Abstract
Mesenchymal stem cells (MSC) are adult stem cells with capacity for self-renewal and multi-lineage differentiation. Initially described in bone marrow, MSC are also present in other organs and tissues. From a therapeutic perspective, facilitated by the ease of preparation and immunologic privilege, MSC are emerging as an extremely promising therapeutic agent for tissue regeneration and repair. Studies in animal models of myocardial infarction have demonstrated the ability of transplanted MSC to engraft and differentiate into cardiomyocytes and vasculature cells. Most importantly, engrafted MSC secrete a wide array of soluble factors that mediate beneficial paracrine effects and greatly contribute to cardiac repair. Together, these properties can be harnessed to both prevent and reverse remodeling in the ischemically injured ventricle. In proof-of-concept and phase I clinical trials, MSC therapy improved left ventricular function, induced reverse remodeling, and decreased scar size. This chapter reviews the current understanding of MSC biology and mechanism of action in cardiac repair of MSC therapy for cardiac disease.
Keywords
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Kannel WB (2000) Incidence and epidemiology of heart failure. Heart Fail Rev 5:167–173
Mosterd A, Hoes AW (2007) Clinical epidemiology of heart failure. Heart 93:1137–1146
McMurray JJ, Pfeffer MA (2005) Heart failure. Lancet 365:1877–1889
Sun Y, Weber KT (2000) Infarct scar: a dynamic tissue. Cardiovasc Res 46:250–256
Anversa P, Kajstura J (1998) Myocyte cell death in the diseased heart. Circ Res 82:1231–1233
Beltrami AP, Urbanek K, Kajstura J, Yan SM, Finato N, Bussani R, Nadal-Ginard B, Silvestri F, Leri A, Beltrami CA, Anversa P (2001) Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med 344:1750–1757
Kajstura J, Leri A, Finato N, Di Loreto C, Beltrami CA, Anversa P (1998) Myocyte proliferation in end-stage cardiac failure in humans. Proc Natl Acad Sci U S A 95:8801–8805
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 (2003) Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114:763–776
Leri A, Kajstura J, Anversa P (2005) Cardiac stem cells and mechanisms of myocardial regeneration. Physiol Rev 85:1373–1416
Parmacek MS, Epstein JA (2005) Pursuing cardiac progenitors: regeneration redux. Cell 120:295–298
Deb A, Wang S, Skelding KA, Miller D, Simper D, Caplice NM (2003) Bone marrow-derived cardiomyocytes are present in adult human heart: A study of gender-mismatched bone marrow transplantation patients. Circulation 107:1247–1249
Jackson KA, Majka SM, Wang H, Pocius J, Hartley CJ, Majesky MW, Entman ML, Michael LH, Hirschi KK, Goodell MA (2001) Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest 107:1395–1402
Cohnheim JF (1867) Uber Entzundung und Eiturung. Virchows Arch Pathol Anat Physiol Klin Med 40:1–79
LaBarge MA, Blau HM (2002) Biological progression from adult bone marrow to mononucleate muscle stem cell to multinucleate muscle fiber in response to injury. Cell 111:589–601
Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, Hedrick MH (2001) Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 7:211–228
Campagnoli C, Roberts IA, Kumar S, Bennett PR, Bellantuono I, Fisk NM (2001) Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood 98:2396–2402
Lyngbaek S, Schneider M, Hansen JL, Sheikh SP (2007) Cardiac regeneration by resident stem and progenitor cells in the adult heart. Basic Res Cardiol 102:101–114
Urbanek K, Torella D, Sheikh F, De Angelis A, Nurzynska D, Silvestri F, Beltrami CA, Bussani R, Beltrami AP, Quaini F, Bolli R, Leri A, Kajstura J, Anversa P (2005) Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failure. Proc Natl Acad Sci U S A 102:8692–8697
