"string theory" of c-kitpos cardiac cells: A new paradigm regarding the nature of these cells that may reconcile apparently discrepant results

Circulation Research

Volumn 116, Issue 7, 2015, Pages 1216-1230

  Keith, Matthew C L ^a   Bolli, Roberto ^a  

^a University of Louisville School of Medicine   (United States)

Author keywords

Muscle development; Myocytes, cardiac; Regeneration

Indexed keywords

ENHANCED GREEN FLUORESCENT PROTEIN; EOMESODERMIN; OCTAMER TRANSCRIPTION FACTOR 4; STEM CELL FACTOR RECEPTOR; TRANSCRIPTION FACTOR GATA 4; TRANSCRIPTION FACTOR NKX2.5; TRANSFORMING GROWTH FACTOR BETA; VASCULOTROPIN RECEPTOR 2; WT1 PROTEIN; CYTOKINE; SIGNAL PEPTIDE;

BONE MARROW DERIVED MESENCHYMAL STEM CELL; CELL DIFFERENTIATION; CELL LINEAGE; CELL MATURATION; DEVELOPMENTAL BIOLOGY; EMBRYO DEVELOPMENT; ENDOTHELIUM CELL; ENZYME MECHANISM; EPICARDIUM; HEART DEVELOPMENT; HEART FIBROBLAST; HEART INFARCTION; HEART MUSCLE BIOPSY; HEART MUSCLE CELL; HUMAN; IN VITRO STUDY; MAMMAL CELL; MESENCHYME; MUSCLE DEVELOPMENT; NONHUMAN; PARACRINE SIGNALING; PHENOTYPIC VARIATION; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; SMOOTH MUSCLE FIBER; STROMA CELL; ADVENTITIA; AUTOTRANSPLANTATION; BIOLOGICAL MODEL; BLOOD VESSEL; CHEMISTRY; CLASSIFICATION; CYTOLOGY; EMBRYOLOGY; ENDOCARDIUM; EPITHELIAL MESENCHYMAL TRANSITION; GRAFT SURVIVAL; HEART; MYOCARDIAL INFARCTION; PERICARDIUM; PHASE 1 CLINICAL TRIAL (TOPIC); PHYSIOLOGY; SMOOTH MUSCLE; STEM CELL; TRANSPLANTATION;

ADVENTITIA; BLOOD VESSELS; CELL DIFFERENTIATION; CELL LINEAGE; CLINICAL TRIALS, PHASE I AS TOPIC; CYTOKINES; ENDOCARDIUM; EPITHELIAL-MESENCHYMAL TRANSITION; GRAFT SURVIVAL; HEART; HUMANS; INTERCELLULAR SIGNALING PEPTIDES AND PROTEINS; MODELS, CARDIOVASCULAR; MUSCLE, SMOOTH; MYOCARDIAL INFARCTION; MYOCYTES, CARDIAC; PARACRINE COMMUNICATION; PERICARDIUM; PROTO-ONCOGENE PROTEINS C-KIT; STEM CELLS; TRANSPLANTATION, AUTOLOGOUS;

EID: 84942885895     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.116.305557     Document Type: Review

References (106)

