Skip to main content
Journal of Cellular and Molecular Medicine logoLink to Journal of Cellular and Molecular Medicine
. 2007 May 1;8(4):498–508. doi: 10.1111/j.1582-4934.2004.tb00474.x

Endothelial progenitor cells: characterization, pathophysiology, and possible clinical relevance

Mihail Hristov 1,, Christian Weber 1
PMCID: PMC6740289  PMID: 15601578

Abstract

Bone marrow and peripheral blood of adults contain a special sub‐type of progenitor cells which are able to differentiate into mature endothelial cells, thus contributing to re‐endothelialization and neo‐vascularization. These angiogenic cells have properties of embryonal angioblasts and were termed endothelial progenitor cells (EPCs). In general, three surface markers (CD133, CD34 and the vascular endothelial growth factor receptor‐2) characterize the early functional angioblast, located predominantly in the bone marrow. Later, when migrating to the systemic circulation EPCs gradually lose their progenitor properties and start to express endothelial marker like VE‐cadherin, endothelial nitric oxide synthase and von Willebrand factor. The number of circulating EPCs in healthy subjects is rather low and a variety of conditions or factors may further influence this number. In the context of possible therapeutic application of EPCs recent clinical studies employing these cells for neo‐vascularization of ischemic organs have just been published. However, the specificity of the observed positive clinical effects, the mechanisms regulating the differentiation of EPCs and their homing to sites of injured tissue remain partially unknown at present.

Keywords: bone marrow, mobilization, chemokines, endothelial cells, angiogenesis, repair

References

  • 1. Davignon J., Ganz P., Role of endothelial dysfunction in atherosclerosis, Circulation, 109: 27–32, 2004. [DOI] [PubMed] [Google Scholar]
  • 2. Dignat‐George F., Sampol J., Circulating endothelial cells in vascular disorders: new insights into an old concept, Eur. J. Haematol., 65: 215–220, 2000. [DOI] [PubMed] [Google Scholar]
  • 3. Carmeliet P., Angiogenesis in health and disease, Nat. Med., 9: 653–660, 2003. [DOI] [PubMed] [Google Scholar]
  • 4. Asahara T., Murohara T., Sullivan A., Silver M., van der Zee R., Li T., Witzenbichler B., Schatteman G., Isner J.M., Isolation of putative progenitor endothelial cells for angiogenesis, Science, 275: 964–967, 1997. [DOI] [PubMed] [Google Scholar]
  • 5. Peichev M., Naiyer A.J., Pereira D., Zhu Z., Lane W.J., Williams M., Oz M.C., Hicklin D.J., Witte L., Moore M.A., Rafii S., Expression of VEGFR‐2 and AC133 by circulating human CD34+ cells identifies a population of functional endothelial precursors, Blood, 95: 952–958, 2000. [PubMed] [Google Scholar]
  • 6. Gehling U.M., Ergün S., Schumacher U., Wagener C., Pantel K., Otte M., Schuch G., Schafhausen P., Mende T., Kilic N., Kluge K., Schafer B., Hossfeld D.K., Fiedler W., in vitro differentiation of endothelial cells from AC133‐positive progenitor cells, Blood, 95: 3106–3112, 2000. [PubMed] [Google Scholar]
  • 7. Quirici N., Soligo D., Caneva L., Servida F., Bossolasco P., Deliliers G.L., Differentiation and expansion of endothelial cells from human bone marrow CD133+ cells, Br. J. Haematol., 115: 186–194, 2001. [DOI] [PubMed] [Google Scholar]
  • 8. Hristov M., Erl W., Weber P.C., Endothelial progenitor cells: mobilization, differentiation, and homing, Arterioscler. Thromb. Vasc. Biol., 23: 1185–1189, 2003. [DOI] [PubMed] [Google Scholar]
