Stem cell death and survival in heart regeneration and repair

Abstract

Cardiovascular diseases are major causes of mortality and morbidity. Cardiomyocyte apoptosis disrupts cardiac function and leads to cardiac decompensation and terminal heart failure. Delineating the regulatory signaling pathways that orchestrate cell survival in the heart has significant therapeutic implications. Cardiac tissue has limited capacity to regenerate and repair. Stem cell therapy is a successful approach for repairing and regenerating ischemic cardiac tissue; however, transplanted cells display very high death percentage, a problem that affects success of tissue regeneration. Stem cells display multipotency or pluripotency and undergo self-renewal, however these events are negatively influenced by upregulation of cell death machinery that induces the significant decrease in survival and differentiation signals upon cardiovascular injury. While efforts to identify cell types and molecular pathways that promote cardiac tissue regeneration have been productive, studies that focus on blocking the extensive cell death after transplantation are limited. The control of cell death includes multiple networks rather than one crucial pathway, which underlies the challenge of identifying the interaction between various cellular and biochemical components. This review is aimed at exploiting the molecular mechanisms by which stem cells resist death signals to develop into mature and healthy cardiac cells. Specifically, we focus on a number of factors that control death and survival of stem cells upon transplantation and ultimately affect cardiac regeneration. We also discuss potential survival enhancing strategies and how they could be meaningful in the design of targeted therapies that improve cardiac function.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2

References

  1. 1.

    Abdelwahid E, Siminiak T, Guarita-Souza LC et al (2011) Stem cell therapy in heart diseases: a review of selected new perspectives, practical considerations and clinical applications. Curr Cardiol Rev 7:201–212

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  2. 2.

    Passier R, van Laake LW, Mummery CL (2008) Stem-cell-based therapy and lessons from the heart. Nature 453:322–329

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Check E (2004) Cardiologists take heart from stem-cell treatment success. Nature 428:880

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Wu X, Ding S, Ding Q, Gray NS, Schultz PG (2004) Small molecules that induce cardiomyogenesis in embryonic stem cells. J Am Chem Soc 126:1590–1591

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Zhang J, Wilson GF, Soerens AG et al (2009) Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ Res 104:e30–41

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  6. 6.

    Orlic D, Kajstura J, Chimenti S et al (2001) Bone marrow cells regenerate infarcted myocardium. Nature 410:701–705

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Strauer BE, Brehm M, Zeus T et al (2002) Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 106:1913–1918

    PubMed  Article  Google Scholar 

  8. 8.

    Jackson KA, Majka SM, Wang H et al (2001) Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Investig 107:1395–1402

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  9. 9.

    Badorff C, Brandes RP, Popp R et al (2003) Transdifferentiation of blood-derived human adult endothelial progenitor cells into functionally active cardiomyocytes. Circulation 107:1024–1032

    PubMed  Article  Google Scholar 

  10. 10.

    Rupp S, Badorff C, Koyanagi M et al (2004) Statin therapy in patients with coronary artery disease improves the impaired endothelial progenitor cell differentiation into cardiomyogenic cells. Basic Res Cardiol 99:61–68

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Zhang J, Wu Y, Chen A, Zhao Q (2015) Mesenchymal stem cells promote cardiac muscle repair via enhanced neovascularization. Cell Physiol Biochem 35:1219–1229

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Gnecchi M, He H, Liang OD et al (2005) Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med 11:367–368

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Gnecchi M, He H, Noiseux N et al (2006) Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J 20:661–669

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Haider H, Ashraf M (2005) Bone marrow stem cell transplantation for cardiac repair. Am J Physiol Heart Circ Physiol 288:H2557–2567

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Kofidis T, de Bruin JL, Yamane T et al (2004) Insulin-like growth factor promotes engraftment, differentiation, and functional improvement after transfer of embryonic stem cells for myocardial restoration. Stem Cells 22:1239–1245

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Li RK, Jia ZQ, Weisel RD, Merante F, Mickle DA (1999) Smooth muscle cell transplantation into myocardial scar tissue improves heart function. J Mol Cell Cardiol 31:513–522

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Li RK, Weisel RD, Mickle DA et al (2000) Autologous porcine heart cell transplantation improved heart function after a myocardial infarction. J Thorac Cardiovasc Surg 119:62–68

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Singla DK, Hacker TA, Ma L et al (2006) Transplantation of embryonic stem cells into the infarcted mouse heart: formation of multiple cell types. J Mol Cell Cardiol 40:195–200

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Singla DK, Lyons GE, Kamp TJ (2007) Transplanted embryonic stem cells following mouse myocardial infarction inhibit apoptosis and cardiac remodeling. Am J Physiol Heart Circ Physiol 293:H1308–1314

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Dimmeler S, Zeiher AM, Schneider MD (2005) Unchain my heart: the scientific foundations of cardiac repair. J Clin Investig 115:572–583

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  21. 21.

    Beltrami AP, Urbanek K, Kajstura J et al (2001) Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med 344:1750–1757

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Bergmann O, Zdunek S, Felker A et al (2015) Dynamics of cell generation and turnover in the human heart. Cell 161:1566–1575

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Hamano K, Li TS, Kobayashi T et al (2002) Therapeutic angiogenesis induced by local autologous bone marrow cell implantation. Ann thorac Surg 73:1210–1215

    PubMed  Article  Google Scholar 

  24. 24.

    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

    PubMed  Article  Google Scholar 

  25. 25.

    Geng YJ (2003) Molecular mechanisms for cardiovascular stem cell apoptosis and growth in the hearts with atherosclerotic coronary disease and ischemic heart failure. Ann N Y Acad Sci 1010:687–697

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Robey TE, Saiget MK, Reinecke H, Murry CE (2008) Systems approaches to preventing transplanted cell death in cardiac repair. J Mol Cell Cardiol 45:567–581

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  27. 27.

    Zhang M, Methot D, Poppa V, Fujio Y, Walsh K, Murry CE (2001) Cardiomyocyte grafting for cardiac repair: graft cell death and anti-death strategies. J Mol Cell Cardiol 33:907–921

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Yang YJ, Qian HY, Huang J et al (2008) Atorvastatin treatment improves survival and effects of implanted mesenchymal stem cells in post-infarct swine hearts. Eur Heart J 29:1578–1590

    PubMed  Article  Google Scholar 

  29. 29.

    Lu WN, Lu SH, Wang HB et al (2009) Functional improvement of infarcted heart by co-injection of embryonic stem cells with temperature-responsive chitosan hydrogel. Tissue Eng Part A 15:1437–1447

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Young PP, Schafer R (2015) Cell-based therapies for cardiac disease: a cellular therapist’s perspective. Transfusion 55:441–451; quiz 440

  31. 31.

