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Endothelial progenitor cells: Characterization, in vitro expansion, and prospects for autologous cell therapy

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Abstract

Injection of hematopoietic stem cells or endothelial progenitor cells (EPCs) expanded ex vivo has been shown to augment neovascularization in adult patients, but the precise origin and identity of the cell population responsible for these clinical benefits are controversial. The limited quantity of EPCs in the circulation has been the main obstacle to clinical trials. Several authors have therefore attempted to expand these cells ex vivo in order to obtain a homogeneous cell therapy product. One possible means of expanding EPCs ex vivo is to activate the thrombin receptor PAR-1 with the specific peptide SFLLRN. Indeed, PAR-1 activation promotes cell proliferation and C-X-C chemokine receptor type 4 (CXCR4) dependent migration and differentiation, with an overall angiogenic effect. This review summarizes the results and rationale of clinical trials of angiogenic therapy, the nature of EPCs, the different methods of ex vivo expansion, and current methods of quantification.

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Abbreviations

AMI:

acute myocardial infarction

BM-MNC:

bone marrow mononuclear cell

CFU:

colony-forming units

CHD:

chronic heart disease

CLI:

critical leg ischemia

CXCR4:

C-X-C chemokine receptor type 4

EPC:

endothelial progenitor cell

hTERT:

human telomerase reverse transcriptase

HUVECs:

human umbilical vein endothelial cells

IM:

intramuscular(ly)

LDL:

low-density lipoprotein

LV:

left ventricular

LVEF:

left ventricular ejection fraction

MAPC:

multipotent adult progenitor cells

MSC:

mesenchymal stem cell

PB-MNC:

peripheral blood mononuclear cell

SDF-1:

stromal derived factor-1

VEGF:

vascular endothelial growth factor

VEGF-R2:

vascular endothelial growth factor receptor 2

References

  • Al-Khaldi A, Eliopoulos N, Martineau D, Lejeune L, Lachapelle K, Galipeau J. Postnatal bone marrow stromal cells elicit a potent VEGF-dependent neoangiogenic response in vivo. Gene Ther. 2003;10:621–9.

    Article  PubMed  CAS  Google Scholar 

  • Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275:964–7.

    Article  PubMed  CAS  Google Scholar 

  • Assmus B, Honold J, Schachinger V, Britten MB, Fischer-Rasokat U, Lehmann R, Teupe C, Pistorius K, Martin H, Abolmaali ND, Tonn T, Dimmeler S, Zeiher AM. Transcoronary transplantation of progenitor cells after myocardial infarction. N Engl J Med. 2006;355:1222–32.

    Article  PubMed  CAS  Google Scholar 

  • 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 AM. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation. 2002;106:3009–17.

    Article  PubMed  Google Scholar 

  • Assmus B, Urbich C, Aicher A, Hofmann WK, Haendeler J, Rossig L, Spyridopoulos I, Zeiher AM, Dimmeler S. HMG-CoA reductase inhibitors reduce senescence and increase proliferation of endothelial progenitor cells via regulation of cell cycle regulatory genes. Circ Res. 2003;92:1049–55.

    Article  PubMed  CAS  Google Scholar 

  • Balsam LB, Wagers AJ, Christensen JL, Kofidis T, Weissman IL, Robbins RC. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature. 2004;428:668–73.

    Article  PubMed  CAS  Google Scholar 

  • Basire A, Sabatier F, Ravet S, Lamy E, Mialhe A, Zabouo G, Paul P, Gurewich V, Sampol J, Dignat-George F. High urokinase expression contributes to the angiogenic properties of endothelial cells derived from circulating progenitors. Thromb Haemost. 2006;95:678–88.

    PubMed  CAS  Google Scholar 

  • Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, Kasahara H, Rota M, Musso E, Urbanek K, Leri A, Kajstura J, Nadal-Ginard B, Anversa P. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell. 2003;114:763–76.

    Article  PubMed  CAS  Google Scholar 

  • Bompais H, Chagraoui J, Canron X, Crisan M, Liu XH, Anjo A, Tolla-Le Port C, Leboeuf M, Charbord P, Bikfalvi A, Uzan G. Human endothelial cells derived from circulating progenitors display specific functional properties compared with mature vessel wall endothelial cells. Blood. 2004;103:2577–84.

    Article  PubMed  CAS  Google Scholar 

  • Britten MB, Abolmaali ND, Assmus B, Lehmann R, Honold J, Schmitt J, Vogl TJ, Martin H, Schachinger V, Dimmeler S, Zeiher AM. Infarct remodeling after intracoronary progenitor cell treatment in patients with acute myocardial infarction (TOPCARE-AMI): mechanistic insights from serial contrast-enhanced magnetic resonance imaging. Circulation. 2003;108:2212–8.