Bollini S, Smart N, Riley PR (2011) Resident cardiac progenitor cells: at the heart of regeneration. J Mol Cell Cardiol 50:296–303
Coppen SR, Fukushima S, Shintani Y, Takahashi K, Varela-Carver A, Salem H, Yashiro K, Yacoub MH, Suzuki K (2008) A factor underlying late-phase arrhythmogenicity after cell therapy to the heart: global downregulation of connexin43 in the host myocardium after skeletal myoblast transplantation. Circulation 118:S138–S144
Eisen HJ (2008) Skeletal myoblast transplantation: no MAGIC bullet for ischemic cardiomyopathy. Nat Clin Pract Cardiovasc Med 5:520–521
Menasche P, Alfieri O, Janssens S, McKenna W, Reichenspurner H, Trinquart L, Vilquin JT, Marolleau JP, Seymour B, Larghero J, Lake S, Chatellier G, Solomon S, Desnos M, Hagege AA (2008) The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. Circulation 117:1189–1200
Kogler G, Sensken S, Airey JA, Trapp T, Muschen M, Feldhahn N, Liedtke S, Sorg RV, Fischer J, Rosenbaum C, Greschat S, Knipper A, Bender J, Degistirici O, Gao J, Caplan AI, Colletti EJ, Almeida-Porada G, Muller HW, Zanjani E, Wernet P (2004) A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential. J Exp Med 200:123–135
Gimble JM, Katz AJ, Bunnell BA (2007) Adipose-derived stem cells for regenerative medicine. Circ Res 100:1249–1260
Quevedo HC, Hatzistergos KE, Oskouei BN, Feigenbaum GS, Rodriguez JE, Valdes D, Pattany PM, Zambrano JP, Hu Q, McNiece I, Heldman AW, Hare JM (2009) Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity. Proc Natl Acad Sci U S A 106:14022–14027
Dexter TM, Allen TD, Lajtha LG (1977) Conditions controlling the proliferation of haemopoietic stem cells in vitro. J Cell Physiol 91:335–344
McCulloch EA, Till JE (1960) The radiation sensitivity of normal mouse bone marrow cells, determined by quantitative marrow transplantation into irradiated mice. Radiat Res 13:115–125
Till JE, McCulloch EA (1961) A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 14:213–222
Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP (1968) Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation 6:230–247
Friedenstein AJ, Chailakhjan RK, Lalykina KS (1970) The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet 3:393–403
Friedenstein AJ, Deriglasova UF, Kulagina NN, Panasuk AF, Rudakowa SF, Luria EA, Ruadkow IA (1974) Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp Hematol 2:83–92
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147
Jaiswal N, Haynesworth SE, Caplan AI, Bruder SP (1997) Osteogenic differentiation of purified, culture-expanded human mesenchymal stem cells in vitro. J Cell Biochem 64:295–312
Johnstone B, Hering TM, Caplan AI, Goldberg VM, Yoo JU (1998) In vitro chondrogenesis of bone marrow-derived mesenchymal progenitor cells. Exp Cell Res 238:265–272
Digirolamo CM, Stokes D, Colter D, Phinney DG, Class R, Prockop DJ (1999) Propagation and senescence of human marrow stromal cells in culture: a simple colony-forming assay identifies samples with the greatest potential to propagate and differentiate. Br J Haematol 107:275–281
Wakitani S, Saito T, Caplan AI (1995) Myogenic cells derived from rat bone marrow mesenchymal stem cells exposed to 5-azacytidine. Muscle Nerve 18:1417–1426
Pittenger MF, Martin BJ (2004) Mesenchymal stem cells and their potential as cardiac therapeutics. Circ Res 95:9–20
Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317
Colter DC, Class R, DiGirolamo CM, Prockop DJ (2000) Rapid expansion of recycling stem cells in cultures of plastic-adherent cells from human bone marrow. Proc Natl Acad Sci U S A 97:3213–3218