    Kochupura PV, Azeloglu EU, Kelly DJ et al (2005) Tissue-engineered myocardial patch derived from extracellular matrix provides regional mechanical function. Circulation 112:I144–149

    PubMed  Google Scholar 

  32. 32.

    Sancricca C, Mirabella M, Gliubizzi C, Broccolini A, Gidaro T, Morosetti R (2010) Vessel-associated stem cells from skeletal muscle: From biology to future uses in cell therapy. World J Stem Cells 2:39–49

    PubMed Central  PubMed  Article  Google Scholar 

  33. 33.

    Pannerec A, Marazzi G, Sassoon D (2012) Stem cells in the hood: the skeletal muscle niche. Trends Mol Med 18:599–606

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Akhmedov AT, Marin-Garcia J (2013) Myocardial regeneration of the failing heart. Heart Fail Rev 18:815–833

    PubMed  Article  Google Scholar 

  35. 35.

    Francisco J, Cunha R, Simeoni R et al (2013) Antibody to nuclear ribonucleoprotein penetrates live human mononuclear cells through Fc receptors. J Biomed Sci Eng 6:1178–1185

    Article  CAS  Google Scholar 

  36. 36.

    Kofidis T, deBruin JL, Tanaka M et al (2005) They are not stealthy in the heart: embryonic stem cells trigger cell infiltration, humoral and T-lymphocyte-based host immune response. Eur J Cardio Thorac Surg 28:461–466

    Article  Google Scholar 

  37. 37.

    Gharaibeh B, Lavasani M, Cummins JH, Huard J (2011) Terminal differentiation is not a major determinant for the success of stem cell therapy - cross-talk between muscle-derived stem cells and host cells. Stem Cell Res Ther 2:31

    PubMed Central  PubMed  Article  Google Scholar 

  38. 38.

    Mylotte LA, Duffy AM, Murphy M et al (2008) Metabolic flexibility permits mesenchymal stem cell survival in an ischemic environment. Stem Cells 26:1325–1336

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Stamm C, Westphal B, Kleine HD et al (2003) Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet 361:45–46

    PubMed  Article  Google Scholar 

  40. 40.

    Katritsis DG, Sotiropoulou PA, Karvouni E et al (2005) Transcoronary transplantation of autologous mesenchymal stem cells and endothelial progenitors into infarcted human myocardium. Catheter Cardiovasc Interv 65:321–329

    PubMed  Article  Google Scholar 

  41. 41.

    Miyahara Y, Nagaya N, Kataoka M et al (2006) Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction. Nat Med 12:459–465

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Silva GV, Litovsky S, Assad JA et al (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

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Quevedo HC, Hatzistergos KE, Oskouei BN et al (2009) Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity. Proc Natl Acad Sci USA 106:14022–14027

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  44. 44.

    Makkar RR, Price MJ, Lill M et al (2005) Intramyocardial injection of allogenic bone marrow-derived mesenchymal stem cells without immunosuppression preserves cardiac function in a porcine model of myocardial infarction. J Cardiovasc Pharmacol Ther 10:225–233

    PubMed  Article  Google Scholar 

  45. 45.

    Yang ZJ, Ma DC, Wang W et al (2006) Experimental study of bone marrow-derived mesenchymal stem cells combined with hepatocyte growth factor transplantation via noninfarct-relative artery in acute myocardial infarction. Gene Ther 13:1564–1568

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    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

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Chen SL, Fang WW, Ye F et al (2004) Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol 94:92–95

    PubMed  Article  Google Scholar 

  48. 48.

    Williams AR, Trachtenberg B, Velazquez DL et al (2011) Intramyocardial stem cell injection in patients with ischemic cardiomyopathy: functional recovery and reverse remodeling. Circ Res 108:792–796

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  49. 49.

    Trachtenberg B, Velazquez DL, Williams AR et al (2011) Rationale and design of the Transendocardial Injection of Autologous Human Cells (bone marrow or mesenchymal) in Chronic Ischemic Left Ventricular Dysfunction and Heart Failure Secondary to Myocardial Infarction (TAC-HFT) trial: A randomized, double-blind, placebo-controlled study of safety and efficacy. Am Heart J 161:487–493

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Fukushima S, Campbell NG, Coppen SR et al (2011) Quantitative assessment of initial retention of bone marrow mononuclear cells injected into the coronary arteries. J Heart Lung Transpl 30:227–233

    Article  Google Scholar 

  51. 51.

    Sirmenis R, Kraniauskas A, Jarasiene R, Baltriukiene D, Kalvelyte A, Bukelskiene V (2011) Recovery of infarcted myocardium in an in vivo experiment. Medicina (Kaunas) 47:607–615

    Google Scholar 

  52. 52.

    Fukushima S, Sawa Y, Suzuki K (2013) Choice of cell-delivery route for successful cell transplantation therapy for the heart. Futur Cardiol 9:215–227

    CAS  Article  Google Scholar 

  53. 53.

    Poynter JA, Herrmann JL, Manukyan MC et al (2011) Intracoronary mesenchymal stem cells promote postischemic myocardial functional recovery, decrease inflammation, and reduce apoptosis via a signal transducer and activator of transcription 3 mechanism. J Am Coll Surg 213:253–260

    PubMed  Article  Google Scholar 

  54. 54.

    Huang H, He J, Teng X et al (2013) Combined intrathymic and intravenous injection of mesenchymal stem cells can prolong the survival of rat cardiac allograft associated with decrease in miR-155 expression. J Surg Res 185:896–903

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Tano N, Narita T, Kaneko M et al (2014) Epicardial placement of mesenchymal stromal cell-sheets for the treatment of ischemic cardiomyopathy; in vivo proof-of-concept study. Mol Ther 22:1864–1871

    PubMed Central  CAS  PubMed  Google Scholar 

  56. 56.

    Menasche P, Vanneaux V, Fabreguettes JR et al (2015) Towards a clinical use of human embryonic stem cell-derived cardiac progenitors: a translational experience. Eur Heart J 36:743–750

    PubMed  Article  Google Scholar 

  57. 57.

    Campbell NG, Suzuki K (2012) Cell delivery routes for stem cell therapy to the heart: current and future approaches. J Cardiovasc Transl Res 5:713–726

    PubMed  Article  Google Scholar 

  58. 58.

    Chen K, Keaney JF Jr (2012) Evolving concepts of oxidative stress and reactive oxygen species in cardiovascular disease. Curr Atheroscler Rep 14:476–483

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Liu Z, Wang H, Wang Y et al (2012) The influence of chitosan hydrogel on stem cell engraftment, survival and homing in the ischemic myocardial microenvironment. Biomaterials 33:3093–3106

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Don CW, Murry CE (2013) Improving survival and efficacy of pluripotent stem cell-derived cardiac grafts. J Cell Mol Med 17:1355–1362

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  61. 61.