    Article  PubMed  CAS  Google Scholar 

  • Caunt M, Huang YQ, Brooks PC, Karpatkin S. Thrombin induces neoangiogenesis in the chick chorioallantoic membrane. J Thromb Haemost. 2003;1:2097–102.

    Article  PubMed  CAS  Google Scholar 

  • Chen JZ, Zhang FR, Tao QM, Wang XX, Zhu JH. Number and activity of endothelial progenitor cells from peripheral blood in patients with hypercholesterolaemia. Clin Sci (Lond). 2004;107:273–80.

    Article  CAS  Google Scholar 

  • Chironi G, Walch L, Pernollet MG, Gariepy J, Levenson J, Rendu F, Simon A. Decreased number of circulating CD34(+)KDR(+) cells in asymptomatic subjects with preclinical atherosclerosis. Atherosclerosis. 2006 (April 16). [Epub. ahead of print].

  • Choi JH, Kim KL, Huh W, Kim B, Byun J, Suh W, Sung J, Jeon ES, Oh HY, Kim DK. Decreased number and impaired angiogenic function of endothelial progenitor cells in patients with chronic renal failure. Arterioscler Thromb Vasc Biol. 2004;24:1246–52.

    Article  PubMed  CAS  Google Scholar 

  • de Groot K, Bahlmann FH, Bahlmann E, Menne J, Haller H, Fliser D. Kidney graft function determines endothelial progenitor cell number in renal transplant recipients. Transplantation. 2005;79:941–5.

    Article  PubMed  Google Scholar 

  • Delorme B, Basire A, Gentile C, Sabatier F, Monsonis F, Desouches C, Blot-Chabaud M, Uzan G, Sampol J, Dignat-George F. Presence of endothelial progenitor cells, distinct from mature endothelial cells, within human CD146+ blood cells. Thromb Haemost. 2005;94:1270–9.

    PubMed  CAS  Google Scholar 

  • Dimmeler S, Aicher A, Vasa M, Mildner-Rihm C, Adler K, Tiemann M, Rutten H, Fichtlscherer S, Martin H, Zeiher AM. HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clin Invest. 2001;108:391–7.

    Article  PubMed  CAS  Google Scholar 

  • Dohmann HF, Perin EC, Takiya CM, Silva GV, Silva SA, Sousa AL, Mesquita CT, Rossi MI, Pascarelli BM, Assis IM, Dutra HS, Assad JA, Castello-Branco RV, Drummond C, Dohmann HJ, Willerson JT, Borojevic R. Transendocardial autologous bone marrow mononuclear cell injection in ischemic heart failure: postmortem anatomicopathologic and immunohistochemical findings. Circulation. 2005;112:521–6.

    Article  PubMed  Google Scholar 

  • Dupuy E, Habib A, Lebret M, Yang R, Levy-Toledano S, Tobelem G. Thrombin induces angiogenesis and vascular endothelial growth factor expression in human endothelial cells: possible relevance to HIF-1alpha. J Thromb Haemost. 2003;1:1096–102.

    Article  PubMed  CAS  Google Scholar 

  • Eizawa T, Ikeda U, Murakami Y, Matsui K, Yoshioka T, Takahashi M, Muroi K, Shimada K. Decrease in circulating endothelial progenitor cells in patients with stable coronary artery disease. Heart. 2004;90:685–6.

    Article  PubMed  CAS  Google Scholar 

  • Elsheikh E, Uzunel M, He Z, Holgersson J, Nowak G, Sumitran-Holgersson S. Only a specific subset of human peripheral-blood monocytes has endothelial-like functional capacity. Blood. 2005;106:2347–55.

    Article  PubMed  CAS  Google Scholar 

  • Erbs S, Linke A, Adams V, Lenk K, Thiele H, Diederich KW, Emmrich F, Kluge R, Kendziorra K, Sabri O, Schuler G, Hambrecht R. Transplantation of blood-derived progenitor cells after recanalization of chronic coronary artery occlusion: first randomized and placebo-controlled study. Circ Res. 2005;97:756–62.

    Article  PubMed  CAS  Google Scholar 

  • Erbs S, Linke A, Schuler G, Hambrecht R. Intracoronary administration of circulating blood-derived progenitor cells after recanalization of chronic coronary artery occlusion improves endothelial function. Circ Res. 2006;98:e48.