1. Hong KU, Guo Y, Li QH, Cao P, Al-Maqtari T, Vajravelu BN, Du J, Book MJ, Zhu X, Nong Y, Bhatnagar A, Bolli R, c-kit+ Cardiac stem cells alleviate post-myocardial infarction left ventricular dysfunction despite poor engraftment and negligible retention in the recipient heart. PLoS One 2014 9 e96725. doi: 10.1371/journal.pone.0096725.
2. Bolli R, Tang XL, Sanganalmath SK, Rimoldi O, Mosna F, Abdel-Latif A, Jneid H, Rota M, Leri A, Kajstura J, Intracoronary delivery of autologous cardiac stem cells improves cardiac function in a porcine model of chronic ischemic cardiomyopathy. Circulation 2013; 128: 122-131. doi: 10.1161/CIRCULATIONAHA.112.001075.
3. Sanganalmath SK, Bolli R, Cell therapy for heart failure: a comprehensive overview of experimental and clinical studies, current challenges, and future directions. Circ Res 2013; 113: 810-834. doi: 10.1161/CIRCRESAHA.113.300219.
4. Tang XL, Rokosh G, Sanganalmath SK, Yuan F, Sato H, Mu J, Dai S, Li C, Chen N, Peng Y, Dawn B, Hunt G, Leri A, Kajstura J, Tiwari S, Shirk G, Anversa P, Bolli R, Intracoronary administration of cardiac progenitor cells alleviates left ventricular dysfunction in rats with a 30-day-old infarction. Circulation 2010 121 293 305
5. Li Q, Guo Y, Ou Q, Chen N, Wu WJ, Yuan F, O'Brien E, Wang T, Luo L, Hunt GN, Zhu X, Bolli R, Intracoronary administration of cardiac stem cells in mice: a new, improved technique for cell therapy in murine models. Basic Res Cardiol 2011; 106: 849-864. doi: 10.1007/s00395-011-0180-1.
6. Bolli R, Chugh AR, D'Amario D, Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet 2011 378 1847 1857
7. Degenhardt K, Singh MK, Epstein JA, New approaches under development: cardiovascular embryology applied to heart disease. J Clin Invest 2013; 123: 71-74. doi: 10.1172/JCI62884.
8. Senyo SE, Steinhauser ML, Pizzimenti CL, Yang VK, Cai L, Wang M, Wu TD, Guerquin-Kern JL, Lechene CP, Lee RT, Mammalian heart renewal by pre-existing cardiomyocytes. Nature 2013; 493: 433-436. doi: 10.1038/nature11682.
9. Garbern JC, Lee RT, Cardiac stem cell therapy and the promise of heart regeneration. Cell Stem Cell 2013; 12: 689-698. doi: 10.1016/j.stem.2013.05.008.
10. 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, Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003 114 763 776
11. Zaruba MM, Soonpaa M, Reuter S, Field LJ, Cardiomyogenic potential of C-kit(+)-expressing cells derived from neonatal and adult mouse hearts. Circulation 2010; 121: 1992-2000. doi: 10.1161/CIRCULATIONAHA.109.909093.
12. Sturzu AC, Wu SM, Developmental and regenerative biology of multipotent cardiovascular progenitor cells. Circ Res 2011; 108: 353-364. doi: 10.1161/CIRCRESAHA.110.227066.
13. Heng BC, Cao T, Milieu-based versus gene-modulatory strategies for directing stem cell differentiation-A major issue of contention in transplantation medicine. In Vitro Cell Dev Biol Anim 2006; 42: 51-53. doi: 10.1290/0504025.1.
14. Heng BC, Haider H, Sim EK, Cao T, Ng SC, Strategies for directing the differentiation of stem cells into the cardiomyogenic lineage in vitro. Cardiovasc Research 2004 62 34 42
15. Ferreira-Martins J, Ogorek B, Cappetta D, Cardiomyogenesis in the developing heart is regulated by c-kit-positive cardiac stem cells. Circ Res 2012 110 701 715