    Li X, Liu X, Tan Y, Tran V, Zhang N, Wen X (2012) Improve the viability of transplanted neural cells with appropriate sized neurospheres coated with mesenchymal stem cells. Med Hypotheses 79:274–277

    PubMed  Article  Google Scholar 

  62. 62.

    You D, Waeckel L, Ebrahimian TG et al (2006) Increase in vascular permeability and vasodilation are critical for proangiogenic effects of stem cell therapy. Circulation 114:328–338

    PubMed  Article  Google Scholar 

  63. 63.

    Ye Z, Zhou Y, Cai H, Tan W (2011) Myocardial regeneration: Roles of stem cells and hydrogels. Adv Drug Deliv Rev 63:688–697

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Garzoni LR, Rossi MI, de Barros AP et al (2009) Dissecting coronary angiogenesis: 3D co-culture of cardiomyocytes with endothelial or mesenchymal cells. Exp Cell Res 315:3406–3418

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Bhang SH, Cho SW, La WG et al (2011) Angiogenesis in ischemic tissue produced by spheroid grafting of human adipose-derived stromal cells. Biomaterials 32:2734–2747

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    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

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Pfeffer MA, Braunwald E (1990) Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation 81:1161–1172

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Fishbein MC, Maclean D, Maroko PR (1978) Experimental myocardial infarction in the rat: qualitative and quantitative changes during pathologic evolution. Am J Pathol 90:57–70

    PubMed Central  CAS  PubMed  Google Scholar 

  69. 69.

    Li L, Bennett SA, Wang L (2012) Role of E-cadherin and other cell adhesion molecules in survival and differentiation of human pluripotent stem cells. Cell Adh Migr 6:59–70

    PubMed Central  PubMed  Article  Google Scholar 

  70. 70.

    Xu Y, Zhu X, Hahm HS et al (2010) Revealing a core signaling regulatory mechanism for pluripotent stem cell survival and self-renewal by small molecules. Proc Natl Acad Sci USA 107:8129–8134

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  71. 71.

    Ohgushi M, Matsumura M, Eiraku M et al (2010) Molecular pathway and cell state responsible for dissociation-induced apoptosis in human pluripotent stem cells. Cell Stem Cell 7:225–239

    CAS  PubMed  Article  Google Scholar 

  72. 72.

    Chen G, Hou Z, Gulbranson DR, Thomson JA (2010) Actin-myosin contractility is responsible for the reduced viability of dissociated human embryonic stem cells. Cell Stem Cell 7:240–248

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  73. 73.

    Bollini S, Riley PR, Smart N (2015) Thymosin beta4: multiple functions in protection, repair and regeneration of the mammalian heart. Expert Opin Biol Ther 15(Suppl 1):S163–174

    PubMed  Article  CAS  Google Scholar 

  74. 74.

    Huang HL, Hsing HW, Lai TC et al (2010) Trypsin-induced proteome alteration during cell subculture in mammalian cells. J Biomed Sci 17:36

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  75. 75.

    Gerard C, Forest MA, Beauregard G, Skuk D, Tremblay JP (2012) Fibrin gel improves the survival of transplanted myoblasts. Cell Transpl 21:127–137

    Article  Google Scholar 

  76. 76.

    Ma J, Holden K, Zhu J, Pan H, Li Y (2011) The application of three-dimensional collagen-scaffolds seeded with myoblasts to repair skeletal muscle defects. J Biomed Biotechnol 2011:812135

    PubMed Central  PubMed  Google Scholar 

  77. 77.

    Forte G, Pagliari S, Pagliari F, Ebara M, Di Nardo P, Aoyagi T (2013) Towards the generation of patient-specific patches for cardiac repair. Stem Cell Rev 9:313–325

    PubMed  Article  Google Scholar 

  78. 78.

    Siepe M, Golsong P, Poppe A et al (2011) Scaffold-based transplantation of akt1-overexpressing skeletal myoblasts: functional regeneration is associated with angiogenesis and reduced infarction size. Tissue Eng Part A 17:205–212

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    Sart S, Ma T, Li Y (2014) Preconditioning stem cells for in vivo delivery. Biores Open Access 3:137–149

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  80. 80.

    Giordano FJ (2005) Oxygen, oxidative stress, hypoxia, and heart failure. J Clin Investig 115:500–508

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  81. 81.

    Song H, Cha MJ, Song BW et al (2010) Reactive oxygen species inhibit adhesion of mesenchymal stem cells implanted into ischemic myocardium via interference of focal adhesion complex. Stem Cells 28:555–563

    CAS  PubMed  Google Scholar 

  82. 82.

    Brown DI, Griendling KK (2015) Regulation of signal transduction by reactive oxygen species in the cardiovascular system. Circ Res 116:531–549

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  83. 83.

    Droge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82:47–95

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Ryter SW, Kim HP, Hoetzel A et al (2007) Mechanisms of cell death in oxidative stress. Antioxid Redox Signal 9:49–89

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Ushio-Fukai M, Rehman J (2014) Redox and metabolic regulation of stem/progenitor cells and their niche. Antioxid Redox Signal 21:1587–1590

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  86. 86.

    Tan SC, Gomes RS, Yeoh KK et al (2015) Preconditioning of cardiosphere-derived cells with hypoxia or prolyl-4-hydroxylase inhibitors increases stemness and decreases reliance on oxidative metabolism. Cell Transpl.

  87. 87.

    Rodrigues M, Turner O, Stolz D, Griffith LG, Wells A (2012) Production of reactive oxygen species by multipotent stromal cells/mesenchymal stem cells upon exposure to fas ligand. Cell Transpl 21:2171–2187

    Article  Google Scholar 

  88. 88.

    Reinecke H, Murry CE (2000) Transmural replacement of myocardium after skeletal myoblast grafting into the heart. Too much of a good thing? Cardiovasc Pathol 9:337–344

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Reinecke H, Murry CE (2003) Cell grafting for cardiac repair. Methods Mol Biol 219:97–112

    PubMed  Google Scholar 

  90. 90.

    Wollert KC, Meyer GP, Lotz J et al (2004) Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 364:141–148

    PubMed  Article  Google Scholar 

  91. 91.

    Suzuki K, Murtuza B, Beauchamp JR et al (2004) Role of interleukin-1beta in acute inflammation and graft death after cell transplantation to the heart. Circulation 110:II219–II224

    PubMed  Google Scholar 

  92. 92.