  • 9. Yin A.H., Miraglia S., Zanjani E.D., Almeida‐Porada G., Ogawa M., Leary A.G., Olweus J., Kearney J., Buck D.W., AC133, a novel marker for human hematopoietic stem and progenitor cells, Blood, 90: 5002–5012, 1997. [PubMed] [Google Scholar]
  • 10. Gulati R., Jevremovic D., Peterson T.E., Chatterjee S., Shah V., Vile R.G., Simari R.D., Diverse origin and function of cells with endothelial phenotype obtained from adult human blood, Circ. Res., 93: 1023–1025, 2003. [DOI] [PubMed] [Google Scholar]
  • 11. Lin Y., Weisdorf D.J., Solovey A., Hebbel R.P., Origins of circulating endothelial cells and endothelial outgrowth from blood, J. Clin. Invest., 105: 71–77, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Rehman J., Li J., Orschell C.M., March K.L., Peripheral blood “endothelial progenitor cells” are derived from monocyte/macrophages and secrete angiogenic growth factors, Circulation, 107: 1164–1169, 2003. [DOI] [PubMed] [Google Scholar]
  • 13. Harraz M., Jiao C., Hanlon H.D., Hartley R.S., Schatteman G.C., CD34‐ blood‐derived human endothelial cell progenitors, Stem Cells, 19: 304–312, 2001. [DOI] [PubMed] [Google Scholar]
  • 14. Fujiyama S., Amano K., Uehira K., Yoshida M., Nishiwaki Y., Nozawa Y., Jin D., Takai S., Miyazaki M., Egashira K., Imada T., Iwasaka T., Matsubara H., Bone marrow monocyte lineage cells adhere on injured endothelium in a monocyte chemoattractant protein‐1‐dependent manner and accelerate reendothelialization as endothelial progenitor cells, Circ. Res., 93: 980–989, 2003. [DOI] [PubMed] [Google Scholar]
  • 15. Zhao Y., Glesne D., Huberman E., A human peripheral blood monocyte‐derived subset acts as pluripotent stem cells, Proc. Natl. Acad. Sci. USA., 100: 2426–2431, 2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Schmeisser A., Garlichs C.D., Zhang H., Eskafi S., Graffy C., Ludwig J., Strasser R.H., Daniel W.G., Monocytes coexpress endothelial and macrophagocytic lineage markers and form cord‐like structures in Matrigel under angiogenic conditions, Cardiovasc. Res., 49: 671–680. 2001. [DOI] [PubMed] [Google Scholar]
  • 17. Urbich C., Heeschen C., Aicher A., Dernbach E., Zeiher A.M., Dimmeler S., Relevance of monocytic features for neovascularization capacity of circulating endothelial progenitor cells, Circulation, 108: 2511–256, 2003. [DOI] [PubMed] [Google Scholar]
  • 18. Ribatti D., Vacca A., Nico B., Ria R., Dammacco F., Cross‐talk between hematopoiesis and angiogenesis signaling pathways, Curr. Mol. Med., 2: 537–543, 2002. [DOI] [PubMed] [Google Scholar]
  • 19. Hill J.M., Zalos G., Halcox J.P., Schenke W.H., Waclawiw M.A., Quyyumi A.A., Finkel T., Circulating endothelial progenitor cells, vascular function, and cardiovascular risk, N. Engl. J. Med., 348: 593–600, 2003. [DOI] [PubMed] [Google Scholar]
  • 20. Heissig B., Hattori K., Dias S., Friedrich M., Ferris B., Hackett N.R., Crystal R.G., Besmer P., Lyden D., Moore M.A., Werb Z., Rafii S., Recruitment of stem and progenitor cells from the bone marrow niche requires MMP‐9 mediated release of kit‐ligand, Cell, 109: 625–637, 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. Aicher A., Heeschen C., Mildner‐Rihm C., Urbich C., Ihling C., Technau‐Ihling K., Zeiher A.M., Dimmeler S., Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells, Nat. Med., 9: 1370–1376, 2003. [DOI] [PubMed] [Google Scholar]
  • 22. Hristov M., Erl W., Linder S., Weber P.C., Apoptotic bodies from endothelial cells enhance the number and initiate the differentiation of human endothelial progenitor cells in vitro, Blood, 104: 2761–2766, 2004. [DOI] [PubMed] [Google Scholar]