    Article  PubMed  CAS  Google Scholar 

  • Fernandez-Aviles F, San Roman JA, Garcia-Frade J, Fernandez ME, Penarrubia MJ, de la Fuente L, Gomez-Bueno M, Cantalapiedra A, Fernandez J, Gutierrez O, Sanchez PL, Hernandez C, Sanz R, Garcia-Sancho J, Sanchez A. Experimental and clinical regenerative capability of human bone marrow cells after myocardial infarction. Circ Res. 2004;95:742–8.

    Article  PubMed  CAS  Google Scholar 

  • Fuchs S, Satler LF, Kornowski R, Okubagzi P, Weisz G, Baffour R, Waksman R, Weissman NJ, Cerqueira M, Leon MB, Epstein SE. Catheter-based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease: a feasibility study. J Am Coll Cardiol. 2003;41:1721–4.

    Article  PubMed  Google Scholar 

  • George J, Goldstein E, Abashidze S, Deutsch V, Shmilovich H, Finkelstein A, Herz I, Miller H, Keren G. Circulating endothelial progenitor cells in patients with unstable angina: association with systemic inflammation. Eur Heart J. 2004;25:1003–8.

    Article  PubMed  CAS  Google Scholar 

  • George J, Shmilovich H, Deutsch V, Miller H, Keren G, Roth A. Comparative analysis of methods for assessment of circulating endothelial progenitor cells. Tissue Eng. 2006;12:331–5.

    Article  PubMed  CAS  Google Scholar 

  • Griffin CT, Srinivasan Y, Zheng YW, Huang W, Coughlin SR. A role for thrombin receptor signaling in endothelial cells during embryonic development. Science. 2001;293:1666–70.

    Article  PubMed  CAS  Google Scholar 

  • Gulati R, Jevremovic D, Peterson TE, Chatterjee S, Shah V, Vile RG, Simari RD. Diverse origin and function of cells with endothelial phenotype obtained from adult human blood. Circ Res. 2003;93:1023–5.

    Article  PubMed  CAS  Google Scholar 

  • He T, Peterson TE, Holmuhamedov EL, Terzic A, Caplice NM, Oberley LW, Katusic ZS. Human endothelial progenitor cells tolerate oxidative stress due to intrinsically high expression of manganese superoxide dismutase. Arterioscler Thromb Vasc Biol. 2004;24:2021–7.

    Article  PubMed  CAS  Google Scholar 

  • Heeschen C, Lehmann R, Honold J, Assmus B, Aicher A, Walter DH, Martin H, Zeiher AM, Dimmeler S. Profoundly reduced neovascularization capacity of bone marrow mononuclear cells derived from patients with chronic ischemic heart disease. Circulation. 2004;109:1615–22.

    Article  PubMed  Google Scholar 

  • Higashi Y, Kimura M, Hara K, Noma K, Jitsuiki D, Nakagawa K, Oshima T, Chayama K, Sueda T, Goto C, Matsubara H, Murohara T, Yoshizumi M. Autologous bone-marrow mononuclear cell implantation improves endothelium-dependent vasodilation in patients with limb ischemia. Circulation. 2004;109:1215–8.

    Article  PubMed  Google Scholar 

  • Hildbrand P, Cirulli V, Prinsen RC, Smith KA, Torbett BE, Salomon DR, Crisa L. The role of angiopoietins in the development of endothelial cells from cord blood CD34+ progenitors. Blood. 2004;104:2010–9.

    Article  PubMed  CAS  Google Scholar 

  • Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, Finkel T. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med. 2003;348:593–600.

    Article  PubMed  Google Scholar 

  • Hofmann M, Wollert KC, Meyer GP, Menke A, Arseniev L, Hertenstein B, Ganser A, Knapp WH, Drexler H. Monitoring of bone marrow cell homing into the infarcted human myocardium. Circulation. 2005;111:2198–202.

    Article  PubMed  Google Scholar 

  • Huang P, Li S, Han M, Xiao Z, Yang R, Han ZC. Autologous transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells improves critical limb ischemia in diabetes. Diabetes Care. 2005;28:2155–60.

    Article  PubMed  Google Scholar 

  • Huang PP, Li SZ, Han MZ, Xiao ZJ, Yang RC, Qiu LG, Han ZC. Autologous transplantation of peripheral blood stem cells as an effective therapeutic approach for severe arteriosclerosis obliterans of lower extremities. Thromb Haemost. 2004;91:606–9.