16. Wu SM, Fujiwara Y, Cibulsky SM, Clapham DE, Lien CL, Schultheiss TM, Orkin SH, Developmental origin of a bipotential myocardial and smooth muscle cell precursor in the mammalian heart. Cell 2006; 127: 1137-1150. doi: 10.1016/j.cell.2006.10.028.
17. Hong KU, Li QH, Guo Y, Patton NS, Moktar A, Bhatnagar A, Bolli R, A highly sensitive and accurate method to quantify absolute numbers of c-kit+ cardiac stem cells following transplantation in mice. Basic Res Cardiol 2013 108 346. doi: 10.1007/s00395-013-0346-0.
18. van Berlo JH, Kanisicak O, Maillet M, Vagnozzi RJ, Karch J, Lin SC, Middleton RC, Marbán E, Molkentin JD, c-kit+ cells minimally contribute cardiomyocytes to the heart. Nature 2014; 509: 337-341. doi: 10.1038/nature13309.
19. Williams AR, Hatzistergos KE, Addicott B, McCall F, Carvalho D, Suncion V, Morales AR, Da Silva J, Sussman MA, Heldman AW, Hare JM, Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and to restore cardiac function after myocardial infarction. Circulation 2013; 127: 213-223. doi: 10.1161/CIRCULATIONAHA.112.131110.
20. Fischer KM, Cottage CT, Wu W, Din S, Gude NA, Avitabile D, Quijada P, Collins BL, Fransioli J, Sussman MA, Enhancement of myocardial regeneration through genetic engineering of cardiac progenitor cells expressing Pim-1 kinase. Circulation 2009; 120: 2077-2087. doi: 10.1161/CIRCULATIONAHA.109.884403.
21. Dawn B, Stein AB, Urbanek K, Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function. Proc Natl Acad Sci U S A 2005 ;102: 3766-3771. XXX. doi: 10.1073/pnas.0405957102.
22. Deutsch MA, Sturzu A, Wu SM, At a crossroad: cell therapy for cardiac repair. Circ Res 2013; 112: 884-890. doi: 10.1161/CIRCRESAHA.112.275974.
23. Mirotsou M, Jayawardena TM, Schmeckpeper J, Gnecchi M, Dzau VJ, Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. J Mol Cell Cardiol 2011; 50: 280-289. doi: 10.1016/j.yjmcc.2010.08.005.
24. Liang X, Ding Y, Zhang Y, Tse HF, Lian Q, Paracrine mechanisms of mesenchymal stem cell-based therapy: Current status and perspectives. Cell Transplant 2014; 23(9) 1045-1059. doi: 10.3727/096368913X667709.
25. D'Amario D, Fiorini C, Campbell PM, Functionally competent cardiac stem cells can be isolated from endomyocardial biopsies of patients with advanced cardiomyopathies. Circ Res 2011; 108: 857-861. doi: 10.1161/CIRCRESAHA.111.241380.
26. Klarmann K, Ortiz M, Davies M, Keller JR, Identification of in vitro growth conditions for c-Kit-negative hematopoietic stem cells. Blood 2003; 102: 3120-3128. doi: 10.1182/blood-2003-04-1249.
27. Brade T, Pane LS, Moretti A, Chien KR, Laugwitz KL, Embryonic heart progenitors and cardiogenesis. Cold Spring Harb Perspect Med 2013 3 a013847. doi: 10.1101/cshperspect.a013847.
28. Xin M, Olson EN, Bassel-Duby R, Mending broken hearts: cardiac development as a basis for adult heart regeneration and repair. Nat Rev Mol Cell Biol 2013; 14: 529-541. doi: 10.1038/nrm3619.
29. Yang L, Soonpaa MH, Adler ED, Roepke TK, Kattman SJ, Kennedy M, Henckaerts E, Bonham K, Abbott GW, Linden RM, Field LJ, Keller GM, Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population. Nature 2008; 453: 524-528. doi: 10.1038/nature06894.
