The Emerging Role of the Bone Marrow-Derived Stem Cells in (Therapeutic) Angiogenesis

Summary

Proper formation of blood vessels (angiogenesis) is essential for development, reproduction and wound healing. When derailed, angiogenesis contributes to numerous lifethreatening disorders. While research has generally been focusing on the two main vascular cell types (endothelial and smooth muscle cells), recent evidence indicates that bone marrow may also contribute to this process, both in the embryo and the adult. Novel vascular progenitors, even one common to both endothelial and smooth muscle cells, have been identified in the embryo. An exciting observation is that endothelial precursors have also been identified in the adult bone marrow. Transplantation studies revealed that these precursors as well as other bone marrow-derived cells contribute to the growth of endothelium-lined vessels (angiogenesis) as well as the expansion of pre-existing collaterals (arteriogenesis) in ischemic disease. These findings have raised hopes that bone marrow-derived cells might one day become useful for cell-based angiogenic therapy.

Key words

Angiogenesis - bone marrow cells - endothelial cells - multipotent progenitors - growth factors

• References

• 1 Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000; 407: 249-57.
• 2 Eichmann A, Corbel C, Le Douarin NM. Segregation of the embryonic vascular and hemopoietic systems. Biochem Cell Biol 1998; 76: 939-46.
• 3 Pardanaud L, Luton D, Prigent M, Bourcheix LM, Catala M, DieterlenLievre E. Two distinct endothelial lineages in ontogeny, one of them related to hemopoiesis. Development 1996; 122: 1363-71.
• 4 Krah K, Mironov V, Risau W, Flamme I. Induction of vasculogenesis in quail blastodisc-derived embryoid bodies. Dev Biol 1994; 164: 123-32.
• 5 Carmeliet P. Developmental biology. Controlling the cellular brakes. Nature 1999; 401: 657-8.
• 6 Vandenbunder B, Pardanaud L, Jaffredo T, Mirabel MA, Stehelin D. Complementary patterns of expression of c-ets 1, c-myb and c-myc in the blood-forming system of the chick embryo. Development 1989; 107: 265-74.
• 7 Thomas PQ, Brown A, Beddington RS. Hex: a homeobox gene revealing peri-implantation asymmetry in the mouse embryo and an early transient marker of endothelial cell precursors. Development 1998; 125: 85-94.
• 8 Belotti D, Clausse N, Flagiello D, Alami Y, Daukandt M, Deroanne C. et al. Expression and modulation of homeobox genes from cluster B in endothelial cells. Lab Invest 1998; 78: 1291-9.
• 9 Boudreau N, Andrews C, Srebrow A, Ravanpay A, Cheresh DA. Induction of the angiogenic phenotype by Hox D3. J Cell Biol 1997; 139: 257-64.
• 10 Elefanty AG, Robb L, Birner R, Begley CG. Hematopoietic-specific genes are not induced during in vitro differentiation of scl-null embryonic stem cells. Blood 1997; 90: 1435-47.
• 11 Robertson SM, Kennedy M, Shannon JM, Keller G. A transitional stage in the commitment of mesoderm to hematopoiesis requiring the transcription factor SCL/tal-1. Development 2000; 127: 2447-59.
• 12 Lyden D, Young AZ, Zagzag D, Yan W, Gerald W, O’Reilly R. et al. Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts. Nature 1999; 401: 670-7.
• 13 Yamaguchi TP, Dumont DJ, Conlon RA, Breitman ML, Rossant J. flk-1, an flt-related receptor tyrosine kinase is an early marker for endothelial cell precursors. Development 1993; 118: 489-98.
• 14 Choi K, Kennedy M, Kazarov A, Papadimitriou JC, Keller G. A common precursor for hematopoietic and endothelial cells. Development 1998; 125: 725-32.
• 15 Cleaver O, Krieg PA. VEGF mediates angioblast migration during development of the dorsal aorta in Xenopus. Development 1998; 125: 3905-14.
• 16 Ash JD, Overbeek PA. Lens-specific VEGF-A expression induces angioblast migration and proliferation and stimulates angiogenic remodeling. Dev Biol 2000; 223: 383-98.
• 17 Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M. et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 1996; 380: 435-9.
• 18 Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML. et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 1995; 376: 62-6.
• 19 Fong GH, Zhang L, Bryce DM, Peng J. Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knock-out mice. Development 1999; 126: 3015-25.