    PubMed  CAS  Google Scholar 

  • Hur J, Yoon CH, Kim HS, Choi JH, Kang HJ, Hwang KK, Oh BH, Lee MM, Park YB. Characterization of two types of endothelial progenitor cells and their different contributions to neovasculogenesis. Arterioscler Thromb Vasc Biol. 2004;24:288–93.

    Article  PubMed  CAS  Google Scholar 

  • Imanishi T, Hano T, Sawamura T, Nishio I. Oxidized low-density lipoprotein induces endothelial progenitor cell senescence, leading to cellular dysfunction. Clin Exp Pharmacol Physiol. 2004;31:407–13.

    Article  PubMed  CAS  Google Scholar 

  • Ingram DA, Caplice NM, Yoder MC. Unresolved questions, changing definitions, and novel paradigms for defining endothelial progenitor cells. Blood. 2005;106:1525–31.

    Article  PubMed  CAS  Google Scholar 

  • Ingram DA, Mead LE, Moore DB, Woodard W, Fenoglio A, Yoder MC. Vessel wall-derived endothelial cells rapidly proliferate because they contain a complete hierarchy of endothelial progenitor cells. Blood. 2005;105:2783–6.

    Article  PubMed  CAS  Google Scholar 

  • Ingram DA, Mead LE, Tanaka H, Meade V, Fenoglio A, Mortell K, Pollok K, Ferkowicz MJ, Gilley D, Yoder MC. Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood. Blood. 2004;104:2752–60.

    Article  PubMed  CAS  Google Scholar 

  • Iwaguro H, Asahara T. Endothelial progenitor cell culture and gene transfer. Methods Mol Med. 2005;112:239–47.

    PubMed  CAS  Google Scholar 

  • Iwaguro H, Yamaguchi J, Kalka C, Murasawa S, Masuda H, Hayashi S, Silver M, Li T, Isner JM, Asahara T. Endothelial progenitor cell vascular endothelial growth factor gene transfer for vascular regeneration. Circulation. 2002;105:732–8.

    Article  PubMed  CAS  Google Scholar 

  • Janssens S, Dubois C, Bogaert J, Theunissen K, Deroose C, Desmet W, Kalantzi M, Herbots L, Sinnaeve P, Dens J, Maertens J, Rademakers F, Dymarkowski S, Gheysens O, Van Cleemput J, Bormans G, Nuyts J, Belmans A, Mortelmans L, Boogaerts M, Van de Werf F. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet. 2006;367:113–21.

    Article  PubMed  Google Scholar 

  • Kalka C, Masuda H, Takahashi T, Gordon R, Tepper O, Gravereaux E, Pieczek A, Iwaguro H, Hayashi SI, Isner JM, Asahara T. Vascular endothelial growth factor(165) gene transfer augments circulating endothelial progenitor cells in human subjects. Circ Res. 2000;86:1198–202.

    PubMed  CAS  Google Scholar 

  • Kang HJ, Kim HS, Zhang SY, Park KW, Cho HJ, Koo BK, Kim YJ, Soo Lee D, Sohn DW, Han KS, Oh BH, Lee MM, Park YB. 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. 2004;363:751–6.

    Article  PubMed  CAS  Google Scholar 

  • Kaushal S, Amiel GE, Guleserian KJ, Shapira OM, Perry T, Sutherland FW, Rabkin E, Moran AM, Schoen FJ, Atala A, Soker S, Bischoff J, Mayer JE, Jr. Functional small-diameter neovessels created using endothelial progenitor cells expanded ex vivo. Nat Med. 2001;7:1035–40.

    Google Scholar 

  • Kawamoto A, Gwon HC, Iwaguro H, Yamaguchi JI, Uchida S, Masuda H, Silver M, Ma H, Kearney M, Isner JM, Asahara T. Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia. Circulation. 2001;103:634–7.

    PubMed  CAS  Google Scholar 

  • Kawamoto A, Iwasaki H, Kusano K, Murayama T, Oyamada A, Silver M, Hulbert C, Gavin M, Hanley A, Ma H, Kearney M, Zak V, Asahara T, Losordo DW. CD34-positive cells exhibit increased potency and safety for therapeutic neovascularization after myocardial infarction compared with total mononuclear cells. Circulation. 2006;114:2163–9.

    Article  PubMed  Google Scholar 

  • Kinnaird T, Stabile E, Burnett MS, Shou M, Lee CW, Barr S, Fuchs S, Epstein SE. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation. 2004;109:1543–9.

    Article  PubMed  CAS  Google Scholar 

  • Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, Homma S, Edwards NM, Itescu S. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med. 2001;7:430–6.

