Ischemic Tissue Repair by Autologous Bone Marrow-Derived Stem Cells: Scientific Basis and Preclinical Data

Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 180)

Abstract

The success of therapies targeting acute myocardial ischemia and the aging of the population due to improved general medical care has resulted in an increasing population of patients with chronic myocardial ischemia and congestive heart failure who remain symptomatic despite having exhausted the currently available therapeutic options. In this chapter we review the scientific underpinnings of autologous bone marrow-derived cell therapy and the early clinical experience that has fuelled interest in this approach.

Keywords

Stem cell Bone marrow Angiogenesis Endothelial progenitor Heart failure Ischemia 
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References

  1. Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Theme H, Iwamoto MA, Parke JE, Nguyen MD, Aiello LM, Ferrara N, King GL (1994) Vascular endothelial growth factor in ocular fluids of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331:1480–1487PubMedCrossRefGoogle Scholar
  2. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967PubMedCrossRefGoogle Scholar
  3. Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M, Kearne M, Magner M, Isner JM (1999) Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 85:221–228PubMedGoogle Scholar
  4. Baumgartner I, Rauh G, Pieczek A, Wuensch D, Magner M, Kearney M, Schainfeld R, Isner JM (2000) Lower-extremity edema associated with gene transfer of naked DNA vascular endothelial growth factor. Ann Intern Med 132:880–884PubMedGoogle Scholar
  5. Campbell WB, Johnston JA, Kernick VF, Rutter EA (1994) Lower limb amputation: striking the balance. Ann R Coll Surg Engl 76:205–209PubMedGoogle Scholar
  6. Dawson I, Keller BP, Brand R, Pesch-Batenburg J, Hajo van Bockel J (1995) Late outcomes of limb loss after failed infrainguinal bypass. J Vasc Surg 21:613–622PubMedCrossRefGoogle Scholar
  7. Dimmeler S, Aicher A, Vasa M, Mildner-Rihm C, Adler K, Tiemann M, Rutten H, Fichtlscherer S, Martin H, Zeiher AM (2001) HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clin Invest 108:391–397PubMedCrossRefGoogle Scholar
  8. Eneroth M, Persson BM (1992) Amputation for occlusive arterial disease. A multicenter study of 177 amputees. Int Orthop 16:382–387CrossRefGoogle Scholar
  9. Flamme I, Risau W (1992) Induction of vasculogenesis and hematopoiesis in vitro. Development 116:435–439PubMedGoogle Scholar
  10. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186PubMedCrossRefGoogle Scholar
  11. Fuchs S, Baffour R, Zhou YF, Shou M, Pierre A, Tio FO, Weissman NJ, Leon MB, Epstein SE, Kornowski R (2001) Transendocardial delivery of autologous bone marrow enhances collateral perfusion and regional function in pigs with chronic experimental myocardial ischemia. J Am Coll Cardiol 37:1726–1732PubMedCrossRefGoogle Scholar
  12. Gilbert SF (1997) Developmental biology, fourth edn. Sinauer Associates, SunderlandGoogle Scholar
  13. Hamano K, Nishida M, Hirata K, Mikamo A, Li TS, Harada M, Miura T, Matsuzaki M, Esato K (2001) Local implantation of autologous bone marrow cells for therapeutic angiogenesis in patients with ischemic heart disease: clinical trials and preliminary results. Jpn Circ J 65:845–847PubMedCrossRefGoogle Scholar
  14. Hariawala MD, Horowitz JR, Esakof D, Sheriff DD, Walter DH, Keyt B, Isner JM, Symes JF (1996) VEGF improves myocardial blood flow but produces EDRF-mediated hypotension in porcine hearts. J Surg Res 63:77–82PubMedCrossRefGoogle Scholar
  15. Harley CB, Futcher AB, Greider CW (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345:458–460PubMedCrossRefGoogle Scholar
  16. Harrington L, Zhou W, McPhail T, Oulton R, Yeung DS, Mar V, Bass MB, Robinson MO (1997) Human telomerase contains evolutionarily conserved catalytic and structural subunits. Genes Dev 11:3109–3115PubMedGoogle Scholar
  17. Hastie ND, Dempster M, Dunlop MG, Thompson AM, Green DK, Allshire RC (1990) Telomere reduction in human colorectal carcinoma and with ageing. Nature 346:866–868PubMedCrossRefGoogle Scholar
  18. Hattori K, Heissig B, Tashiro K, Honjo T, Tateno M, Shieh JH, Hackett NR, Quitoriano MS, Crystal RG, Rafii S, Moore MA (2001) Plasma elevation of stromal cell-derived factor-1 induces mobilization of mature and immature hematopoietic progenitor and stem cells. Blood 97:3354–3360PubMedCrossRefGoogle Scholar