• 20 Hatzopoulos A, Folkman J, Vasile E, Eiselen GK, Rosenberg RD. Isolation and characterization of endothelial progenitor cells from mouse embryos. Development 1998; 125: 1457-68.
• 21 Zhong TP, Rosenberg M, Mohideen MA, Weinstein B, Fishman MC. Gridlock, an HLH gene required for assembly of the aorta in zebrafish. Science 2000; 287: 1820-4.
• 22 Shutter JR, Scully S, Fan W, Richards WG, Kitajewski J, Deblandre GA. et al. Dll4, a novel Notch ligand expressed in arterial endothelium. Genes Dev 2000; 14: 1313-8.
• 23 Krebs LT, Xue Y, Norton CR, Shutter JR, Maguire M, Sundberg JP. et al. Notch signaling is essential for vascular morphogenesis in mice. Genes Dev 2000; 14: 1343-52.
• 24 Xue Y, Gao X, Lindsell CE, Norton CR, Chang B, Hicks C. et al. Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1. Hum Mol Genet 1999; 8: 723-30.
• 25 Leimeister C, Schumacher N, Steidl C, Gessler M. Analysis of HeyL expression in wild-type and Notch pathway mutant mouse embryos. Mech Dev 2000; 98: 175-8.
• 26 Wilkinson DG. Eph receptors and ephrins: regulators of guidance and assembly. Int Rev Cytol 2000; 196: 177-244.
• 27 Gale NW, Yancopoulos GD. Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development. Genes Dev 1999; 13: 1055-66.
• 28 McBride JL, Ruiz JC. Ephrin-A1 is expressed at sites of vascular development in the mouse. Mech Dev 1998; 77: 201-4.
• 29 Helbling PM, Saulnier DM, Brandli AW. The receptor tyrosine kinase EphB4 and ephrin-B ligands restrict angiogenic growth of embryonic veins in Xenopus laevis. Development 2000; 127: 269-78.
• 30 Adams RH, Wilkinson GA, Weiss C, Diella F, Gale NW, Deutsch U. et al. Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev 1999; 13: 295-306.
• 31 Wang HU, Chen ZF, Anderson DJ. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 1998; 93: 741-53.
• 32 Ekman N, Arighi E, Rajantie I, Saharinen P, Ristimaki A, Silvennoinen O. et al. Bmx tyrosine kinase is specifically expressed in the endocardium and the endothelium of large arteries. Circulation 1997; 96: 1729-32.
• 33 Thurston G, Baluk P, McDonald DM. Determinants of endothelial cell phenotype in venules. Microcirculation 2000; 7: 67-80.
• 34 Lindahl P, Hellstrom M, Kalen M, Betsholtz C. Endothelial-perivascular cell signaling in vascular development: lessons from knockout mice. Curr Opin Lipidol 1998; 9: 407-11.
• 35 Rubin LL, Staddon JM. The cell biology of the blood-brain barrier. Annu Rev Neurosci 1999; 22: 11-28.
• 36 Tsukita S, Furuse M. Occludin and claudins in tight-junction strands: leading or supporting players?. Trends Cell Biol 1999; 9: 268-73.
• 37 Bazzoni G, Martinez Estrada O, Dejana E. Molecular structure and functional role of vascular tight junctions. Trends Cardiovasc Med 1999; 9: 147-52.
• 38 Risau W. Differentiation of endothelium. FASEB J 1995; 9: 926-33.
• 39 Risau W. Development and differentiation of endothelium. Kidney Int Suppl 1998; 67: S3-6.
• 40 Schweitzer KM, Drager AM, Van der Valk P, Thijsen SF, Zevenbergen A, Theijsmeijer AP. et al. Constitutive expression of E-selectin and vascular cell adhesion molecule-1 on endothelial cells of hematopoietic tissues. Am J Pathol 1996; 148: 165-75.
• 41 Jacobsen K, Kravitz J, Kincade PW, Osmond DG. Adhesion receptors on bone marrow stromal cells: in vivo expression of vascular cell adhesion molecule-1 by reticular cells and sinusoidal endothelium in normal and gamma-irradiated mice. Blood 1996; 87: 73-82.
• 42 Naiyer A, Jo Dy, Ahn J, Mohle R, Peichev M, Lam G. et al. Stromal derived factor-1-induced chemokinesis of cord blood CD34(+) cells (long-term culture-initiating cells) through endothelial cells is mediated by E-selectin. Blood 1999; 94: 4011-9.