Barry FP, Murphy JM, English K, Mahon BP (2005) Immunogenicity of adult mesenchymal stem cells: lessons from the fetal allograft. Stem Cells Dev 14:252–265
Ryan JM, Barry FP, Murphy JM, Mahon BP (2005) Mesenchymal stem cells avoid allogeneic rejection. J Inflamm (Lond) 2:8
Nauta AJ, Westerhuis G, Kruisselbrink AB, Lurvink EG, Willemze R, Fibbe WE (2006) Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a nonmyeloablative setting. Blood 108:2114–2120
Dzau VJ, Gnecchi M, Pachori AS (2005) Enhancing stem cell therapy through genetic modification. J Am Coll Cardiol 46:1351–1353
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 9:1195–1201
Matsumoto R, Omura T, Yoshiyama M, Hayashi T, Inamoto S, Koh KR, Ohta K, Izumi Y, Nakamura Y, Akioka K, Kitaura Y, Takeuchi K, Yoshikawa J (2005) Vascular endothelial growth factor-expressing mesenchymal stem cell transplantation for the treatment of acute myocardial infarction. Arterioscler Thromb Vasc Biol 25:1168–1173
Roufosse CA, Direkze NC, Otto WR, Wright NA (2004) Circulating mesenchymal stem cells. Int J Biochem Cell Biol 36:585–597
Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM (2002) Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418:41–49
Yoon YS, Wecker A, Heyd L, Park JS, Tkebuchava T, Kusano K, Hanley A, Scadova H, Qin G, Cha DH, Johnson KL, Aikawa R, Asahara T, Losordo DW (2005) Clonally expanded novel multipotent stem cells from human bone marrow regenerate myocardium after myocardial infarction. J Clin Invest 115:326–338
Williams AR, Hare JM (2011) Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circ Res 109:923–940
Melo LG, Pachori AS, Kong D, Gnecchi M, Wang K, Pratt RE, Dzau VJ (2004) Molecular and cell-based therapies for protection, rescue, and repair of ischemic myocardium: reasons for cautious optimism. Circulation 109:2386–2393
Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD (2002) Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 105:93–98
Tomita S, Li RK, Weisel RD, Mickle DA, Kim EJ, Sakai T, Jia ZQ (1999) Autologous transplantation of bone marrow cells improves damaged heart function. Circulation 100:II247–II256
van der Bogt KE, Schrepfer S, Yu J, Sheikh AY, Hoyt G, Govaert JA, Velotta JB, Contag CH, Robbins RC, Wu JC (2009) Comparison of transplantation of adipose tissue- and bone marrow-derived mesenchymal stem cells in the infarcted heart. Transplantation 87:642–652
Muller-Ehmsen J, Krausgrill B, Burst V, Schenk K, Neisen UC, Fries JW, Fleischmann BK, Hescheler J, Schwinger RH (2006) Effective engraftment but poor mid-term persistence of mononuclear and mesenchymal bone marrow cells in acute and chronic rat myocardial infarction. J Mol Cell Cardiol 41:876–884
Noiseux N, Gnecchi M, Lopez-Ilasaca M, Zhang L, Solomon SD, Deb A, Dzau VJ, Pratt RE (2006) Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Mol Ther 14:840–850
Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, Fike JR, Lee HO, Pfeffer K, Lois C, Morrison SJ, Alvarez-Buylla A (2003) Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 425:968–973
Gnecchi M, He H, Liang OD, Melo LG, Morello F, Mu H, Noiseux N, Zhang L, Pratt RE, Ingwall JS, Dzau VJ (2005) Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med 11:367–368
Gnecchi M, He H, Noiseux N, Liang OD, Zhang L, Morello F, Mu H, Melo LG, Pratt RE, Ingwall JS, Dzau VJ (2006) Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J 20:661–669
Kinnaird T, Stabile E, Burnett MS, Shou M, Lee CW, Barr S, Fuchs S, Epstein SE (2004) Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation 109:1543–1549
Olivetti G, Capasso JM, Sonnenblick EH, Anversa P (1990) Side-to-side slippage of myocytes participates in ventricular wall remodeling acutely after myocardial infarction in rats. Circ Res 67:23–34