    Article  PubMed  CAS  Google Scholar 

  • Kondo T, Hayashi M, Takeshita K, Numaguchi Y, Kobayashi K, Iino S, Inden Y, Murohara T. Smoking cessation rapidly increases circulating progenitor cells in peripheral blood in chronic smokers. Arterioscler Thromb Vasc Biol. 2004;24:1442–7.

    Article  PubMed  CAS  Google Scholar 

  • Lafay M, Laguna R, Le Bonniec BF, Lasne D, Aiach M, Rendu F. Thrombomodulin modulates the mitogenic response to thrombin of human umbilical vein endothelial cells. Thromb Haemost. 1998;79:848–52.

    PubMed  CAS  Google Scholar 

  • Laufs U, Urhausen A, Werner N, Scharhag J, Heitz A, Kissner G, Bohm M, Kindermann W, Nickenig G. Running exercise of different duration and intensity: effect on endothelial progenitor cells in healthy subjects. Eur J Cardiovasc Prev Rehabil. 2005;12:407–14.

    Article  PubMed  Google Scholar 

  • Laufs U, Wassmann S, Czech T, Munzel T, Eisenhauer M, Bohm M, Nickenig G. Physical inactivity increases oxidative stress, endothelial dysfunction, and atherosclerosis. Arterioscler Thromb Vasc Biol. 2005;25:809–14.

    Article  PubMed  CAS  Google Scholar 

  • Lee SH, Wolf PL, Escudero R, Deutsch R, Jamieson SW, Thistlethwaite PA. Early expression of angiogenesis factors in acute myocardial ischemia and infarction. N Engl J Med. 2000;342:626–33.

    Article  PubMed  CAS  Google Scholar 

  • Lin Y, Chang L, Solovey A, Healey JF, Lollar P, Hebbel RP. Use of blood outgrowth endothelial cells for gene therapy for hemophilia A. Blood. 2002;99:457–62.

    Article  PubMed  CAS  Google Scholar 

  • Lin Y, Weisdorf DJ, Solovey A, Hebbel RP. Origins of circulating endothelial cells and endothelial outgrowth from blood. J Clin Invest. 2000;105:71–7.

    PubMed  CAS  Google Scholar 

  • Llevadot J, Murasawa S, Kureishi Y, Uchida S, Masuda H, Kawamoto A, Walsh K, Isner JM, Asahara T. HMG-CoA reductase inhibitor mobilizes bone marrow–derived endothelial progenitor cells. J Clin Invest. 2001;108:399–405.

    Article  PubMed  CAS  Google Scholar 

  • Loomans CJ, de Koning EJ, Staal FJ, Rookmaaker MB, Verseyden C, de Boer HC, Verhaar MC, Braam B, Rabelink TJ, van Zonneveld AJ. Endothelial progenitor cell dysfunction: a novel concept in the pathogenesis of vascular complications of type 1 diabetes. Diabetes. 2004;53:195–9.

    Article  PubMed  CAS  Google Scholar 

  • Lunde K, Solheim S, Aakhus S, Arnesen H, Abdelnoor M, Egeland T, Endresen K, Ilebekk A, Mangschau A, Fjeld JG, Smith HJ, Taraldsrud E, Grogaard HK, Bjornerheim R, Brekke M, Muller C, Hopp E, Ragnarsson A, Brinchmann JE, Forfang K. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med. 2006;355:1199–209.

    Article  PubMed  CAS  Google Scholar 

  • Major CD, Santulli RJ, Derian CK, Andrade-Gordon P. Extracellular mediators in atherosclerosis and thrombosis: lessons from thrombin receptor knockout mice. Arterioscler Thromb Vasc Biol. 2003;23:931–9.

    Article  PubMed  CAS  Google Scholar 

  • Meyer GP, Wollert KC, Lotz J, Steffens J, Lippolt P, Fichtner S, Hecker H, Schaefer A, Arseniev L, Hertenstein B, Ganser A, Drexler H. Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months' follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial. Circulation. 2006;113:1287–94.

    Article  PubMed  Google Scholar 

  • Michaud SE, Dussault S, Haddad P, Groleau J, Rivard A. Circulating endothelial progenitor cells from healthy smokers exhibit impaired functional activities. Atherosclerosis. 2006;187(2):423–32.

    Article  PubMed  CAS  Google Scholar 

  • Murasawa S, Llevadot J, Silver M, Isner JM, Losordo DW, Asahara T. Constitutive human telomerase reverse transcriptase expression enhances regenerative properties of endothelial progenitor cells. Circulation. 2002;106:1133–9.