  19. Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, Finkel T (2003) Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 348:593–600PubMedCrossRefGoogle Scholar
  20. Horowitz JR, Rivard A, van der Zee R, Hariawala MD, Sheriff DD, Esakof DD, Chaudhry M, Symes JF, Isner JM (1997) Vascular endothelial growth factor/vascular permeability factor produces nitric oxide-dependent hypotension. Arterioscler Thromb Vasc Biol 17:2793–2800PubMedGoogle Scholar
  21. Iwaguro H, Yamaguchi J, Kalka C, Murasawa S, Masuda H, Hayashi S, Silver M, Li T, Isner JM, Asahara T (2002) Endothelial progenitor cell vascular endothelial growth factor gene transfer for vascular regeneration. Circulation 105:732–738PubMedCrossRefGoogle Scholar
  22. Kamihata H, Matsubara H, Nishiue T, Fujiyama S, Tsutsumi Y, Ozono R, Masaki H, Mori Y, Iba O, Tateishi E, Kosaki A, Shintani S, Murohara T, Imaizumi T, Iwasaka T (2001) Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation 104:1046–1052PubMedGoogle Scholar
  23. Kawamoto A, Gwon HC, Iwaguro H, Yamaguchi JI, Uchida S, Masuda H, Silver M, Ma H, Kearney M, Isner JM, Asahara T (2001) Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia. Circulation 103:634–637PubMedGoogle Scholar
  24. Kawamoto A, Tkebuchava T, Yamaguchi J, Nishimura H, Yoon YS, Milliken C, Uchida S, Masuo O, Iwaguro H, Ma H, Hanley A, Silver M, Kearney M, Losordo DW, Isner JM, Asahara T (2003) Intramyocardial transplantation of autologous endothelial progenitor cells for therapeutic neovascularization of myocardial ischemia. Circulation 107:461–468PubMedCrossRefGoogle Scholar
  25. Kilian A, Bowtell DD, Abud HE, Hime GR, Venter DJ, Keese PK, Duncan EL, Reddel RR, Jefferson RA (1997) Isolation of a candidate human telomerase catalytic subunit gene, which reveals complex splicing patterns in different cell types. Hum Mol Genet 6:2011–2019PubMedCrossRefGoogle Scholar
  26. Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, Homma S, Edwards NM, Itescu S (2001) Neovascularization of ischemic myocardium by human bone marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 7:430–436PubMedCrossRefGoogle Scholar
  27. Lataillade JJ, Clay D, Dupuy C, Rigal S, Jasmin C, Bourin P, Le Bousse-Kerdiles MC (2000) Chemokine SDF-1 enhances circulating CD34(+) cell proliferation in synergy with cytokines: possible role in progenitor survival. Blood 95:756–768PubMedGoogle Scholar
  28. Mangi AA, Noiseux N, Kong D, He H, Rezvani M, Ingwall JS, Dzau VJ (2003) Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med 9:1195–1201PubMedCrossRefGoogle Scholar
  29. Meyerson M, Counter CM, Eaton EN, Ellisen LW, Steiner P, Caddle SD, Ziaugra L, Beijersbergen RL, Davidoff MJ, Liu Q, Bacchetti S, Haber DA, Weinberg RA (1997) hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell 90:785–795PubMedCrossRefGoogle Scholar
  30. Mohle R, Bautz F, Rafii S, Moore MA, Brugger W, Kanz L (1998) The chemokine receptor CXCR-4 is expressed on CD34+ hematopoietic progenitors and leukemic cells and mediates transendothelial migration induced by stromal cell-derived factor-1. Blood 91:4523–4530PubMedGoogle Scholar
  31. Moulton KS, Heller E, Konerding MA, Flynn E, Palinski W, Folkman J (1999) Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E-deficient mice. Circulation 99:1726–1732PubMedGoogle Scholar
  32. Murasawa S, Llevadot J, Silver M, Isner JM, Losordo DW, Asahara T (2002) Constitutive human telomerase reverse transcriptase expression enhances regenerative properties of endothelial progenitor cells. Circulation 106:1133–1139PubMedCrossRefGoogle Scholar
  33. Murohara T, Ikeda H, Duan J, Shintani S, Sasaki KI, Eguchi H, Onitsuka I, Matsui K, Imaizumi T (2000) Transplanted cord blood-derived endothelial precursor cells augment postnatal neovascularization. J Clin Invest 105:1527–1536PubMedGoogle Scholar
  34. Nakamura TM, Morin GB, Chapman KB, Weinrich SL, Andrews WH, Lingner J, Harley CB, Cech TR (1997) Telomerase catalytic subunit homologs from fission yeast and human. Science 277:955–959PubMedCrossRefGoogle Scholar
  35. Rafii S (2000) Circulating endothelial precursors: mystery, reality, and promise. J Clin Invest 105:17–19PubMedCrossRefGoogle Scholar
  36. Rajagopalan S, Mohler ER 3rd, Lederman RJ, Mendelsohn FO, Saucedo JF, Goldman CK, Blebea J, Macko J, Kessler PD, Rasmussen HS, Annex BH (2003) Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease: a phase II randomized, double-blind, controlled study of adenoviral delivery of vascular endothelial growth factor 121 in patients with disabling intermittent claudication. Circulation 108:1933–1938PubMedCrossRefGoogle Scholar