    Suzuki K, Murtuza B, Beauchamp JR et al (2004) Dynamics and mediators of acute graft attrition after myoblast transplantation to the heart. FASEB J 18:1153–1155

    CAS  PubMed  Google Scholar 

  93. 93.

    Murtuza B, Suzuki K, Bou-Gharios G et al (2004) Transplantation of skeletal myoblasts secreting an IL-1 inhibitor modulates adverse remodeling in infarcted murine myocardium. Proc Natl Acad Sci USA 101:4216–4221

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  94. 94.

    Rowart P, Erpicum P, Detry O et al (2015) Mesenchymal Stromal Cell Therapy in Ischemia/Reperfusion Injury. J Immunol Res 2015:602597

    PubMed Central  PubMed  Article  Google Scholar 

  95. 95.

    De Miguel MP, Fuentes-Julian S, Blazquez-Martinez A et al (2012) Immunosuppressive properties of mesenchymal stem cells: advances and applications. Curr Mol Med 12:574–591

    PubMed  Article  Google Scholar 

  96. 96.

    Teramura Y, Asif S, Ekdahl KN, Nilsson B (2015) Cell surface engineering for regulation of immune reactions in cell therapy. Adv Exp Med Biol 865:189–209

    PubMed  Article  Google Scholar 

  97. 97.

    Guo J, Zheng D, Li WF, Li HR, Zhang AD, Li ZC (2014) Insulin-like growth factor 1 treatment of MSCs attenuates inflammation and cardiac dysfunction following MI. Inflammation 37:2156–2163

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Choi HJ, Seon MR, Lim SS, Kim JS, Chun HS, Park JH (2008) Hexane/ethanol extract of Glycyrrhiza uralensis licorice suppresses doxorubicin-induced apoptosis in H9c2 rat cardiac myoblasts. Exp Biol Med 233:1554–1560

    CAS  Article  Google Scholar 

  99. 99.

    Madonna R, Taylor DA, Geng YJ et al (2013) Transplantation of mesenchymal cells rejuvenated by the overexpression of telomerase and myocardin promotes revascularization and tissue repair in a murine model of hindlimb ischemia. Circ Res 113:902–914

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Smith MI, Huang YY, Deshmukh M (2009) Skeletal muscle differentiation evokes endogenous XIAP to restrict the apoptotic pathway. PLoS ONE 4:e5097

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  101. 101.

    Zhang L, Xing D, Liu L, Gao X, Chen M (2007) TNFalpha induces apoptosis through JNK/Bax-dependent pathway in differentiated, but not naive PC12 cells. Cell Cycle 6:1479–1486

    CAS  PubMed  Google Scholar 

  102. 102.

    Luo W, Cao J, Li J, He W (2008) Adipose tissue-specific PPARgamma deficiency increases resistance to oxidative stress. Exp Gerontol 43:154–163

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    Cecchi C, Pensalfini A, Liguri G et al (2008) Differentiation increases the resistance of neuronal cells to amyloid toxicity. Neurochem Res 33:2516–2531

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Kalvelyte A, Krestnikova N, Stulpinas A et al (2013) Long-term muscle-derived cell culture: multipotency and susceptibility to cell death stimuli. Cell Biol Int 37:292–304

    CAS  PubMed  Article  Google Scholar 

  105. 105.

    George S, Heng BC, Vinoth KJ, Kishen A, Cao T (2009) Comparison of the response of human embryonic stem cells and their differentiated progenies to oxidative stress. Photomedicine Laser Surg 27:669–674

    CAS  Article  Google Scholar 

  106. 106.

    Drowley L, Okada M, Beckman S et al (2010) Cellular antioxidant levels influence muscle stem cell therapy. Mol Ther 18:1865–1873

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  107. 107.

    Sehgal V, Ram PT (2013) Network Motifs in JNK Signaling. Genes & cancer 4:409–413

    CAS  Article  Google Scholar 

  108. 108.

    Mangi AA, Noiseux N, Kong D et al (2003) Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med 9:1195–1201

    CAS  PubMed  Article  Google Scholar 

  109. 109.

    Jiang BH, Aoki M, Zheng JZ, Li J, Vogt PK (1999) Myogenic signaling of phosphatidylinositol 3-kinase requires the serine-threonine kinase Akt/protein kinase B. Proc Natl Acad Sci USA 96:2077–2081

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  110. 110.

    Fujio Y, Guo K, Mano T, Mitsuuchi Y, Testa JR, Walsh K (1999) Cell cycle withdrawal promotes myogenic induction of Akt, a positive modulator of myocyte survival. Mol Cell Biol 19:5073–5082

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  111. 111.

    Han D, Huang W, Ma S et al (2015) Ghrelin improves functional survival of engrafted adipose-derived mesenchymal stem cells in ischemic heart through PI3K/Akt signaling pathway. BioMed Res Int 2015:858349

    PubMed Central  PubMed  Google Scholar 

  112. 112.

    Lin Z, Zhou P, von Gise A et al (2015) Pi3kcb links Hippo-YAP and PI3K-AKT signaling pathways to promote cardiomyocyte proliferation and survival. Circ Res 116:35–45

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  113. 113.

    Vandromme M, Rochat A, Meier R et al (2001) Protein kinase B beta/Akt2 plays a specific role in muscle differentiation. J Biol Chem 276:8173–8179

    CAS  PubMed  Article  Google Scholar 

  114. 114.

    Sussman MA, Volkers M, Fischer K et al (2011) Myocardial AKT: the omnipresent nexus. Physiol Rev 91:1023–1070

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  115. 115.

    Matsui T, Tao J, del Monte F et al (2001) Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo. Circulation 104:330–335

    CAS  PubMed  Article  Google Scholar 

  116. 116.

    Shiraishi I, Melendez J, Ahn Y et al (2004) Nuclear targeting of Akt enhances kinase activity and survival of cardiomyocytes. Circ Res 94:884–891

    CAS  PubMed  Article  Google Scholar 

  117. 117.

    Gude N, Muraski J, Rubio M et al (2006) Akt promotes increased cardiomyocyte cycling and expansion of the cardiac progenitor cell population. Circ Res 99:381–388

    CAS  PubMed  Article  Google Scholar 

  118. 118.

    Sussman M (2007) “AKT”ing lessons for stem cells: regulation of cardiac myocyte and progenitor cell proliferation. Trends Cardiovasc Med 17:235–240

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  119. 119.

    Xu J, Liao K (2004) Protein kinase B/AKT 1 plays a pivotal role in insulin-like growth factor-1 receptor signaling induced 3T3-L1 adipocyte differentiation. J Biol Chem 279:35914–35922

    CAS  PubMed  Article  Google Scholar 

  120. 120.

