Abstract
Recent evidences suggest that endothelial progenitor cells (EPCs) derived from bone marrow (BM) contribute to de novo vessel formation in adults occurring as physiological and pathological responses. Emerging preclinical trials have shown that EPCs home to sites of neovascularization after ischemic events in limb and myocardium. On the basis of these aspects, EPCs are expected to develop as a key strategy of therapeutic applications for the ischemic organs. Such clinical requirements of EPCs will tentatively accelerate the translational research aiming at the devices to acquire the optimized quality and quantity of EPCs. In this review, we attempt to discuss about biological features of EPCs and speculate on the clinical potential of EPCs for therapeutic neovascularization.
Keywords: endothelial progenitor cell (EPC), vasculogenesis, angiogenesis, therapeutic neovascularization, cardiovascular disease, cell therapy
References
- 1. 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]
- 2. Shi Q., Rafii S., Wu M.H., Wijelath E.S., Yu C., Ishida A., Fujita Y., Kothari S., Mohle R., Sauvage L.R., Moore M.A., Storb R.F., Hammond W.P., Evidence for circulating bone marrow‐derived endothelial cells, Blood, 92: 362–367, 1998. [PubMed] [Google Scholar]
- 3. Asahara T., Masuda H., Takahashi T., Kalka C., Pastore C., Silver M., Kearne M., Magner M., Isner J.M., Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization, Circ Res, 85: 221–228, 1999. [DOI] [PubMed] [Google Scholar]
- 4. Gehling U.M., Ergun 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 CD 133‐positive progenitor cells, Blood, 95: 3106–3112, 2000. [PubMed] [Google Scholar]
- 5. Gunsilius E., Petzer A.L., Duba H.C., Kahler C.M., Gastl G., Circulating endothelial cells after transplantation, Lancet, 357: 1449–1450, 2001. [DOI] [PubMed] [Google Scholar]
- 6. 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]
- 7. 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 CD133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors, Blood, 95: 952–958, 2000. [PubMed] [Google Scholar]
- 8. Nieda M., Nicol A., Denning Kendall P., Sweetenham J., Bradley B., Hows J., Endothelial cell precursors are normal components of human umbilical cord blood, Br J Haematol, 98: 775–777, 1997. [DOI] [PubMed] [Google Scholar]
- 9. 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., 105: 1527–1536, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Hatzopoulos A.K., Folkman J., Vasile E., Eiselen G.K., Rosenberg R.D., Isolation and characterization of endothelial progenitor cells from mouse embryos, Development, 125: 1457–1468, 1998. [DOI] [PubMed] [Google Scholar]
- 11. Springer M.L., Chen A.S., Kraft P.E., Bednarski M., Blau H.M., VEGF gene delivery to muscle: potential role for vasculogenesis in adults, Mol. Cell, 2: 549–58, 1998. [DOI] [PubMed] [Google Scholar]
- 12. 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(+)CD133(+) endothelial precursor cells, Circ. Res., 88: 167–174, 2001. [DOI] [PubMed] [Google Scholar]
- 13. Asahara T., Takahashi T., Masuda H., Kalka C., Chen D., Iwaguro H., Inai Y., Silver M., Isner J.M., VEGF contributes to postnatal neovascularization by mobilizing bone marrow‐derived endothelial progenitor cells, EMBO J., 18: 3964–3972, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. 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, 105: 732–738, 2002. [DOI] [PubMed] [Google Scholar]
- 15. Kalka C., Masuda H., Takahashi T., Kalka Moll WM., Silver M., Kearney M., Li T., Isner JM., Asahara T., Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization, Proc. Natl. Acad. Sci. USA, 97: 3422–3427, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Schatteman GC., Hanlon HD., Jiao C., Dodds SG., Christy BA., Blood‐derived angioblasts accelerate blood‐flow restoration in diabetic mice, J. Clin. Invest., 106: 571–578, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. 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]
- 18. Edelberg JM., Tang L., Hattori K., Lyden D., Rafii S., Young adult bone marrow‐derived endothelial precursor cells restore aging‐impaired cardiac angiogenic function, Circ. Res., 90: E89–E93, 2002. [DOI] [PubMed] [Google Scholar]
- 19. Shintani S., Murohara T., Ikeda H., Ueno T., Honma T., Katoh A., Sasaki Ki., 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]