Caulfield JB, Leinbach R, Gold H (1976) The relationship of myocardial infarct size and prognosis. Circulation 53:I141–I144
Fukuda K (2001) Development of regenerative cardiomyocytes from mesenchymal stem cells for cardiovascular tissue engineering. Artif Organs 25:187–193
Hakuno D, Fukuda K, Makino S, Konishi F, Tomita Y, Manabe T, Suzuki Y, Umezawa A, Ogawa S (2002) Bone marrow-derived regenerated cardiomyocytes (CMG Cells) express functional adrenergic and muscarinic receptors. Circulation 105:380–386
Makino S, Fukuda K, Miyoshi S, Konishi F, Kodama H, Pan J, Sano M, Takahashi T, Hori S, Abe H, Hata J, Umezawa A, Ogawa S (1999) Cardiomyocytes can be generated from marrow stromal cells in vitro. J Clin Invest 103:697–705
Rangappa S, Entwistle JW, Wechsler AS, Kresh JY (2003) Cardiomyocyte-mediated contact programs human mesenchymal stem cells to express cardiogenic phenotype. J Thorac Cardiovasc Surg 126:124–132
Xu M, Wani M, Dai YS, Wang J, Yan M, Ayub A, Ashraf M (2004) Differentiation of bone marrow stromal cells into the cardiac phenotype requires intercellular communication with myocytes. Circulation 110:2658–2665
Liechty KW, MacKenzie TC, Shaaban AF, Radu A, Moseley AM, Deans R, Marshak DR, Flake AW (2000) Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep. Nat Med 6:1282–1286
Pochampally RR, Neville BT, Schwarz EJ, Li MM, Prockop DJ (2004) Rat adult stem cells (marrow stromal cells) engraft and differentiate in chick embryos without evidence of cell fusion. Proc Natl Acad Sci U S A 101:9282–9285
Kawada H, Fujita J, Kinjo K, Matsuzaki Y, Tsuma M, Miyatake H, Muguruma Y, Tsuboi K, Itabashi Y, Ikeda Y, Ogawa S, Okano H, Hotta T, Ando K, Fukuda K (2004) Nonhematopoietic mesenchymal stem cells can be mobilized and differentiate into cardiomyocytes after myocardial infarction. Blood 104:3581–3587
Nagaya N, Fujii T, Iwase T, Ohgushi H, Itoh T, Uematsu M, Yamagishi M, Mori H, Kangawa K, Kitamura S (2004) Intravenous administration of mesenchymal stem cells improves cardiac function in rats with acute myocardial infarction through angiogenesis and myogenesis. Am J Physiol Heart Circ Physiol 287:H2670–H2676
Amado LC, Saliaris AP, Schuleri KH, St John M, Xie JS, Cattaneo S, Durand DJ, Fitton T, Kuang JQ, Stewart G, Lehrke S, Baumgartner WW, Martin BJ, Heldman AW, Hare JM (2005) Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proc Natl Acad Sci U S A 102:11474–11479
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 1926
Wang JS, Shum-Tim D, Chedrawy E, Chiu RC (2001) The coronary delivery of marrow stromal cells for myocardial regeneration: pathophysiologic and therapeutic implications. J Thorac Cardiovasc Surg 122:699–705
Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9:653–660
Nguyen LL, D’Amore PA (2001) Cellular interactions in vascular growth and differentiation. Int Rev Cytol 204:1–48
Asahara T, Kawamoto A, Masuda H (2011) Concise review: circulating endothelial progenitor cells for vascular medicine. Stem Cells 29:1650–1655
Gnecchi M, Zhang Z, Ni A, Dzau VJ (2008) Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res 103:1204–1219
Davani S, Marandin A, Mersin N, Royer B, Kantelip B, Herve P, Etievent JP, Kantelip JP (2003) Mesenchymal progenitor cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a rat cellular cardiomyoplasty model. Circulation 108(Suppl 1):II253–II258
Psaltis PJ, Zannettino AC, Worthley SG, Gronthos S (2008) Concise review: mesenchymal stromal cells: potential for cardiovascular repair. Stem Cells 26:2201–2210