    Mukherjee A, Rotwein P (2009) Akt promotes BMP2-mediated osteoblast differentiation and bone development. J Cell Sci 122:716–726

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  121. 121.

    Stulpinas A, Imbrasaite A, Kalvelyte AV (2012) Daunorubicin induces cell death via activation of apoptotic signalling pathway and inactivation of survival pathway in muscle-derived stem cells. Cell Biol Toxicol 28:103–114

    CAS  PubMed  Article  Google Scholar 

  122. 122.

    McDonald GT, Sullivan R, Pare GC, Graham CH (2010) Inhibition of phosphatidylinositol 3-kinase promotes tumor cell resistance to chemotherapeutic agents via a mechanism involving delay in cell cycle progression. Exp Cell Res 316:3197–3206

    CAS  PubMed  Article  Google Scholar 

  123. 123.

    Suvasini R, Somasundaram K (2010) Essential role of PI3-kinase pathway in p53-mediated transcription: Implications in cancer chemotherapy. Oncogene 29:3605–3618

    CAS  PubMed  Article  Google Scholar 

  124. 124.

    Elmadbouh I, Haider H, Jiang S, Idris NM, Lu G, Ashraf M (2007) Ex vivo delivered stromal cell-derived factor-1alpha promotes stem cell homing and induces angiomyogenesis in the infarcted myocardium. J Mol Cell Cardiol 42:792–803

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  125. 125.

    Hur J, Yoon CH, Lee CS et al (2007) Akt is a key modulator of endothelial progenitor cell trafficking in ischemic muscle. Stem Cells 25:1769–1778

    CAS  PubMed  Article  Google Scholar 

  126. 126.

    McDevitt TC, Laflamme MA, Murry CE (2005) Proliferation of cardiomyocytes derived from human embryonic stem cells is mediated via the IGF/PI 3-kinase/Akt signaling pathway. J Mol Cell Cardiol 39:865–873

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  127. 127.

    Tateishi K, Ashihara E, Honsho S et al (2007) Human cardiac stem cells exhibit mesenchymal features and are maintained through Akt/GSK-3beta signaling. Biochem Biophys Res Commun 352:635–641

    CAS  PubMed  Article  Google Scholar 

  128. 128.

    Otsu K, Yamashita N, Nishida K et al (2003) Disruption of a single copy of the p38alpha MAP kinase gene leads to cardioprotection against ischemia-reperfusion. Biochem Biophys Res Commun 302:56–60

    CAS  PubMed  Article  Google Scholar 

  129. 129.

    Molkentin JD, Dorn GW 2nd (2001) Cytoplasmic signaling pathways that regulate cardiac hypertrophy. Annu Rev Physiol 63:391–426

    CAS  PubMed  Article  Google Scholar 

  130. 130.

    Rose BA, Force T, Wang Y (2010) Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale. Physiol Rev 90:1507–1546

    CAS  PubMed  Article  Google Scholar 

  131. 131.

    Chen M, Bi LL, Wang ZQ, Zhao F, Gan XD, Wang YG (2013) Time-dependent regulation of neuregulin-1beta/ErbB/ERK pathways in cardiac differentiation of mouse embryonic stem cells. Mol Cell Biochem 380:67–72

    CAS  PubMed  Article  Google Scholar 

  132. 132.

    Kitta K, Day RM, Kim Y, Torregroza I, Evans T, Suzuki YJ (2003) Hepatocyte growth factor induces GATA-4 phosphorylation and cell survival in cardiac muscle cells. J Biol Chem 278:4705–4712

    CAS  PubMed  Article  Google Scholar 

  133. 133.

    Parrizas M, Blakesley VA, Beitner-Johnson D, Le Roith D (1997) The proto-oncogene Crk-II enhances apoptosis by a Ras-dependent, Raf-1/MAP kinase-independent pathway. Biochem Biophys Res Commun 234:616–620

    CAS  PubMed  Article  Google Scholar 

  134. 134.

    Sheng Z, Knowlton K, Chen J, Hoshijima M, Brown JH, Chien KR (1997) Cardiotrophin 1 (CT-1) inhibition of cardiac myocyte apoptosis via a mitogen-activated protein kinase-dependent pathway. Divergence from downstream CT-1 signals for myocardial cell hypertrophy. J Biol Chem 272:5783–5791

    CAS  PubMed  Article  Google Scholar 

  135. 135.

    De Windt LJ, Lim HW, Taigen T et al (2000) Calcineurin-mediated hypertrophy protects cardiomyocytes from apoptosis in vitro and in vivo: An apoptosis-independent model of dilated heart failure. Circ Res 86:255–263

    PubMed  Article  Google Scholar 

  136. 136.

    Iwai-Kanai E, Hasegawa K, Fujita M et al (2002) Basic fibroblast growth factor protects cardiac myocytes from iNOS-mediated apoptosis. J Cell Physiol 190:54–62

    CAS  PubMed  Article  Google Scholar 

  137. 137.

    Dang LT, Feric NT, Laschinger C et al (2014) Inhibition of apoptosis in human induced pluripotent stem cells during expansion in a defined culture using angiopoietin-1 derived peptide QHREDGS. Biomaterials 35:7786–7799

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  138. 138.

    Yamamoto K, Ichijo H, Korsmeyer SJ (1999) BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G(2)/M. Mol Cell Biol 19:8469–8478

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  139. 139.

    Tournier C, Hess P, Yang DD et al (2000) Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science 288:870–874

    CAS  PubMed  Article  Google Scholar 

  140. 140.

    Remondino A, Kwon SH, Communal C et al (2003) Beta-adrenergic receptor-stimulated apoptosis in cardiac myocytes is mediated by reactive oxygen species/c-Jun NH2-terminal kinase-dependent activation of the mitochondrial pathway. Circ Res 92:136–138

    CAS  PubMed  Article  Google Scholar 

  141. 141.

    Andreka P, Zang J, Dougherty C, Slepak TI, Webster KA, Bishopric NH (2001) Cytoprotection by Jun kinase during nitric oxide-induced cardiac myocyte apoptosis. Circ Res 88:305–312

    CAS  PubMed  Article  Google Scholar 

  142. 142.

    Dougherty CJ, Kubasiak LA, Prentice H, Andreka P, Bishopric NH, Webster KA (2002) Activation of c-Jun N-terminal kinase promotes survival of cardiac myocytes after oxidative stress. Biochem J 362:561–571

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  143. 143.

    Cicconi S, Ventura N, Pastore D et al (2003) Characterization of apoptosis signal transduction pathways in HL-5 cardiomyocytes exposed to ischemia/reperfusion oxidative stress model. J Cell Physiol 195:27–37

    CAS  PubMed  Article  Google Scholar 

  144. 144.