- 20. Bhattacharya V., McSweeney PA., Shi Q., Bruno B., Ishida A., Nash R., Storb RF., Sauvage LR., Hammond WP., Wu MH., Enhanced endothelialization and microvessel formation in polyester grafts seeded with CD34(+) bone marrow cells, Blood, 95: 581–585, 2000. [PubMed] [Google Scholar]
- 21. Kaushal S., Amiel GE., 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]
- 22. Crosby J.R., Kaminski W.E., Schatteman G., Martin P.J., Raines E.W., Seifert R.A., Bowen Pope D.F., Endothelial cells of hematopoietic origin make a significant contribution to adult blood vessel formation, Circ. Res., 87: 728–730, 2000. [DOI] [PubMed] [Google Scholar]
- 23. Murayama T., Tepper O.M., Silver M., Ma H., Losordo D.W., Isner J.M., Asahara T., Kalka C., Determination of bone marrow‐derived endothelial progenitor cell significance in angiogenic growth factor‐induced neovascularization in vivo, Exp. Hematol., 30: 967–972, 2002. [DOI] [PubMed] [Google Scholar]
- 24. Reyes M., Dudek A., Jahagirdar B., Koodie L., Marker P.H., Verfaillie C.M., Origin of endothelial progenitors in human postnatal bone marrow, J. Clin. Invest., 109: 337–346, 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Tamaki T., Akatsuka A., Ando K., Nakamura Y., Matsuzawa H., Hotta T., Roy R.R., Edgerton V.R., Identification of myogenic‐endothelial progenitor cells in the interstitial spaces of skeletal muscle, J. Cell. Biol., 157: 571–577, 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. 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]
- 27. 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: 2781–6, 2002. [DOI] [PubMed] [Google Scholar]
- 28. 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]
- 29. 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., 86: 1198–1202, 2000. [DOI] [PubMed] [Google Scholar]
- 30. Hattori K., Dias S., Heissig B., Hackett NR., Lyden D., Tateno M., Hicklin DJ., Zhu Z., Witte L., Crystal R.G., Moore M.A., Rafii S., Vascular endothelial growth factor and angiopoietin‐1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells, J. Exp. Med., 193: 1005–1014, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. 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]
- 32. Heeschen C., Aicher A., Lehmann R., Fichtlscherer S., Vasa M., Urbich C., Mildner Rihm C., Martin H., Zeiher A.M., Dimmeler S., Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization, Blood, 102: 1340–1346. 2003. [DOI] [PubMed] [Google Scholar]
- 33. Iwakura A., Luedemann C., Shastry S., Hanley A., Kearney M., Aikawa R., Isner J.M., Asahara T., Losordo D.W., Estrogen‐mediated, endothelial nitric oxide synthase‐dependent mobilization of bone marrow‐derived endothelial progenitor cells contributes to reendothelialization after arterial injury, Circulation, 108: 3115–3121, 2003. [DOI] [PubMed] [Google Scholar]
- 34. 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]
- 35. Kureishi Y., Luo Z., Shiojima I., Bialik A., Fulton D., Lefer D.J., Sessa W.C., Walsh K., The HMG‐CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals, Nat. Med., 6: 1004–1010, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. 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]
- 37. 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., 108: 391–397, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. Lyden D., Hattori K., Dias S., Costa C., Blaikie P., Butros L., Chadburn A., Heissig B., Marks W., Witte L., Wu Y., Hicklin D., Zhu Z., Hackett N.R., Crystal RG., Moore M.A., Hajjar K.A., Manova K., Benezra R., Rafii S., Impaired recruitment of bone‐marrow‐derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth, Nat. Med., 7: 1194–1201, 2001. [DOI] [PubMed] [Google Scholar]
- 39. 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]
- 40. Taguchi A., Soma T., Tanaka H., Kanda T., Nishimura H., Yoshikawa H., Tsukamoto Y., Iso H., Fujimori Y., Stern D.M., Naritomi H., Matsuyama T., Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model, J. Clin. Invest., 114: 330–338, 2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41. Nagaya N., Kangawa K., Kanda M., Uematsu M., Horio T., Fukuyama N., Hino J., Harada Shiba M., Okumura H., Tabata Y., Mochizuki N., Chiba Y., Nishioka K., Miyatake K., Asahara T., Hara H., Mori H., Hybrid cell‐gene therapy for pulmonary hypertension based on phagocytosing action of endothelial progenitor cells, Circulation, 108: 889–895, 2003. [DOI] [PubMed] [Google Scholar]