    Article  PubMed  CAS  Google Scholar 

  • Murohara T, Ikeda H, Duan J, Shintani S, Sasaki K, Eguchi H, Onitsuka I, Matsui K, Imaizumi T. Transplanted cord blood-derived endothelial precursor cells augment postnatal neovascularization. J Clin Invest. 2000;105:1527–36.

    Article  PubMed  CAS  Google Scholar 

  • Murry CE, Soonpaa MH, Reinecke H, Nakajima H, Nakajima HO, Rubart M, Pasumarthi KB, Virag JI, Bartelmez SH, Poppa V, Bradford G, Dowell JD, Williams DA, Field LJ. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature. 2004;428:664–8.

    Article  PubMed  CAS  Google Scholar 

  • Olivot JM, Estebanell E, Lafay M, Brohard B, Aiach M, Rendu F. Thrombomodulin prolongs thrombin-induced extracellular signal-regulated kinase phosphorylation and nuclear retention in endothelial cells. Circ Res. 2001;88:681–7.

    PubMed  CAS  Google Scholar 

  • Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM, Leri A, Anversa P. Bone marrow cells regenerate infarcted myocardium. Nature. 2001;410:701–5.

    Article  PubMed  CAS  Google Scholar 

  • Oswald J, Boxberger S, Jorgensen B, Feldmann S, Ehninger G, Bornhauser M, Werner C. Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem Cells. 2004;22:377–84.

    Article  PubMed  Google Scholar 

  • Peichev M, Naiyer AJ, Pereira D, Zhu Z, Lane WJ, Williams M, Oz MC, Hicklin DJ, Witte L, Moore MA, Rafii S. Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood. 2000;95:952–8.

    PubMed  CAS  Google Scholar 

  • Perin EC, Dohmann HF, Borojevic R, Silva SA, Sousa AL, Mesquita CT, Rossi MI, Carvalho AC, Dutra HS, Dohmann HJ, Silva GV, Belem L, Vivacqua R, Rangel FO, Esporcatte R, Geng YJ, Vaughn WK, Assad JA, Mesquita ET, Willerson JT. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation. 2003;107:2294–302.

    Article  PubMed  Google Scholar 

  • Perin EC, Dohmann HF, Borojevic R, Silva SA, Sousa AL, Silva GV, Mesquita CT, Belem L, Vaughn WK, Rangel FO, Assad JA, Carvalho AC, Branco RV, Rossi MI, Dohmann HJ, Willerson JT. Improved exercise capacity and ischemia 6 and 12 months after transendocardial injection of autologous bone marrow mononuclear cells for ischemic cardiomyopathy. Circulation. 2004;110:II213–8.

    Google Scholar 

  • Planat-Benard V, Silvestre JS, Cousin B, Andre M, Nibbelink M, Tamarat R, Clergue M, Manneville C, Saillan-Barreau C, Duriez M, Tedgui A, Levy B, Penicaud L, Casteilla L. Plasticity of human adipose lineage cells toward endothelial cells: physiological and therapeutic perspectives. Circulation. 2004;109:656–63.

    Article  PubMed  Google Scholar 

  • Quirici N, Soligo D, Caneva L, Servida F, Bossolasco P, Deliliers GL. Differentiation and expansion of endothelial cells from human bone marrow CD133(+) cells. Br J Haematol. 2001;115:186–94.

    Article  PubMed  CAS  Google Scholar 

  • Reyes M, Dudek A, Jahagirdar B, Koodie L, Marker PH, Verfaillie CM. Origin of endothelial progenitors in human postnatal bone marrow. J Clin Invest. 2002;109:337–46.

    Article  PubMed  CAS  Google Scholar 

  • Romagnani P, Annunziato F, Liotta F, Lazzeri E, Mazzinghi B, Frosali F, Cosmi L, Maggi L, Lasagni L, Scheffold A, Kruger M, Dimmeler S, Marra F, Gensini G, Maggi E, Romagnani S. CD14+CD34low cells with stem cell phenotypic and functional features are the major source of circulating endothelial progenitors. Circ Res. 2005;97:314–22.

    Article  PubMed  CAS  Google Scholar 

  • Saigawa T, Kato K, Ozawa T, Toba K, Makiyama Y, Minagawa S, Hashimoto S, Furukawa T, Nakamura Y, Hanawa H, Kodama M, Yoshimura N, Fujiwara H, Namura O, Sogawa M, Hayashi J, Aizawa Y. Clinical application of bone marrow implantation in patients with arteriosclerosis obliterans, and the association between efficacy and the number of implanted bone marrow cells. Circ J. 2004;68:1189–93.