    Stewart CE, Newcomb PV, Holly JM (2004) Multifaceted roles of TNF-alpha in myoblast destruction: a multitude of signal transduction pathways. J Cell Physiol 198:237–247

    CAS  PubMed  Article  Google Scholar 

  145. 145.

    Liu QC, Zha XH, Faralli H et al (2012) Comparative expression profiling identifies differential roles for Myogenin and p38alpha MAPK signaling in myogenesis. J Mol Cell Biol 4:386–397

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  146. 146.

    Xiao F, Wang H, Fu X, Li Y, Wu Z (2012) TRAF6 promotes myogenic differentiation via the TAK1/p38 mitogen-activated protein kinase and Akt pathways. PLoS ONE 7:e34081

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  147. 147.

    Kaiser RA, Bueno OF, Lips DJ et al (2004) Targeted inhibition of p38 mitogen-activated protein kinase antagonizes cardiac injury and cell death following ischemia-reperfusion in vivo. J Biol Chem 279:15524–15530

    CAS  PubMed  Article  Google Scholar 

  148. 148.

    Mackay K, Mochly-Rosen D (2000) Involvement of a p38 mitogen-activated protein kinase phosphatase in protecting neonatal rat cardiac myocytes from ischemia. J Mol Cell Cardiol 32:1585–1588

    CAS  PubMed  Article  Google Scholar 

  149. 149.

    Sharov VG, Todor A, Suzuki G, Morita H, Tanhehco EJ, Sabbah HN (2003) Hypoxia, angiotensin-II, and norepinephrine mediated apoptosis is stimulus specific in canine failed cardiomyocytes: a role for p38 MAPK, Fas-L and cyclin D1. Eur J Heart Fail 5:121–129

    CAS  PubMed  Article  Google Scholar 

  150. 150.

    Communal C, Colucci WS, Singh K (2000) p38 mitogen-activated protein kinase pathway protects adult rat ventricular myocytes against beta -adrenergic receptor-stimulated apoptosis. Evidence for Gi-dependent activation. J Biol Chem 275:19395–19400

    CAS  PubMed  Article  Google Scholar 

  151. 151.

    Payne KA, Meszaros LB, Phillippi JA, Huard J (2010) Effect of phosphatidyl inositol 3-kinase, extracellular signal-regulated kinases 1/2, and p38 mitogen-activated protein kinase inhibition on osteogenic differentiation of muscle-derived stem cells. Tissue Eng Part A 16:3647–3655

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  152. 152.

    Wei H, Li Z, Hu S, Chen X, Cong X (2010) Apoptosis of mesenchymal stem cells induced by hydrogen peroxide concerns both endoplasmic reticulum stress and mitochondrial death pathway through regulation of caspases, p38 and JNK. J Cell Biochem 111:967–978

    CAS  PubMed  Article  Google Scholar 

  153. 153.

    Evans CH, Huard J (2015) Gene therapy approaches to regenerating the musculoskeletal system. Nat Rev Rheumatol 11:234–242

    CAS  PubMed  Article  Google Scholar 

  154. 154.

    Kim WH, Jung DW, Williams DR (2015) Making cardiomyocytes with your chemistry set: Small molecule-induced cardiogenesis in somatic cells. World J Cardiol 7:125–133

    PubMed Central  PubMed  Article  Google Scholar 

  155. 155.

    Pasha Z, Haider H, Ashraf M (2011) Efficient non-viral reprogramming of myoblasts to stemness with a single small molecule to generate cardiac progenitor cells. PLoS ONE 6:e23667

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  156. 156.

    Sawyers CL (2002) Rational therapeutic intervention in cancer: kinases as drug targets. Curr Opin Genet Dev 12:111–115

    CAS  PubMed  Article  Google Scholar 

  157. 157.

    Kyttaris VC (2012) Kinase inhibitors: a new class of antirheumatic drugs. Drug Des Dev Ther 6:245–250

    CAS  Article  Google Scholar 

  158. 158.

    Scatena M, Almeida M, Chaisson ML, Fausto N, Nicosia RF, Giachelli CM (1998) NF-kappaB mediates alphavbeta3 integrin-induced endothelial cell survival. J Cell Biol 141:1083–1093

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  159. 159.

    Watanabe K, Ueno M, Kamiya D et al (2007) A ROCK inhibitor permits survival of dissociated human embryonic stem cells. Nat Biotechnol 25:681–686

    CAS  PubMed  Article  Google Scholar 

  160. 160.

    Milisav I, Ribaric S, Suput D (2015) Targeting stress responses for regenerative medicine. Methods Mol Biol 1292:235–243

    PubMed  Article  Google Scholar 

  161. 161.

    Zhang Y, Liang X, Liao S et al (2015) Potent paracrine effects of human induced pluripotent stem cell-derived mesenchymal stem cells attenuate doxorubicin-induced cardiomyopathy. Sci Rep 5:11235

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  162. 162.

    Wang M, Tan J, Coffey A, Fehrenbacher J, Weil BR, Meldrum DR (2009) Signal transducer and activator of transcription 3-stimulated hypoxia inducible factor-1alpha mediates estrogen receptor-alpha-induced mesenchymal stem cell vascular endothelial growth factor production. J Thorac Cardiovasc Surg 138:163–171, 171 e161.

  163. 163.

    Wang Y, Crisostomo PR, Wang M, Markel TA, Novotny NM, Meldrum DR (2008) TGF-alpha increases human mesenchymal stem cell-secreted VEGF by MEK- and PI3-K- but not JNK- or ERK-dependent mechanisms. Am J Physiol Regul Integr Comp Physiol 295:R1115–1123

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  164. 164.

    Wang ZJ, Zhang FM, Wang LS, Yao YW, Zhao Q, Gao X (2009) Lipopolysaccharides can protect mesenchymal stem cells (MSCs) from oxidative stress-induced apoptosis and enhance proliferation of MSCs via Toll-like receptor(TLR)-4 and PI3K/Akt. Cell Biol Int 33:665–674

    CAS  PubMed  Article  Google Scholar 

  165. 165.

    Yun SP, Lee MY, Ryu JM, Song CH, Han HJ (2009) Role of HIF-1alpha and VEGF in human mesenchymal stem cell proliferation by 17beta-estradiol: involvement of PKC, PI3K/Akt, and MAPKs. Am J Physiol Cell Physiol 296:C317–326

    CAS  PubMed  Article  Google Scholar 

  166. 166.