Silva GV, Litovsky S, Assad JA, Sousa AL, Martin BJ, Vela D, Coulter SC, Lin J, Ober J, Vaughn WK, Branco RV, Oliveira EM, He R, Geng YJ, Willerson JT, Perin EC (2005) Mesenchymal stem cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a canine chronic ischemia model. Circulation 111:150–156
Hatzistergos KE, Quevedo H, Oskouei BN, Hu Q, Feigenbaum GS, Margitich IS, Mazhari R, Boyle AJ, Zambrano JP, Rodriguez JE, Dulce R, Pattany PM, Valdes D, Revilla C, Heldman AW, McNiece I, Hare JM (2010) Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ Res 107:913–922
Loffredo F, Lee RT (2008) Therapeutic vasculogenesis: it takes two. Circ Res 103:128–130
Melero-Martin JM, De Obaldia ME, Kang SY, Khan ZA, Yuan L, Oettgen P, Bischoff J (2008) Engineering robust and functional vascular networks in vivo with human adult and cord blood-derived progenitor cells. Circ Res 103:194–202
Au P, Tam J, Fukumura D, Jain RK (2008) Bone marrow-derived mesenchymal stem cells facilitate engineering of long-lasting functional vasculature. Blood 111:4551–4558
Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS, Andriolo G, Sun B, Zheng B, Zhang L, Norotte C, Teng PN, Traas J, Schugar R, Deasy BM, Badylak S, Buhring HJ, Giacobino JP, Lazzari L, Huard J, Peault B (2008) A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3:301–313
Haynesworth SE, Baber MA, Caplan AI (1996) Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro: effects of dexamethasone and IL-1 alpha. J Cell Physiol 166:585–592
Kinnaird T, Stabile E, Burnett MS, Lee CW, Barr S, Fuchs S, Epstein SE (2004) Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res 94:678–685
Jiang S, Haider HK, Idris NM, Salim A, Ashraf M (2006) Supportive interaction between cell survival signaling and angiocompetent factors enhances donor cell survival and promotes angiomyogenesis for cardiac repair. Circ Res 99:776–784
Tomita S, Mickle DA, Weisel RD, Jia ZQ, Tumiati LC, Allidina Y, Liu P, Li RK (2002) Improved heart function with myogenesis and angiogenesis after autologous porcine bone marrow stromal cell transplantation. J Thorac Cardiovasc Surg 123:1132–1140
Bock-Marquette I, Saxena A, White MD, Dimaio JM, Srivastava D (2004) Thymosin beta4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair. Nature 432:466–472
Lim SY, Kim YS, Ahn Y, Jeong MH, Hong MH, Joo SY, Nam KI, Cho JG, Kang PM, Park JC (2006) The effects of mesenchymal stem cells transduced with Akt in a porcine myocardial infarction model. Cardiovasc Res 70:530–542
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 5:434–438
Uemura R, Xu M, Ahmad N, Ashraf M (2006) Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling. Circ Res 98:1414–1421
Xu M, Uemura R, Dai Y, Wang Y, Pasha Z, Ashraf M (2007) In vitro and in vivo effects of bone marrow stem cells on cardiac structure and function. J Mol Cell Cardiol 42:441–448
Berry MF, Engler AJ, Woo YJ, Pirolli TJ, Bish LT, Jayasankar V, Morine KJ, Gardner TJ, Discher DE, Sweeney HL (2006) Mesenchymal stem cell injection after myocardial infarction improves myocardial compliance. Am J Physiol Heart Circ Physiol 290:H2196–H2203
Xu X, Xu Z, Xu Y, Cui G (2005) Selective down-regulation of extracellular matrix gene expression by bone marrow derived stem cell transplantation into infarcted myocardium. Circ J 69:1275–1283
Feygin J, Mansoor A, Eckman P, Swingen C, Zhang J (2007) Functional and bioenergetic modulations in the infarct border zone following autologous mesenchymal stem cell transplantation. Am J Physiol Heart Circ Physiol 293:H1772–H1780
Gnecchi M, He H, Melo LG, Noiseaux N, Morello F, de Boer RA, Zhang L, Pratt RE, Dzau VJ, Ingwall JS (2009) Early beneficial effects of bone marrow-derived mesenchymal stem cells overexpressing Akt on cardiac metabolism after myocardial infarction. Stem Cells 27:971–979