• 43 Prosper F, Stroncek D, McCarthy JB, Verfaillie CM. Mobilization and homing of peripheral blood progenitors is related to reversible downregulation of alpha4 beta1 integrin expression and function. J Clin Invest 1998; 101: 2456-67.
• 44 Partanen TA, Arola J, Saaristo A, Jussila L, Ora A, Miettinen M. et al. VEGF-C and VEGF-D expression in neuroendocrine cells and their receptor, VEGFR-3, in fenestrated blood vessels in human tissues. FASEB J 2000; 14: 2087-96.
• 45 Liu ZY, Ganju RK, Wang JF, Schweitzer K, Weksler B, Avraham S. et al. Characterization of signal transduction pathways in human bone marrow endothelial cells. Blood 1997; 90: 2253-9.
• 46 Hobbs SK, Monsky WL, Yuan F, Roberts WG, Griffin L, Torchilin VP. et al. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc Natl Acad Sci USA 1998; 95: 4607-12.
• 47 Hashizume H, Baluk P, Morikawa S, McLean JW, Thurston G, Roberge S. et al. Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol 2000; 156: 1363-80.
• 48 Dvorak HF. VPF/VEGF and the angiogenic response. Semin Perinatol 2000; 24: 75-8.
• 49 Jain RK, Safabakhsh N, Sckell A, Chen Y, Jiang P, Benjamin L. et al. Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: role of vascular endothelial growth factor. Proc Natl Acad Sci USA 1998; 95: 10820-5.
• 50 Fukumura D, Yuan F, Monsky WL, Chen Y, Jain RK. Effect of host microenvironment on the microcirculation of human colon adenocarcinoma. Am J Pathol 1997; 151: 679-88.
• 51 Fukumura D, Xavier R, Sugiura T, Chen Y, Park EC, Lu N. et al. Tumor induction of VEGF promoter activity in stromal cells. Cell 1998; 94: 715-25.
• 52 Fidler IJ. Modulation of the organ microenvironment for treatment of cancer metastasis. J Natl Cancer Inst 1995; 87: 1588-92.
• 53 Jain RK, Munn LL. Leaky vessels?. Call Ang1! Nat Med 2000; 6: 131-2.
• 54 Eliceiri BP, Cheresh DA. The role of alphav integrins during angiogenesis: insights into potential mechanisms of action and clinical development. J Clin Invest 1999; 103: 1227-30.
• 55 Huang X, Molema G, King S, Watkins L, Edgington TS, Thorpe PE. Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature. Science 1997; 275: 547-50.
• 56 Arap W, Pasqualini R, Ruoslahti E. Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science 1998; 279: 377-80.
• 57 Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Peter J. et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol 1999; 155: 739-52.
• 58 Chang YS, Di Tomaso E, McDonald DM, Jones R, Jain RK, Munn LL. Mosaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood. Proc Natl Acad Sci USA 2000; 97: 14608-13.
• 59 Folberg R, Hendrix MJ, Maniotis AJ. Vasculogenic mimicry and tumor angiogenesis. Am J Pathol 2000; 156: 361-81.
• 60 Takakura N, Watanabe T, Suenobu S, Yamada Y, Noda T, Ito Y. et al. A role for hematopoietic stem cells in promoting angiogenesis. Cell 2000; 102: 199-209.
• 61 Rucker HK, Wynder HJ, Thomas WE. Cellular mechanisms of CNS pericytes. Brain Res Bull 2000; 51: 363-9.
• 62 Gittenberger-de Groot AC, DeRuiter MC, Bergwerff M, Poelmann RE. Smooth muscle cell origin and its relation to heterogeneity in development and disease. Arterioscler Thromb Vasc Biol 1999; 19: 1589-94.
• 63 Nakajima Y, Mironov V, Yamagishi T, Nakamura H, Markwald RR. Expression of smooth muscle alpha-actin in mesenchymal cells during formation of avian endocardial cushion tissue: a role for transforming growth factor beta3. Dev Dyn 1997; 209: 296-309.
• 64 Hellstrom M, Kaln M, Lindahl P, Abramsson A, Betsholtz C. Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 1999; 126: 3047-55.