    Fan VH, Tamama K, Au A et al (2007) Tethered epidermal growth factor provides a survival advantage to mesenchymal stem cells. Stem Cells 25:1241–1251

    CAS  PubMed  Article  Google Scholar 

  167. 167.

    Abdelwahid E, Yokokura T, Krieser RJ, Balasundaram S, Fowle WH, White K (2007) Mitochondrial disruption in Drosophila apoptosis. Dev Cell 12:793–806

    CAS  PubMed  Article  Google Scholar 

  168. 168.

    Tait SW, Green DR (2010) Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 11:621–632

    CAS  PubMed  Article  Google Scholar 

  169. 169.

    Deuse T, Wang D, Stubbendorff M et al (2015) SCNT-derived ESCs with mismatched mitochondria trigger an immune response in allogeneic hosts. Cell Stem Cell 16:33–38

    CAS  PubMed  Article  Google Scholar 

  170. 170.

    Zhu W, Chen J, Cong X, Hu S, Chen X (2006) Hypoxia and serum deprivation-induced apoptosis in mesenchymal stem cells. Stem Cells 24:416–425

    PubMed  Article  Google Scholar 

  171. 171.

    O’Rourke B (2004) Evidence for mitochondrial K + channels and their role in cardioprotection. Circ Res 94:420–432

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  172. 172.

    Haider H, Ashraf M (2008) Strategies to promote donor cell survival: combining preconditioning approach with stem cell transplantation. J Mol Cell Cardiol 45:554–566

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  173. 173.

    Laflamme MA, Chen KY, Naumova AV et al (2007) Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol 25:1015–1024

    CAS  PubMed  Article  Google Scholar 

  174. 174.

    Noort WA, Feye D, Van Den Akker F et al (2010) Mesenchymal stromal cells to treat cardiovascular disease: strategies to improve survival and therapeutic results. Panminerva Med 52:27–40

    CAS  PubMed  Google Scholar 

  175. 175.

    Lu G, Haider HK, Jiang S, Ashraf M (2009) Sca-1+ stem cell survival and engraftment in the infarcted heart: dual role for preconditioning-induced connexin-43. Circulation 119:2587–2596

    PubMed Central  PubMed  Article  Google Scholar 

  176. 176.

    Tilkorn DJ, Davies EM, Keramidaris E et al (2012) The in vitro preconditioning of myoblasts to enhance subsequent survival in an in vivo tissue engineering chamber model. Biomaterials 33:3868–3879

    CAS  PubMed  Article  Google Scholar 

  177. 177.

    Calabrese EJ, Bachmann KA, Bailer AJ et al (2007) Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework. Toxicol Appl Pharmacol 222:122–128

    CAS  PubMed  Article  Google Scholar 

  178. 178.

    Hausenloy DJ, Yellon DM (2006) Survival kinases in ischemic preconditioning and postconditioning. Cardiovasc Res 70:240–253

    CAS  PubMed  Article  Google Scholar 

  179. 179.

    Chen J, Crawford R, Chen C, Xiao Y (2013) The key regulatory roles of the PI3K/Akt signaling pathway in the functionalities of mesenchymal stem cells and applications in tissue regeneration. Tissue Eng Part B Rev 19:516–528

    CAS  PubMed  Article  Google Scholar 

  180. 180.

    Gough DR, Cotter TG (2011) Hydrogen peroxide: a Jekyll and Hyde signalling molecule. Cell Death Dis 2:e213

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  181. 181.

    Gao F, Hu XY, Xie XJ et al (2010) Heat shock protein 90 protects rat mesenchymal stem cells against hypoxia and serum deprivation-induced apoptosis via the PI3K/Akt and ERK1/2 pathways. J Zhejiang Univ Sci B 11:608–617

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  182. 182.

    Cizkova D, Rosocha J, Vanicky I, Radonak J, Galik J, Cizek M (2006) Induction of mesenchymal stem cells leads to HSP72 synthesis and higher resistance to oxidative stress. Neurochem Res 31:1011–1020

    CAS  PubMed  Article  Google Scholar 

  183. 183.

    Das B, Bayat-Mokhtari R, Tsui M et al (2012) HIF-2alpha suppresses p53 to enhance the stemness and regenerative potential of human embryonic stem cells. Stem Cells 30:1685–1695

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  184. 184.

    Datta SR, Brunet A, Greenberg ME (1999) Cellular survival: a play in three Akts. Genes Dev 13:2905–2927

    CAS  PubMed  Article  Google Scholar 

  185. 185.

    Jagnandan D, Church JE, Banfi B, Stuehr DJ, Marrero MB, Fulton DJ (2007) Novel mechanism of activation of NADPH oxidase 5. calcium sensitization via phosphorylation. J Biol Chem 282:6494–6507

    CAS  PubMed  Article  Google Scholar 

  186. 186.

    Rodrigues M, Blair H, Stockdale L, Griffith L, Wells A (2013) Surface tethered epidermal growth factor protects proliferating and differentiating multipotential stromal cells from FasL-induced apoptosis. Stem Cells 31:104–116

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  187. 187.

    Rodrigues M, Yates CC, Nuschke A, Griffith L, Wells A (2013) The matrikine tenascin-C protects multipotential stromal cells/mesenchymal stem cells from death cytokines such as FasL. Tissue Eng Part A 19:1972–1983

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  188. 188.

    Qu Q, Sun G, Murai K et al (2013) Wnt7a regulates multiple steps of neurogenesis. Mol Cell Biol 33:2551–2559

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  189. 189.

    Bentzinger CF, von Maltzahn J, Dumont NA et al (2014) Wnt7a stimulates myogenic stem cell motility and engraftment resulting in improved muscle strength. J Cell Biol 205:97–111

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  190. 190.

    Di Santo S, Yang Z, Wyler von Ballmoos M et al (2009) Novel cell-free strategy for therapeutic angiogenesis: in vitro generated conditioned medium can replace progenitor cell transplantation. PLoS ONE 4:e5643

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  191. 191.

    Lavasani M, Robinson AR, Lu A et al (2012) Muscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model. Nat Commun 3:608

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  192. 192.

    Jin H, Sanberg PR, Henning RJ (2013) Human umbilical cord blood mononuclear cell-conditioned media inhibits hypoxic-induced apoptosis in human coronary artery endothelial cells and cardiac myocytes by activation of the survival protein Akt. Cell Transpl 22:1637–1650

    Article  Google Scholar 

  193. 193.

    Shintani Y, Fukushima S, Varela-Carver A et al (2009) Donor cell-type specific paracrine effects of cell transplantation for post-infarction heart failure. J Mol Cell Cardiol 47:288–295

    CAS  PubMed  Article  Google Scholar 

  194. 194.