Takahashi M, Li TS, Suzuki R, Kobayashi T, Ito H, Ikeda Y, Matsuzaki M, Hamano K (2006) Cytokines produced by bone marrow cells can contribute to functional improvement of the infarcted heart by protecting cardiomyocytes from ischemic injury. Am J Physiol Heart Circ Physiol 291:H886–H893
Mirotsou M, Zhang Z, Deb A, Zhang L, Gnecchi M, Noiseux N, Mu H, Pachori A, Dzau V (2007) Secreted frizzled related protein 2 (Sfrp2) is the key Akt-mesenchymal stem cell-released paracrine factor mediating myocardial survival and repair. Proc Natl Acad Sci U S A 104:1643–1648
Alfaro MP, Pagni M, Vincent A, Atkinson J, Hill MF, Cates J, Davidson JM, Rottman J, Lee E, Young PP (2008) The Wnt modulator sFRP2 enhances mesenchymal stem cell engraftment, granulation tissue formation and myocardial repair. Proc Natl Acad Sci U S A 105:18366–18371
Lee RH, Pulin AA, Seo MJ, Kota DJ, Ylostalo J, Larson BL, Semprun-Prieto L, Delafontaine P, Prockop DJ (2009) Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell 5:54–63
Estrada R, Li N, Sarojini H, An J, Lee MJ, Wang E (2009) Secretome from mesenchymal stem cells induces angiogenesis via Cyr61. J Cell Physiol 219:563–571
Sze SK, de Kleijn DP, Lai RC, Khia Way Tan E, Zhao H, Yeo KS, Low TY, Lian Q, Lee CN, Mitchell W, El Oakley RM, Lim SK (2007) Elucidating the secretion proteome of human embryonic stem cell-derived mesenchymal stem cells. Mol Cell Proteomics 6:1680–1689
Post MJ, Laham R, Sellke FW, Simons M (2001) Therapeutic angiogenesis in cardiology using protein formulations. Cardiovasc Res 49:522–531
Malik DK, Baboota S, Ahuja A, Hasan S, Ali J (2007) Recent advances in protein and peptide drug delivery systems. Curr Drug Deliv 4:141–151
Segers VF, Tokunou T, Higgins LJ, MacGillivray C, Gannon J, Lee RT (2007) Local delivery of protease-resistant stromal cell derived factor-1 for stem cell recruitment after myocardial infarction. Circulation 116:1683–1692
Lai RC, Arslan F, Lee MM, Sze NS, Choo A, Chen TS, Salto-Tellez M, Timmers L, Lee CN, El Oakley RM, Pasterkamp G, de Kleijn DP, Lim SK (2010) Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res 4:214–222
Martinez MC, Andriantsitohaina R (2011) Microparticles in angiogenesis: therapeutic potential. Circ Res 109:110–119
Janowska-Wieczorek A, Wysoczynski M, Kijowski J, Marquez-Curtis L, Machalinski B, Ratajczak J, Ratajczak MZ (2005) Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int J Cancer 113:752–760
Chen TS, Lai RC, Lee MM, Choo AB, Lee CN, Lim SK (2010) Mesenchymal stem cell secretes microparticles enriched in pre-microRNAs. Nucleic Acids Res 38:215–224
Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, Geuze HJ (1996) B lymphocytes secrete antigen-presenting vesicles. J Exp Med 183:1161–1172
Raposo G, Tenza D, Mecheri S, Peronet R, Bonnerot C, Desaymard C (1997) Accumulation of major histocompatibility complex class II molecules in mast cell secretory granules and their release upon degranulation. Mol Biol Cell 8:2631–2645
Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, Ricciardi-Castagnoli P, Raposo G, Amigorena S (1998) Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med 4:594–600
Peters PJ, Geuze HJ, Van der Donk HA, Slot JW, Griffith JM, Stam NJ, Clevers HC, Borst J (1989) Molecules relevant for T cell-target cell interaction are present in cytolytic granules of human T lymphocytes. Eur J Immunol 19:1469–1475
Heijnen HF, Schiel AE, Fijnheer R, Geuze HJ, Sixma JJ (1999) Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. Blood 94:3791–3799
Fevrier B, Vilette D, Archer F, Loew D, Faigle W, Vidal M, Laude H, Raposo G (2004) Cells release prions in association with exosomes. Proc Natl Acad Sci U S A 101:9683–9688