30. Noseda M, Peterkin T, Simões FC, Patient R, Schneider MD, Cardiopoietic factors: extracellular signals for cardiac lineage commitment. Circ Res 2011; 108: 129-152. doi: 10.1161/CIRCRESAHA.110.223792.
31. Kimelman D, Mesoderm induction: from caps to chips. Nat Rev Genet 2006; 7: 360-372. doi: 10.1038/nrg1837.
32. Kattman SJ, Huber TL, Keller GM, Multipotent flk-1+ cardiovascular progenitor cells give rise to the cardiomyocyte, endothelial, and vascular smooth muscle lineages. Dev Cell 2006; 11: 723-732. doi: 10.1016/j.devcel.2006.10.002.
33. Wu SM, Mesp1 at the heart of mesoderm lineage specification. Cell Stem Cell 2008; 3: 1-2. doi: 10.1016/j.stem.2008.06.017.
34. Bondue A, Blanpain C, Mesp1: a key regulator of cardiovascular lineage commitment. Circ Res 2010; 107: 1414-1427. doi: 10.1161/CIRCRESAHA.110.227058.
35. Abu-Issa R, Waldo K, Kirby ML, Heart fields: one, two or more? Dev Biol 2004; 272: 281-285. doi: 10.1016/j.ydbio.2004.05.016.
36. Gittenberger-de Groot AC, Blom NM, Aoyama N, Sucov H, Wenink AC, Poelmann RE, The role of neural crest and epicardium-derived cells in conduction system formation. Novartis Foundation Symposium 2003 250 125 134; discussion 134-141, 276-129
37. Abu-Issa R, Heart fields: spatial polarity and temporal dynamics. Anat Rec (Hoboken) 2014; 297: 175-182. doi: 10.1002/ar.22831.
38. Harris IS, Black BL, Development of the endocardium. Pediatr Cardiol 2010; 31: 391-399. doi: 10.1007/s00246-010-9642-8.
39. von Gise A, Pu WT, Endocardial and epicardial epithelial to mesenchymal transitions in heart development and disease. Circ Res 2012; 110: 1628-1645. doi: 10.1161/CIRCRESAHA.111.259960.
40. Sun Y, Liang X, Najafi N, Cass M, Lin L, Cai CL, Chen J, Evans SM, Islet 1 is expressed in distinct cardiovascular lineages, including pacemaker and coronary vascular cells. Dev Biol 2007; 304: 286-296. doi: 10.1016/j.ydbio.2006.12.048.
41. Laugwitz KL, Moretti A, Lam J, Gruber P, Chen Y, Woodard S, Lin LZ, Cai CL, Lu MM, Reth M, Platoshyn O, Yuan JX, Evans S, Chien KR, Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 2005; 433: 647-653. doi: 10.1038/nature03215.
42. Moretti A, Caron L, Nakano A, Lam JT, Bernshausen A, Chen Y, Qyang Y, Bu L, Sasaki M, Martin-Puig S, Sun Y, Evans SM, Laugwitz KL, Chien KR, Multipotent embryonic isl1+ progenitor cells lead to cardiac, smooth muscle, and endothelial cell diversification. Cell 2006; 127: 1151-1165. doi: 10.1016/j.cell.2006.10.029.
43. Kraus F, Haenig B, Kispert A, Cloning and expression analysis of the mouse T-box gene Tbx18. Mech Dev 2001 100 83 86
44. Bu L, Jiang X, Martin-Puig S, Caron L, Zhu S, Shao Y, Roberts DJ, Huang PL, Domian IJ, Chien KR, Human ISL1 heart progenitors generate diverse multipotent cardiovascular cell lineages. Nature 2009; 460: 113-117. doi: 10.1038/nature08191.
45. Zhou B, Ma Q, Rajagopal S, Wu SM, Domian I, Rivera-Feliciano J, Jiang D, von Gise A, Ikeda S, Chien KR, Pu WT, Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart. Nature 2008; 454: 109-113. doi: 10.1038/nature07060.