  • 23. Strehlow K., Werner N., Berweiler J., Link A., Dirnagl U., Priller J., Laufs K., Ghaeni L., Milosevic M., Bohm M., Nickenig G., Estrogen increases bone marrow‐derived endothelial progenitor cell production and diminishes neointima formation, Circulation, 107: 3059–3065, 2003. [DOI] [PubMed] [Google Scholar]
  • 24. Adams V., Lenk K., Linke A., Lenz D., Erbs S., Sandri M., Tarnok A., Gielen S., Emmrich F., Schuler G., Hambrecht R., Increase of circulating endothelial progenitor cells in patients with coronary artery disease after exercise‐induced ischemia, Arterioscler Thromb Vasc Biol., 24: 684–690, 2004. [DOI] [PubMed] [Google Scholar]
  • 25. Vasa M., Fichtlscherer S., Aicher A., Adler K., Urbich C., Martin H., Zeiher A.M., Dimmeler S., Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease, Circ Res. 89: e1–e7, 2001. [DOI] [PubMed] [Google Scholar]
  • 26. Tepper O.M., Galiano R.D., Capla J.M., Kalka C., Gagne P.J., Jacobowitz G.R., Levine J.P., Gurtner G.C., Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures, Circulation, 106: 2781–2786, 2002. [DOI] [PubMed] [Google Scholar]
  • 27. Loomans C.J., de Koning E.J., Staal F.J., Rookmaaker M.B., Verseyden C., de Boer H.C., Verhaar M.C., Braam B., Rabelink T.J., van Zonneveld A.J., Endothelial progenitor cell dysfunction: a novel concept in the pathogenesis of vascular complications of type 1 diabetes, Diabetes, 53: 195–199, 2004. [DOI] [PubMed] [Google Scholar]
  • 28. Shintani S., Murohara T., Ikeda H., Ueno T., Honma T., Katoh A., Sasaki K., Shimada T., Oike Y., Imaizumi T., Mobilization of endothelial progenitor cells in patients with acute myocardial infarction, Circulation, 103: 2776–2779, 2001. [DOI] [PubMed] [Google Scholar]
  • 29. Gill M., Dias S., Hattori K., Rivera M.L., Hicklin D., Witte L., Girardi L., Yurt R., Himel H., Rafii S., Vascular trauma induces rapid but transient mobilization of VEGFR2(+)AC133(+) endothelial precursor cells, Circ. Res., 88: 167–174, 2001. [DOI] [PubMed] [Google Scholar]
  • 30. Valgimigli M., Rigolin G.M., Fucili A., Della Porta M., Soukhomovskaia O., Malagutti P., Bugli A.M., Bragotti L.Z., Francolini G., Mauro E., Castoldi G., Ferrari R., CD34+ and endothelial progenitor cells in patients with various degrees of congestive heart failure, Circulation, 110: 1209–1212, 2004. [DOI] [PubMed] [Google Scholar]
  • 31. Llevadot J., Murasawa S., Kureishi Y., Uchida S., Masuda H., Kawamoto A., Walsh K., Isner J.M., Asahara T., HMG‐CoA reductase inhibitor mobilizes bone marrow‐derived endothelial progenitor cells, J. Clin. Invest., 108: 399–405, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. Walter D.H., Rittig K., Bahlmann F.H., Kirchmair R., Silver M., Murayama T., Nishimura H., Losordo D.W., Asahara T., Isner J.M., Statin therapy accelerates reendothelialization: a novel effect involving mobilization and incorporation of bone marrow‐derived endothelial progenitor cells, Circulation, 105: 3017–3024, 2002. [DOI] [PubMed] [Google Scholar]
  • 33. Werner N., Priller J., Laufs U., Endres M., Bohm M., Dirnagl U., Nickenig G., Bone marrow‐derived progenitor cells modulate vascular reendothelialization and neointima formation: effect of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibition, Arterioscler. Thromb. Vasc. Biol., 22: 1567–1572, 2002. [DOI] [PubMed] [Google Scholar]