    Article  PubMed  Google Scholar 

  • Sainz J, Al Haj Zen A, Caligiuri G, Demerens C, Urbain D, Lemitre M, Lafont A. Isolation of “side population" progenitor cells from healthy arteries of adult mice. Arterioscler Thromb Vasc Biol. 2006;26:281–6.

    Article  PubMed  CAS  Google Scholar 

  • Schachinger V, Assmus B, Britten MB, Honold J, Lehmann R, Teupe C, Abolmaali ND, Vogl TJ, Hofmann WK, Martin H, Dimmeler S, Zeiher AM. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI Trial. J Am Coll Cardiol. 2004;44:1690–9.

    Article  PubMed  Google Scholar 

  • Schachinger V, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Holschermann H, Yu J, Corti R, Mathey DG, Hamm CW, Suselbeck T, Assmus B, Tonn T, Dimmeler S, Zeiher AM. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med. 2006;355:1210–21.

    Article  PubMed  CAS  Google Scholar 

  • Schatteman GC, Hanlon HD, Jiao C, Dodds SG, Christy BA. Blood-derived angioblasts accelerate blood-flow restoration in diabetic mice. J Clin Invest. 2000;106:571–8.

    PubMed  CAS  Google Scholar 

  • Sharpe EE, 3rd, Teleron AA, Li B, Price J, Sands MS, Alford K, Young PP. The origin and in vivo significance of murine and human culture-expanded endothelial progenitor cells. Am J Pathol. 2006;168:1710–21.

    Google Scholar 

  • 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. 2001;103:2776–9.

    PubMed  CAS  Google Scholar 

  • Smadja DM, Bieche I, Emmerich J, Aiach M, Gaussem P. PAR-1 activation has different effects on the angiogenic activity of endothelial progenitor cells derived from human adult and cord blood. J Thromb Haemost. 2006a;4:2729–31.

    Article  CAS  Google Scholar 

  • Smadja DM, Bieche I, Uzan G, Bompais H, Muller L, Boisson-Vidal C, Vidaud M, Aiach M, Gaussem P. PAR-1 activation on human late endothelial progenitor cells enhances angiogenesis in vitro with upregulation of the SDF-1/CXCR4 system. Arterioscler Thromb Vasc Biol. 2005;25:2321–7.

    Article  PubMed  CAS  Google Scholar 

  • Smadja DM, Laurendeau I, Avignon C, Vidaud M, Aiach M, Gaussem P. The angiopoietin pathway is modulated by PAR-1 activation on human endothelial progenitor cells. J Thromb Haemost. 2006b;4:2051–8.

    Article  CAS  Google Scholar 

  • Stamm C, Kleine HD, Westphal B, Petzsch M, Kittner C, Nienaber CA, Freund M, Steinhoff G. CABG and bone marrow stem cell transplantation after myocardial infarction. Thorac Cardiovasc Surg. 2004;52:152–8.

    Article  PubMed  CAS  Google Scholar 

  • Stamm C, Westphal B, Kleine HD, Petzsch M, Kittner C, Klinge H, Schumichen C, Nienaber CA, Freund M, Steinhoff G. Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet. 2003;361:45–6.

    Article  PubMed  Google Scholar 

  • Strauer BE, Brehm M, Zeus T, Bartsch T, Schannwell C, Antke C, Sorg RV, Kogler G, Wernet P, Muller HW, Kostering M. Regeneration of human infarcted heart muscle by intracoronary autologous bone marrow cell transplantation in chronic coronary artery disease: the IACT Study. J Am Coll Cardiol. 2005;46:1651–8.

    Article  PubMed  Google Scholar 

  • Strauer BE, Brehm M, Zeus T, Kostering M, Hernandez A, Sorg RV, Kogler G, Wernet P. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation. 2002;106:1913–8.

    Article  PubMed  Google Scholar 

  • Takahashi T, Kalka C, Masuda H, Chen D, Silver M, Kearney M, Magner M, Isner JM, Asahara T. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med. 1999;5:434–8.

    Article  PubMed  CAS  Google Scholar 

  • 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. 2002;360:427–35.

    Article  PubMed  Google Scholar 

  • Tepper OM, Galiano RD, Capla JM, Kalka C, Gagne PJ, Jacobowitz GR, Levine JP, Gurtner GC. Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation. 2002;106:2781–6.

    Article  PubMed  Google Scholar 

  • Tse HF, Kwong YL, Chan JK, Lo G, Ho CL, Lau CP. Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet. 2003;361:47–9.