  37. Risau W (1995) Differentiation of endothelium. FASEB J 9:926–933PubMedGoogle Scholar
  38. Risau W, Flamme I (1995) Vasculogenesis. Annu Rev Cell Dev Biol 11:73–91PubMedCrossRefGoogle Scholar
  39. Salcedo R, Wasserman K, Young HA, Grimm MC, Howard OM, Anver MR, Kleinman HK, Murphy WJ, Oppenheim JJ (1999) Vascular endothelial growth factor and basic fibroblast growth factor induce expression of CXCR4 on human endothelial cells: in vivo neovascularization induced by stromal-derived factor-1alpha. Am J Pathol 154:1125–1135PubMedGoogle Scholar
  40. Shake JG, Gruber PJ, Baumgartner WA, Senechal G, Meyers J, Redmond JM, Pittenger MF, Martin BJ (2002) Mesenchymal stem cell implantation in a swine myocardial infarct model: engraftment and functional effects. Ann Thorac Surg 73:1919–1925; discussion 1926PubMedCrossRefGoogle Scholar
  41. Shi Q, Rafii S, Wu MH, Wijelath ES, Yu C, Ishida A, Fujita Y, Kothari S, Mohle R, Sauvage LR, Moore MA, Storb RF, Hammond WP (1998) Evidence for circulating bone marrow-derived endothelial cells. Blood 92:362–367PubMedGoogle Scholar
  42. Shintani S, Kusano K, Ii M, Iwakura A, Heyd L, Curry C, Wecker A, Gavin M, Ma H, Kearney M, Silver M, Thorne T, Murohara T, Losordo DW (2006) Synergistic effect of combined intramyocardial CD34+ cells and VEGF2 gene therapy after MI. Nat Clin Pract Cardiovasc Med 3[Suppl 1]:S123–S128PubMedCrossRefGoogle Scholar
  43. Skinner JA, Cohen AT (1996) Amputation for premature peripheral atherosclerosis: do young patients do better? Lancet 348:1396PubMedCrossRefGoogle Scholar
  44. Suzuki K, Murtuza B, Smolenski RT, Sammut IA, Suzuki N, Kaneda Y, Yacoub MH (2001) Cell transplantation for the treatment of acute myocardial infarction using vascular endothelial growth factor-expressing skeletal myoblasts. Circulation 104:I207–I212PubMedGoogle Scholar
  45. Takahashi T, Kalka C, Masuda H, Chen D, Silver M, Kearney M, Magner M, Isner JM, Asahara T (1999) Ischemia-and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med 5:434–438PubMedCrossRefGoogle Scholar
  46. Tepper OM, Galiano RD, Capla JM, Kalka C, Gagne PJ, Jacobowitz GR, Levine JP, Gurtner GC (2002) Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation 106:2781–2786PubMedCrossRefGoogle Scholar
  47. Thurston G, Suri C, Smith K, McClain J, Sato TN, Yancopoulos GD, McDonald DM (1999) Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 286:2511–2514PubMedCrossRefGoogle Scholar
  48. Vale PR, Rauh G, Wuensch DI, Pieczek A, Schainfeld RM (1998) Influence of vascular endothelial growth factor on diabetic retinopathy. Circulation 17:I–353Google Scholar
  49. Van Belle E, Tio F, Couffinhal T, Maillard L, Passeri J, Isner JM (1996) Stent endothelialization: time course, impact of local catheter delivery, feasibility of recombinant protein administration, and response to cytokine expedition. Circulation 94:I–259Google Scholar
  50. Van Belle E, Tio FO, Chen D, Maillard L, Kearney M, Isner JM (1997) Passivation of metallic stents following arterial gene transfer of phVEGF165 inhibits thrombus formation and intimal thickening. J Am Coll Cardiol 29:1371–1379PubMedCrossRefGoogle Scholar
  51. Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H, Zeiher AM, Dimmeler S (2001) Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 89:E1–E7PubMedGoogle Scholar
  52. Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, Link A, Bohm M, Nickenig G (2005) Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 353:999–1007PubMedCrossRefGoogle Scholar
  53. Wright WE, Shay JW (1992) The two-stage mechanism controlling cellular senescence and immortalization. Exp Gerontol 27:383–389PubMedCrossRefGoogle Scholar
  54. Yamaguchi J, Kusano KF, Masuo O, Kawamoto A, Silver M, Murasawa S, Bosch-Marce M, Masuda H, Losordo DW, Isner JM, Asahara T (2003) Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization. Circulation 107:1322–1328PubMedCrossRefGoogle Scholar
  55. Yoon YS, Park JS, Tkebuchava T, Luedeman C, Losordo DW (2004) Unexpected severe calcification after transplantation of bone marrow cells in acute myocardial infarction. Circulation 109:3154–3157PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2007

Authors and Affiliations

  1. 1.Division of CardiologyCaritas St. Elizabeth’s Medical CenterBostonUSA
  2. 2.Northwestern University Feinberg School of MedicineChicagoUSA

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