• 65 Hirschi KK, Rohovsky SA, D’Amore PA. PDGF, TGF-beta, and heterotypic cell-cell interactions mediate endothelial cell-induced recruitment of 10T1/2 cells and their differentiation to a smooth muscle fate [published erratum appears in J Cell Biol 1998; 141: 1287]. J Cell Biol 1998; 141: 805-14.
• 66 Dettman RW, Denetclaw Jr W, Ordahl CP, Bristow J. Common epicardial origin of coronary vascular smooth muscle, perivascular fibroblasts, and intermyocardial fibroblasts in the avian heart. Dev Biol 1998; 193: 169-81.
• 67 Landerholm TE, Dong XR, Lu J, Belaguli NS, Schwartz RJ, Majesky MW. A role for serum response factor in coronary smooth muscle differentiation from proepicardial cells. Development 1999; 126: 2053-62.
• 68 Creazzo TL, Godt RE, Leatherbury L, Conway SJ, Kirby ML. Role of cardiac neural crest cells in cardiovascular development. Annu Rev Physiol 1998; 60: 267-86.
• 69 Yamashita J, Itoh H, Hirashima M, Ogawa M, Nishikawa S, Yurugi T. et al. Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature 2000; 408: 92-6.
• 70 Eisenberg LM, Markwald RR. Molecular regulation of atrioventricular valvuloseptal morphogenesis. Circ Res 1995; 77: 1-6.
• 71 Asahara T, Takahashi T, Masuda H, Kalda C, Chen D, Iwaguro H. et al. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. Embo J 1999; 18: 3964-72.
• 72 Kalka C, Masuda H, Takahashi T, Gordon R, Tepper O, Gravereaux E. et al. Vascular endothelial growth factor(165) gene transfer augments circulating endothelial progenitor cells in human subjects. Circ Res 2000; 86: 1198-202.
• 73 Rafii S. Circulating endothelial precursors: mystery, reality, and promise. J Clin Invest 2000; 105: 17-9.
• 74 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.
• 75 Peichev M, Naiyer AJ, Pereira D, Zhu Z, Lane WJ, Williams M. et al. Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood 2000; 95: 952-8.
• 76 Shi Q, Rafii S, Wu MH, Wijelath ES, Yu C, Ishida A. et al. Evidence for circulating bone marrow-derived endothelial cells. Blood 1998; 92: 362-7.
• 77 Rafii S, Oz MC, Seldomridge JA, Ferris B, Asch AS, Nachman RL. et al. Characterization of hematopoietic cells arising on the textured surface of left ventricular assist devices. Ann Thorac Surg 1995; 60: 1627-32.
• 78 Bhattacharya V, McSweeney PA, Shi Q, Bruno B, Ishida A, Nash R. et al. Enhanced endothelialization and microvessel formation in polyester grafts seeded with CD34(+) bone marrow cells. Blood 2000; 95: 581-5.
• 79 Gehling UM, Ergun S, Schumacher U, Wagener C, Pantel K, Otte M. et al. In vitro differentiation of endothelial cells from AC133-positive progenitor cells. Blood 2000; 95: 3106-12.
• 80 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.
• 81 Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M. et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 1999; 85: 221-8.
• 82 Gunsilius E, Duba HC, Petzer AL, Kahler CM, Grunewald K, Stockhammer G. et al. Evidence from a leukaemia model for maintenance of vascular endothelium by bone-marrow-derived endothelial cells. Lancet 2000; 355: 1688-91.
• 83 Isner JM, Asahara T. Angiogenesis and vasculogenesis as therapeutic strategies for postnatal neovascularization. J Clin Invest 1999; 103: 1231-6.
• 84 Takahashi T, Kalka C, Masuda H, Chen D, Silver M, Kearney M. et al. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med 1999; 5: 434-8.
• 85 Gill M, Dias S, Hattori K, Rivera ML, Hicklin D, Witte L. et al. Vascular trauma induces rapid but transient mobilization of VEGFR2(+)AC133(+) endothelial precursor cells. Circ Res 2001; 88: 167-74.
• 86 Bautz F, Rafii S, Kanz L, Mohle R. Expression and secretion of vascular endothelial growth factor-A by cytokine-stimulated hematopoietic progenitor cells. Possible role in the hematopoietic microenvironment. Exp Hematol 2000; 28: 700-6.
