Tissue regeneration using endothelial colony-forming cells: promising cells for vascular repair

Article metrics

Abstract

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

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1
Figure 2

References

  1. 1

    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.

  2. 2

    Manley BJ, Owen LS, Hooper SB et al. Towards evidence-based resuscitation of the newborn infant. Lancet 2017;389:1639–48.

  3. 3

    Owen LS, Manley BJ, Davis PG et al. The evolution of modern respiratory care for preterm infants. Lancet 2017;389:1649–59.

  4. 4

    Neu J . Preterm infant nutrition, gut bacteria, and necrotizing enterocolitis. Curr Opin Clin Nutr Metab Care 2015;18:285–8.

  5. 5

    Hartnett ME . Role of cytokines and treatment algorithms in retinopathy of prematurity. Curr Opin Ophthalmol 2017;28:282–8.

  6. 6

    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.

  7. 7

    Medina RJ, Barber CL, Sabatier F et al. Endothelial progenitors: a consensus statement on nomenclature. Stem Cells Transl Med 2017;6:1316–20.

  8. 8

    Basile DP, Yoder MC . Circulating and tissue resident endothelial progenitor cells. J Cell Physiol 2014;229:10–6.

  9. 9

    Asahara T, Murohara T, Sullivan A et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997;275:964–7.

  10. 10

    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.

  11. 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.

  12. 12

    Asahara T, Kawamoto A, Masuda H . Concise review: circulating endothelial progenitor cells for vascular medicine. Stem Cells 2011;29:1650–5.

  13. 13

    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.

  14. 14

    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.

  15. 15

    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.

  16. 16

    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.

  17. 17

    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.

  18. 18

    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.

  19. 19

    Yoder MC . Is endothelium the origin of endothelial progenitor cells? Arterioscler Thromb Vasc Biol 2010;30:1094–103.

  20. 20

    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.

  21. 21

    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.

  22. 22

    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.

  23. 23

    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.

  24. 24

    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.

  25. 25

    Takahashi K, Yamanaka S . A decade of transcription factor-mediated reprogramming to pluripotency. Nat Rev Mol Cell Biol 2016;17:183–93.

  26. 26

    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.

  27. 27

    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.

  28. 28

    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.

  29. 29

    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.

  30. 30

    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.

  31. 31

    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.

  32. 32

    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.

  33. 33

    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.

  34. 34

    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.

  35. 35

    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.

  36. 36

    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.

  37. 37

    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.

  38. 38

    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.

  39. 39

    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.

  40. 40

    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.

  41. 41

    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.

  42. 42

    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.

  43. 43

    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.

  44. 44

    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.

  45. 45

    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.

  46. 46

    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.

  47. 47

    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.

  48. 48

    Sakimoto S, Marchetti V, Aguilar E et al. CD44 expression in endothelial colony-forming cells regulates neurovascular trophic effect. JCI Insight 2017;2:e89906.

  49. 49

    Bonventre JV, Yang L . Cellular pathophysiology of ischemic acute kidney injury. J Clin Invest 2011;121:4210–21.

  50. 50

    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.

  51. 51

    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.

  52. 52

    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.

  53. 53

    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.

  54. 54

    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.

  55. 55

    Hanahan D, Weinberg RA . Hallmarks of cancer: the next generation. Cell 2011;144:646–74.

  56. 56

    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.

  57. 57

    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.

  58. 58

    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.

  59. 59

    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.

  60. 60

    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.

  61. 61

    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.

  62. 62

    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.

  63. 63

    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.

  64. 64

    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.

  65. 65

    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.

  66. 66

    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.

  67. 67

    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.

  68. 68

    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.

  69. 69

    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.

  70. 70

    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.

  71. 71

    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.

  72. 72

    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.

  73. 73

    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.

  74. 74

    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.

  75. 75

    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.

  76. 76

    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.

  77. 77

    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.

  78. 78

    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.

  79. 79

    Nakatsuji N, Nakajima F, Tokunaga K . HLA-haplotype banking and iPS cells. Nat Biotechnol 2008;26:739–40.

  80. 80

    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.

  81. 81

    Abrahimi P, Qin L, Chang WG et al. Blocking MHC class II on human endothelium mitigates acute rejection. JCI Insight 2016;1:e85293.

  82. 82

    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.

  83. 83

    Chen YT, Bradley A . A new positive/negative selectable marker, puDeltatk, for use in embryonic stem cells. Genesis 2000;28:31–5.

Download references

Author information

Correspondence to Mervin C Yoder.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Further reading