Wolfers J, Lozier A, Raposo G, Regnault A, Thery C, Masurier C, Flament C, Pouzieux S, Faure F, Tursz T, Angevin E, Amigorena S, Zitvogel L (2001) Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nat Med 7:297–303
Sullivan R, Saez F, Girouard J, Frenette G (2005) Role of exosomes in sperm maturation during the transit along the male reproductive tract. Blood Cells Mol Dis 35:1–10
Pisitkun T, Shen RF, Knepper MA (2004) Identification and proteomic profiling of exosomes in human urine. Proc Natl Acad Sci U S A 101:13368–13373
Caby MP, Lankar D, Vincendeau-Scherrer C, Raposo G, Bonnerot C (2005) Exosomal-like vesicles are present in human blood plasma. Int Immunol 17:879–887
Admyre C, Grunewald J, Thyberg J, Gripenback S, Tornling G, Eklund A, Scheynius A, Gabrielsson S (2003) Exosomes with major histocompatibility complex class II and co-stimulatory molecules are present in human BAL fluid. Eur Respir J 22:578–583
Kukielka GL, Hawkins HK, Michael L, Manning AM, Youker K, Lane C, Entman ML, Smith CW, Anderson DC (1993) Regulation of intercellular adhesion molecule-1 (ICAM-1) in ischemic and reperfused canine myocardium. J Clin Invest 92:1504–1516
Rieu S, Geminard C, Rabesandratana H, Sainte-Marie J, Vidal M (2000) Exosomes released during reticulocyte maturation bind to fibronectin via integrin alpha4beta1. Eur J Biochem 267:583–590
Parolini I, Federici C, Raggi C, Lugini L, Palleschi S, De Milito A, Coscia C, Iessi E, Logozzi M, Molinari A, Colone M, Tatti M, Sargiacomo M, Fais S (2009) Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem 284:34211–34222
Schrader J (1985) Mechanisms of ischemic injury in the heart. Basic Res Cardiol 80(Suppl 2):135–139
Chen TS, Arslan F, Yin Y, Tan SS, Lai RC, Choo AB, Padmanabhan J, Lee CN, de Kleijn DP, Lim SK (2011) Enabling a robust scalable manufacturing process for therapeutic exosomes through oncogenic immortalization of human ESC-derived MSCs. J Transl Med 9:47
Penn MS, Mangi AA (2008) Genetic enhancement of stem cell engraftment, survival, and efficacy. Circ Res 102:1471–1482
Pasha Z, Wang Y, Sheikh R, Zhang D, Zhao T, Ashraf M (2008) Preconditioning enhances cell survival and differentiation of stem cells during transplantation in infarcted myocardium. Cardiovasc Res 77:134–142
Davis ME, Hsieh PC, Grodzinsky AJ, Lee RT (2005) Custom design of the cardiac microenvironment with biomaterials. Circ Res 97:8–15
Rossi DJ, Bryder D, Zahn JM, Ahlenius H, Sonu R, Wagers AJ, Weissman IL (2005) Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci U S A 102:9194–9199
Dzau VJ, Gnecchi M, Pachori AS, Morello F, Melo LG (2005) Therapeutic potential of endothelial progenitor cells in cardiovascular diseases. Hypertension 46:7–18
Eschenhagen T, Zimmermann WH (2005) Engineering myocardial tissue. Circ Res 97:1220–1231
Acknowledgments
Massimiliano Gnecchi is supported by the Ministero Italiano della Sanità (GR-2008-1142871 and RF-IAI-2008-1216776), the Ministero italiano degli Affari Esteri and the Fondazione Cariplo (2007–5984).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media New York
About this chapter
Cite this chapter
Gnecchi, M., Cervio, E. (2013). Mesenchymal Stem Cell Therapy for Heart Disease. In: Chase, L., Vemuri, M. (eds) Mesenchymal Stem Cell Therapy. Stem Cell Biology and Regenerative Medicine. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-200-1_13
Download citation
DOI: https://doi.org/10.1007/978-1-62703-200-1_13
Published:
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-62703-199-8
Online ISBN: 978-1-62703-200-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)