cells Dev 2012;21:2364–73.
Abrahimi P, Qin L, Chang WG et al. Blocking MHC class II on human endothelium mitigates acute rejection. JCI Insight 2016;1:e85293.
Nanda D, de Jong M, Vogels R et al. Imaging expression of adenoviral HSV1-tk suicide gene transfer using the nucleoside analogue FIRU. Eur J Nucl Med Mol Imaging 2002;29:939–47.
Chen YT, Bradley A . A new positive/negative selectable marker, puDeltatk, for use in embryonic stem cells. Genesis 2000;28:31–5.
The authors declare no conflict of interest.
About this article
Current Stem Cell Reports (2019)
Two types of high inductive electromagnetic stimulation and their different effects on endothelial cells
Physiological Research (2019)
Journal of Tissue Engineering and Regenerative Medicine (2019)
Cytokine-Like 1 Is a Novel Proangiogenic Factor Secreted by and Mediating Functions of Endothelial Progenitor Cells
Circulation Research (2019)
Pathologic up-regulation of TNFSF15–TNFRSF25 axis sustains endothelial dysfunction in unprovoked venous thromboembolism
Cardiovascular Research (2019)