46. Zhou B, Honor LB, He H, Ma Q, Oh JH, Butterfield C, Lin RZ, Melero-Martin JM, Dolmatova E, Duffy HS, Gise A, Zhou P, Hu YW, Wang G, Zhang B, Wang L, Hall JL, Moses MA, McGowan FX, Pu WT, Adult mouse epicardium modulates myocardial injury by secreting paracrine factors. The Journal of clinical investigation 2011 121 1894 1904
47. Poelmann RE, Lie-Venema H, Gittenberger-de Groot AC, The role of the epicardium and neural crest as extracardiac contributors to coronary vascular development. Tex Heart Inst J 2002 29 255 261
48. Cai CL, Martin JC, Sun Y, Cui L, Wang L, Ouyang K, Yang L, Bu L, Liang X, Zhang X, Stallcup WB, Denton CP, McCulloch A, Chen J, Evans SM, A myocardial lineage derives from Tbx18 epicardial cells. Nature 2008; 454: 104-108. doi: 10.1038/nature06969.
49. Katz TC, Singh MK, Degenhardt K, Rivera-Feliciano J, Johnson RL, Epstein JA, Tabin CJ, Distinct compartments of the proepicardial organ give rise to coronary vascular endothelial cells. Dev Cell 2012; 22: 639-650. doi: 10.1016/j.devcel.2012.01.012.
50. Wada AM, Smith TK, Osler ME, Reese DE, Bader DM, Epicardial/Mesothelial cell line retains vasculogenic potential of embryonic epicardium. Circ Res 2003; 92: 525-531. doi: 10.1161/01.RES.0000060484.11032.0B.
51. van Tuyn J, Atsma DE, Winter EM, van der Velde-van Dijke I, Pijnappels DA, Bax NA, Knaän-Shanzer S, Gittenberger-de Groot AC, Poelmann RE, van der Laarse A, van der Wall EE, Schalij MJ, de Vries AA, Epicardial cells of human adults can undergo an epithelial-to-mesenchymal transition and obtain characteristics of smooth muscle cells in vitro. Stem Cells 2007; 25: 271-278. doi: 10.1634/stemcells.2006-0366.
52. Smart N, Risebro CA, Melville AA, Moses K, Schwartz RJ, Chien KR, Riley PR, Thymosin beta4 induces adult epicardial progenitor mobilization and neovascularization. Nature 2007; 445: 177-182. doi: 10.1038/nature05383.
53. Gittenberger-de Groot AC, Vrancken Peeters MP, Mentink MM, Gourdie RG, Poelmann RE, Epicardium-derived cells contribute a novel population to the myocardial wall and the atrioventricular cushions. Circulation research 1998 82 1043 1052
54. Misfeldt AM, Boyle SC, Tompkins KL, Bautch VL, Labosky PA, Baldwin HS, Endocardial cells are a distinct endothelial lineage derived from Flk1+ multipotent cardiovascular progenitors. Dev Biol 2009; 333: 78-89. doi: 10.1016/j.ydbio.2009.06.033.
55. He L, Tian X, Zhang H, Wythe JD, Zhou B, Fabp4-CreER lineage tracing revealstwo distinctive coronary vascular populations. J Cell Mol Med 2014; 18: 2152-2156. doi: 10.1111/jcmm.12415.
56. Puri MC, Partanen J, Rossant J, Bernstein A, Interaction of the TEK and TIE receptor tyrosine kinases during cardiovascular development. Development 1999 126 4569 4580
57. von Gise A, Zhou B, Honor LB, Ma Q, Petryk A, Pu WT, WT1 regulates epicardial epithelial to mesenchymal transition through β-catenin and retinoic acid signaling pathways. Dev Biol 2011; 356: 421-431. doi: 10.1016/j.ydbio.2011.05.668.
58. Christoffels VM, Grieskamp T, Norden J, Mommersteeg MT, Rudat C, Kispert A, Tbx18 and the fate of epicardial progenitors. Nature 2009 458 E8 9; discussion E9-10
59. Rinkevich Y, Mori T, Sahoo D, Xu PX, Bermingham JR Jr, Weissman IL, Identification and prospective isolation of a mesothelial precursor lineage giving rise to smooth muscle cells and fibroblasts for mammalian internal organs, and their vasculature. Nat Cell Biol 2012; 14: 1251-1260. doi: 10.1038/ncb2610.