  • 34. Dimmeler S., Aicher A., Vasa M., Mildner‐Rihm C., Adler K., Tiemann M., Rutten H., Fichtlscherer S., Martin H., Zeiher A.M., HMG‐CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3‐kinase/Akt pathway, J. Clin. Invest., 108: 391–397, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. Kalka C., Masuda H., Takahashi T., Gordon R., Tepper O., Gravereaux E., Pieczek A., Iwaguro H., Hayashi S.I., Isner J.M., Asahara T., Vascular endothelial growth factor165 gene transfer augments circulating endothelial progenitor cells in human subjects, Circ. Res., 86: 1198–1202, 2000. [DOI] [PubMed] [Google Scholar]
  • 36. Takahashi T., Kalka C., Masuda H., Chen D., Silver M., Kearney M., Magner M., Isner J.M., Asahara T., Ischemia‐ and cytokine‐induced mobilization of bone marrow‐derived endothelial progenitor cells for neovascularization, Nat. Med., 5: 434–438, 1999. [DOI] [PubMed] [Google Scholar]
  • 37. Bahlmann F.H., De Groot K., Spandau J.M., Landry A.L., Hertel B., Duckert T., Boehm S.M., Menne J., Haller H., Fliser D., Erythropoietin regulates endothelial progenitor cells, Blood, 103: 921–926, 2004. [DOI] [PubMed] [Google Scholar]
  • 38. Weber C., Schober A., Zernecke A., Chemokines: key regulators of mononuclear cell recruitment in atherosclerotic vascular disease, Arterioscler. Thromb. Vasc. Biol., 24: 1997–2008, 2004. [DOI] [PubMed] [Google Scholar]
  • 39. Yamaguchi J., Kusano K.F., Masuo O., Kawamoto A., Silver M., Murasawa S., Bosch‐Marce M., Masuda H., Losordo D.W., Isner J.M., Asahara T., Stromal cell‐derived factor‐1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization, Circulation, 107: 1322–1328, 2003. [DOI] [PubMed] [Google Scholar]
  • 40. Schober A., Knarren S., Lietz M., Lin E.A., Weber C., Crucial role of stromal cell‐derived factor‐1 alpha in neointima formation after vascular injury in apolipoprotein E‐deficient mice, Circulation, 108: 2491–2497, 2003. [DOI] [PubMed] [Google Scholar]
  • 41. Liehn E.A., Schober A., Weber C., Blockade of keratinocyte‐derived chemokine inhibits endothelial recovery and enhances plaque formation after arterial injury in apolipoprotein E‐deficient mice, Arterioscler. Thromb. Vasc. Biol., 24: 1891–1896, 2004. [DOI] [PubMed] [Google Scholar]
  • 42. George J., Herz I., Goldstein E., Abashidze S., Deutch V., Finkelstein A., Michowitz Y., Miller H., Keren G., Number and adhesive properties of circulating endothelial progenitor cells in patients with in‐stent restenosis, Arterioscler. Thromb. Vasc. Biol. 23: e57–60, 2003. [DOI] [PubMed] [Google Scholar]
  • 43. Iwaguro H., Yamaguchi J., Kalka C., Murasawa S., Masuda H., Hayashi S., Silver M., Li T., Isner J.M., Asahara T., Endothelial progenitor cell vascular endothelial growth factor gene transfer for vascular regeneration, Circulation, 105: 732–738, 2002. [DOI] [PubMed] [Google Scholar]
  • 44. Kalka C., Tehrani H., Laudenberg B., Vale P.R., Isner J.M., Asahara T., Symes J.F., VEGF gene transfer mobilizes endothelial progenitor cells in patients with inoperable coronary disease, Ann. Thorac. Surg., 70: 829–834, 2000. [DOI] [PubMed] [Google Scholar]
  • 45. Hiasa K., Ishibashi M., Ohtani K., Inoue S., Zhao Q., Kitamoto S., Sata M., Ichiki T., Takeshita A., Egashira K., Gene transfer of stromal cell‐derived factor‐1 alpha enhances ischemic vasculogenesis and angiogenesis via vascular endothelial growth factor/endothelial nitric oxide synthase‐related pathway: next‐generation chemokine therapy for therapeutic neovascularization, Circulation, 109: 2454–2461, 2004. [DOI] [PubMed] [Google Scholar]