    Chen TS, Lai RC, Lee MM, Choo AB, Lee CN, Lim SK (2010) Mesenchymal stem cell secretes microparticles enriched in pre-microRNAs. Nucl Acids Res 38:215–224

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  195. 195.

    Huang L, Ma W, Ma Y, Feng D, Chen H, Cai B (2015) Exosomes in mesenchymal stem cells, a new therapeutic strategy for cardiovascular diseases? Int J Biol Sci 11:238–245

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  196. 196.

    Nakamura Y, Miyaki S, Ishitobi H et al (2015) Mesenchymal-stem-cell-derived exosomes accelerate skeletal muscle regeneration. FEBS Lett 589:1257–1265

    CAS  PubMed  Article  Google Scholar 

  197. 197.

    Ibrahim AG, Cheng K, Marban E (2014) Exosomes as critical agents of cardiac regeneration triggered by cell therapy. Stem Cell Rep 2:606–619

    CAS  Article  Google Scholar 

  198. 198.

    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

    PubMed  Article  Google Scholar 

  199. 199.

    Mukherjee S, Lekli I, Das M, Azzi A, Das DK (2008) Cardioprotection with alpha-tocopheryl phosphate: amelioration of myocardial ischemia reperfusion injury is linked with its ability to generate a survival signal through Akt activation. Biochim Biophys Acta 1782:498–503

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  200. 200.

    Houbaviy HB, Murray MF, Sharp PA (2003) Embryonic stem cell-specific MicroRNAs. Dev Cell 5:351–358

    CAS  PubMed  Article  Google Scholar 

  201. 201.

    Crippa S, Cassano M, Sampaolesi M (2012) Role of miRNAs in muscle stem cell biology: proliferation, differentiation and death. Curr Pharm Des 18:1718–1729

    CAS  PubMed  Article  Google Scholar 

  202. 202.

    Nie Y, Han BM, Liu XB et al (2011) Identification of MicroRNAs involved in hypoxia- and serum deprivation-induced apoptosis in mesenchymal stem cells. Int J Biol Sci 7:762–768

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  203. 203.

    Guo C, Deng Y, Liu J, Qian L (2015) Cardiomyocyte-specific role of miR-24 in promoting cell survival. J Cell Mol Med 19:103–112

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  204. 204.

    Ruan W, Xu JM, Li SB, Yuan LQ, Dai RP (2012) Effects of down-regulation of microRNA-23a on TNF-alpha-induced endothelial cell apoptosis through caspase-dependent pathways. Cardiovasc Res 93:623–632

    CAS  PubMed  Article  Google Scholar 

  205. 205.

    Mao J, Lv Z, Zhuang Y (2014) MicroRNA-23a is involved in tumor necrosis factor-alpha induced apoptosis in mesenchymal stem cells and myocardial infarction. Exp Mol Pathol 97:23–30

    CAS  PubMed  Article  Google Scholar 

  206. 206.

    Kim HW, Haider HK, Jiang S, Ashraf M (2009) Ischemic preconditioning augments survival of stem cells via miR-210 expression by targeting caspase-8-associated protein 2. J Biol Chem 284:33161–33168

    PubMed  Article  CAS  Google Scholar 

  207. 207.

    Dakhlallah D, Zhang J, Yu L, Marsh CB, Angelos MG, Khan M (2015) MicroRNA-133a engineered mesenchymal stem cells augment cardiac function and cell survival in the infarct heart. J Cardiovasc Pharmacol 65:241–251

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  208. 208.

    Glass C, Singla DK (2011) MicroRNA-1 transfected embryonic stem cells enhance cardiac myocyte differentiation and inhibit apoptosis by modulating the PTEN/Akt pathway in the infarcted heart. Am J Physiol Heart Circ Physiol 301:H2038–2049

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  209. 209.

    Bao C, Guo J, Zheng M, Chen Y, Lin G, Hu M (2010) Enhancement of the survival of engrafted mesenchymal stem cells in the ischemic heart by TNFR gene transfection. Biochem Cell Biol 88:629–634

    CAS  PubMed  Article  Google Scholar 

  210. 210.

    Bialas M, Krupka M, Janeczek A et al (2011) Transient and stable transfections of mouse myoblasts with genes coding for pro-angiogenic factors. J Physiol Pharmacol 62:219–228

    CAS  PubMed  Google Scholar 

  211. 211.

    Blumenthal B, Poppe A, Golsong P et al (2011) Functional regeneration of ischemic myocardium by transplanted cells overexpressing stromal cell-derived factor-1 (SDF-1): intramyocardial injection versus scaffold-based application. Eur J Cardio Thorac Surg 40:e135–141

    Google Scholar 

  212. 212.

    Kutschka I, Kofidis T, Chen IY et al (2006) Adenoviral human BCL-2 transgene expression attenuates early donor cell death after cardiomyoblast transplantation into ischemic rat hearts. Circulation 114:I174–180

    PubMed  Google Scholar 

  213. 213.

    Liang X, Ding Y, Zhang Y et al (2015) Activation of NRG1-ERBB4 signaling potentiates mesenchymal stem cell-mediated myocardial repairs following myocardial infarction. Cell Death Dis 6:e1765

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  214. 214.

    Song SW, Chang W, Song BW et al (2009) Integrin-linked kinase is required in hypoxic mesenchymal stem cells for strengthening cell adhesion to ischemic myocardium. Stem Cells 27:1358–1365

    CAS  PubMed  Article  Google Scholar 

  215. 215.

    Henry TD, Grines CL, Watkins MW et al (2007) Effects of Ad5FGF-4 in patients with angina: an analysis of pooled data from the AGENT-3 and AGENT-4 trials. J Am Coll Cardiol 50:1038–1046

    CAS  PubMed  Article  Google Scholar 

  216. 216.

    Welman T, Michel S, Segaren N, Shanmugarajah K (2015) Bioengineering for organ transplantation: progress and challenges. Bioengineered 6:257–261

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgments

We thank Denislam Zaripov for skillful art drawing. E.A. was supported by the National Heart, Lung, and Blood Institute (NIH/NHLBI), grant SP0012613. A.S. and A.K. were supported by the European Social Fund under National Integrated Programme Biotechnology & Biopharmacy, Grant VP1-3.1-SMM-08-K01-005.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Eltyeb Abdelwahid.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Abdelwahid, E., Kalvelyte, A., Stulpinas, A. et al. Stem cell death and survival in heart regeneration and repair. Apoptosis 21, 252–268 (2016). https://doi.org/10.1007/s10495-015-1203-4

Download citation

Keywords

  • Cell death
  • Stem cells
  • Apoptosis
  • Therapy
  • Heart
  • Regeneration