    Article  PubMed  Google Scholar 

  • Tsopanoglou NE, Maragoudakis ME. On the mechanism of thrombin-induced angiogenesis. Potentiation of vascular endothelial growth factor activity on endothelial cells by up-regulation of its receptors. J Biol Chem. 1999;274:23969–76.

    CAS  Google Scholar 

  • Urbich C, Dernbach E, Zeiher AM, Dimmeler S. Double-edged role of statins in angiogenesis signaling. Circ Res. 2002;90:737–44.

    Article  PubMed  CAS  Google Scholar 

  • Urbich C, Dimmeler S. Endothelial progenitor cells: characterization and role in vascular biology. Circ Res. 2004;95:343–53.

    Article  PubMed  CAS  Google Scholar 

  • Urbich C, Heeschen C, Aicher A, Dernbach E, Zeiher AM, Dimmeler S. Relevance of monocytic features for neovascularization capacity of circulating endothelial progenitor cells. Circulation. 2003;108:2511–6.

    Article  PubMed  Google Scholar 

  • Valgimigli M, Rigolin GM, Fucili A, Porta MD, Soukhomovskaia O, Malagutti P, Bugli AM, Bragotti LZ, Francolini G, Mauro E, Castoldi G, Ferrari R. CD34 + and endothelial progenitor cells in patients with various degrees of congestive heart failure. Circulation. 2004;110:1209–12.

    Article  PubMed  CAS  Google Scholar 

  • Vasa M, Fichtlscherer S, Adler K, Aicher A, Martin H, Zeiher AM, Dimmeler S. Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation. 2001;103:2885–90.

    PubMed  CAS  Google Scholar 

  • Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H, Zeiher AM, Dimmeler S. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res. 2001;89:E1–7.

    PubMed  CAS  Google Scholar 

  • Wang X, Chen J, Tao Q, Zhu J, Shang Y. Effects of ox-LDL on number and activity of circulating endothelial progenitor cells. Drug Chem Toxicol. 2004;27:243–55.

    Article  PubMed  CAS  Google Scholar 

  • Wollert KC, Meyer GP, 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. 2004;364:141–8.

    Article  PubMed  Google Scholar 

  • Wurmser AE, Nakashima K, Summers RG, Toni N, D'Amour KA, Lie DC, Gage FH. Cell fusion-independent differentiation of neural stem cells to the endothelial lineage. Nature. 2004;430:350–6.

    Article  PubMed  CAS  Google Scholar 

  • Yin YJ, Salah Z, Maoz M, Ram SC, Ochayon S, Neufeld G, Katzav S, Bar-Shavit R. Oncogenic transformation induces tumor angiogenesis: a role for PAR1 activation. Faseb J. 2003;17:163–74.

    Article  PubMed  CAS  Google Scholar 

  • Yoder MC, Mead LE, Prater D, Krier TR, Mroueh KN, Li F, Krasich R, Temm CJ, Prchal JT, Ingram DA. Re-defining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood. 2006 (Oct. 19). [Epub. ahead of print].

  • Yoon CH, Hur J, Park KW, Kim JH, Lee CS, Oh IY, Kim TY, Cho HJ, Kang HJ, Chae IH, Yang HK, Oh BH, Park YB, Kim HS. Synergistic neovascularization by mixed transplantation of early endothelial progenitor cells and late outgrowth endothelial cells: the role of angiogenic cytokines and matrix metalloproteinases. Circulation. 2005;112:1618–27.

    Article  PubMed  Google Scholar 

  • Zemani F, Benisvy D, Galy-Fauroux I, Lokajczyk A, Colliec-Jouault S, Uzan G, Fischer AM, Boisson-Vidal C. Low-molecular-weight fucoidan enhances the proangiogenic phenotype of endothelial progenitor cells. Biochem Pharmacol. 2005;70:1167–75.

    Article  PubMed  CAS  Google Scholar 

  • Zhang H, Vakil V, Braunstein M, Smith EL, Maroney J, Chen L, Dai K, Berenson JR, Hussain MM, Klueppelberg U, Norin AJ, Akman HO, Ozcelik T, Batuman OA. Circulating endothelial progenitor cells in multiple myeloma: implications and significance. Blood. 2005;105:3286–94.

    Article  PubMed  CAS  Google Scholar 

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Smadja, D.M., Cornet, A., Emmerich, J. et al. Endothelial progenitor cells: Characterization, in vitro expansion, and prospects for autologous cell therapy. Cell Biol Toxicol 23, 223–239 (2007). https://doi.org/10.1007/s10565-007-0177-6

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