  • 46. Kawamoto A., Gwon H.C., Iwaguro H., Yamaguchi J.I., Uchida S., Masuda H., Silver M., Ma H., Kearney M., Isner J.M., Asahara T., Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia, Circulation, 103: 634–637, 2001. [DOI] [PubMed] [Google Scholar]
  • 47. Kocher A.A., Schuster M.D., Szabolcs M.J., Takuma S., Burkhoff D., Wang J., Homma S., Edwards N.M., Itescu S., Neovascularization of ischemic myocardium by human bone‐marrow‐derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function, Nat. Med., 7: 430–436, 2001. [DOI] [PubMed] [Google Scholar]
  • 48. Tateishi‐Yuyama E., Matsubara H., Murohara T., Ikeda U., Shintani S., Masaki H., Amano K., Kishimoto Y., Yoshimoto K., Akashi H., Shimada K., Iwasaka T., Imaizumi T., Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone‐marrow cells: a pilot study and a randomised controlled trial, Lancet, 360: 427–435, 2002. [DOI] [PubMed] [Google Scholar]
  • 49. Strauer B.E., Brehm M., Zeus T., Kostering M., Hernandez A., Sorg R.V., Kogler G., Wernet P., Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans, Circulation, 106: 1913–1918, 2002. [DOI] [PubMed] [Google Scholar]
  • 50. Assmus B., Schachinger V., Teupe C., Britten M., Lehmann R., Dobert N., Grunwald F., Aicher A., Urbich C., Martin H., Hoelzer D., Dimmeler S., Zeiher A.M., Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE‐AMI), Circulation, 106: 3009–3017, 2002. [DOI] [PubMed] [Google Scholar]
  • 51. Stamm C., Westphal B., Kleine H.D., Petzsch M., Kittner C., Klinge H., Schumichen C., Nienaber C.A., Freund M., Steinhoff G., Autologous bone‐marrow stem‐cell transplantation for myocardial regeneration, Lancet, 361: 45–46, 2003. [DOI] [PubMed] [Google Scholar]
  • 52. Wollert K.C., Meyer G.P., Lotz J., Ringes‐Lichtenberg S., Lippolt P., Breidenbach C., Fichtner S., Korte T., Hornig B., Messinger D., Arseniev L., Hertenstein B., Ganser A., Drexler H., Intracoronary autologous bone‐marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial, Lancet, 364: 141–148, 2004. [DOI] [PubMed] [Google Scholar]
  • 53. Kang H.J., Kim H.S., Zhang S.Y., Park K.W., Cho H.J., Koo B.K., Kim Y.J., Soo Lee D., Sohn D.W., Han K.S., Oh B.H., Lee M.M., Park Y.B., Effects of intracoronary infusion of peripheral blood stem‐cells mobilised with granulocyte‐colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell randomised clinical trial, Lancet, 363: 751–756, 2004. [DOI] [PubMed] [Google Scholar]
  • 54. Murry C.E., Soonpaa M.H., Reinecke H., Nakajima H., Nakajima H.O., Rubart M., Pasumarthi K.B., Virag J.I., Bartelmez S.H., Poppa V., Bradford G., Dowell J.D., Williams D.A., Field L.J., Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts, Nature, 428: 664–668, 2004. [DOI] [PubMed] [Google Scholar]
  • 55. Kaushal S., Amiel G.E., Guleserian K.J., Shapira O.M., Perry T., Sutherland F.W., Rabkin E., Moran A.M., Schoen F.J., Atala A., Soker S., Bischoff J., Mayer J.E. Jr., Functional small‐diameter neovessels created using endothelial progenitor cells expanded ex vivo, Nat. Med., 7: 1035–1040, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56. Kong D., Melo L.G., Mangi A.A., Zhang L., Lopez‐Ilasaca M., Perrella M.A., Liew C.C., Pratt R.E., Dzau V.J., Enhanced inhibition of neointimal hyperplasia by genetically engineered endothelial progenitor cells, Circulation, 109: 1769–1775, 2004. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Cellular and Molecular Medicine are provided here courtesy of Blackwell Publishing

RESOURCES