• 87 Lundberg LG, Lerner R, Sundelin P, Rogers R, Folkman J, Palmblad J. Bone marrow in polycythemia vera, chronic myelocytic leukemia, and myelofibrosis has an increased vascularity [published erratum appears in Am J Pathol 2000; 157: 690]. Am J Pathol 2000; 157: 15-9.
• 88 Polverini PJ. Role of the macrophage in angiogenesis-dependent diseases. EXS 1997; 79: 11-28.
• 89 Sunderkotter C, Steinbrink K, Goebeler M, Bhardwaj R, Sorg C. Macrophages and angiogenesis. J Leukoc Biol 1994; 55: 410-22.
• 90 Browder T, Folkman J, Pirie-Shepherd S. The hemostatic system as a regulator of angiogenesis. J Biol Che 2000; 275: 1521-4.
• 91 Pinedo HM, Verheul HM, D’Amato RJ, Folkman J. Involvement of platelets in tumour angiogenesis?. Lancet 1998; 352: 1775-7.
• 92 Bajou K, Noel A, Gerard RD, Masson V, Brunner N, Holst-Hansen C. et al. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat Med 1998; 4: 923-8.
• 93 Seljelid R, Jozefowski S, Sveinbjornsson B. Tumor stroma. Anticancer Res 1999; 19: 4809-22.
• 94 Schaper W, Ito WD. Molecular mechanisms of coronary collateral vessel growth. Circ Res 1996; 79: 911-9.
• 95 Coussens LM, Raymond WW, Bergers G, Laig-Webster M, Behrendtsen O, Werb Z. et al. Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev 1999; 13: 1382-97.
• 96 Heymans S, Luttun A, Nuyens D, Theilmeier G, Creemers E, Moons L. et al. Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. Nat Med 1999; 5: 1135-42.
• 97 Carmeliet P, Collen D. Development and disease in proteinase-deficient mice: role of the plasminogen, matrix metalloproteinase and coagulation system. Thromb Res 1998; 91: 255-85.
• 98 Hunt JS, Petroff MG, Burnett TG. Uterine leukocytes: key players in pregnancy. Semin Cell Dev Biol 2000; 11: 127-37.
• 99 Wang C, Umesaki N, Nakamura H, Tanaka T, Nakatani K, Sakaguchi I. et al. Expression of vascular endothelial growth factor by granulated metrial gland cells in pregnant murine uteri. Cell Tissue Res 2000; 300: 285-93.
• 100 Melder RJ, Koenig GC, Witwer BP, Safabakhsh N, Munn LL, Jain RK. During angiogenesis, vascular endothelial growth factor and basic fibro-blast growth factor regulate natural killer cell adhesion to tumor endothelium. Nat Med 1996; 2: 992-7.
• 101 Metcalfe DD, Baram D, Mekori YA. Mast cells. Physiol Rev 1997; 77: 1033-79.
• 102 Starkey JR, Crowle PK, Taubenberger S. Mast-cell-deficient W/Wv mice exhibit a decreased rate of tumor angiogenesis. Int J Cancer 1988; 42: 48-52.
• 103 Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K. et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2000; 2: 737-44.
• 104 Buschmann I, Schaper W. The pathophysiology of the collateral circulation (arteriogenesis). J Pathol 2000; 190: 338-42.
• 105 Hamano K, Li TS, Kobayashi T, Kobayashi S, Matsuzaki M, Esato K. Angiogenesis induced by the implantation of self-bone marrow cells: a new material for therapeutic angiogenesis. Cell Transplant 2000; 9: 439-43.
• 106 Kobayashi T, Hamano K, Li TS, Katoh T, Kobayashi S, Matsuzaki M. et al. Enhancement of angiogenesis by the implantation of self bone marrow cells in a rat ischemic heart model. J Surg Res 2000; 89: 189-95.
• 107 Tomita S, Li RK, Weisel RD, Mickle DA, Kim EJ, Sakai T. et al. Auto-logous transplantation of bone marrow cells improves damaged heart function. Circulation 1999; 100: II247-56.
• 108 Kalka C, Masuda H, Takahashi T, Kalka-Moll WM, Silver M, Kearney M. et al. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci USA 2000; 97: 3422-7.
• 109 Kalka C, Tehrani H, Laudenberg B, Vale PR, Isner JM, Asahara T. et al. VEGF gene transfer mobilizes endothelial progenitor cells in patients with inoperable coronary disease. Ann Thorac Surg 2000; 70: 829-34.