60. Kikuchi K, Gupta V, Wang J, Holdway JE, Wills AA, Fang Y, Poss KD, tcf21+ epicardial cells adopt non-myocardial fates during zebrafish heart development and regeneration. Development 2011; 138: 2895-2902. doi: 10.1242/dev.067041.
61. Acharya A, Baek ST, Banfi S, Eskiocak B, Tallquist MD, Efficient inducible Cre-mediated recombination in Tcf21 cell lineages in the heart and kidney. Genesis 2011; 49: 870-877. doi: 10.1002/dvg.20750.
62. Porrello ER, Olson EN, A neonatal blueprint for cardiac regeneration. Stem Cell Res 2014; 13: 556-570. doi: 10.1016/j.scr.2014.06.003.
63. de la Pompa JL, Timmerman LA, Takimoto H, Yoshida H, Elia AJ, Samper E, Potter J, Wakeham A, Marengere L, Langille BL, Crabtree GR, Mak TW, Role of the nf-atc transcription factor in morphogenesis of cardiac valves and septum. Nature 1998 392 182 186
64. Castaldo C, Di Meglio F, Nurzynska D, Romano G, Maiello C, Bancone C, Müller P, Böhm M, Cotrufo M, Montagnani S, CD117-positive cells in adult human heart are localized in the subepicardium, and their activation is associated with laminin-1 and alpha6 integrin expression. Stem Cells 2008; 26: 1723-1731. doi: 10.1634/stemcells.2007-0732.
65. Di Meglio F, Castaldo C, Nurzynska D, Miraglia R, Romano V, Russolillo V, Giuseppina L, Vosa C, Montagnani S, Localization and origin of cardiac CD117-positive cells: identification of a population of epicardially-derived cells in adult human heart. Ital J Anat Embryol 2010 115 71 78
66. Di Meglio F, Castaldo C, Nurzynska D, Romano V, Miraglia R, Bancone C, Langella G, Vosa C, Montagnani S, Epithelial-mesenchymal transition of epicardial mesothelium is a source of cardiac CD117-positive stem cells in adult human heart. J Mol Cell Cardiol 2010; 49: 719-727. doi: 10.1016/j.yjmcc.2010.05.013.
67. Limana F, Bertolami C, Mangoni A, Di Carlo A, Avitabile D, Mocini D, Iannelli P, De Mori R, Marchetti C, Pozzoli O, Gentili C, Zacheo A, Germani A, Capogrossi MC, Myocardial infarction induces embryonic reprogramming of epicardial c-kit(+) cells: role of the pericardial fluid. J Mol Cell Cardiol 2010; 48: 609-618. doi: 10.1016/j.yjmcc.2009.11.008.
68. Matuszczak S, Czapla J, Jarosz-Biej M, Wisniewska E, Cichon T, Smolarczyk R, Kobusinska M, Gajda K, Wilczek P, Sliwka J, Zembala M, Zembala M, Szala S, Characteristic of c-kit progenitor cells in explanted human hearts. Clin Res Cardiol 2014; 103(9) 711-718. doi: 10.1007/s00392-014-0705-3.
69. Bondue A, Tännler S, Chiapparo G, Chabab S, Ramialison M, Paulissen C, Beck B, Harvey R, Blanpain C, Defining the earliest step of cardiovascular progenitor specification during embryonic stem cell differentiation. J Cell Biol 2011; 192: 751-765. doi: 10.1083/jcb.201007063.
70. Porrello ER, Mahmoud AI, Simpson E, Hill JA, Richardson JA, Olson EN, Sadek HA, Transient regenerative potential of the neonatal mouse heart. Science 2011; 331: 1078-1080. doi: 10.1126/science.1200708.
71. Limana F, Capogrossi MC, Germani A, The epicardium in cardiac repair: from the stem cell view. Pharmacol Ther 2011; 129: 82-96. doi: 10.1016/j.pharmthera.2010.09.002.
72. Gambini E, Pompilio G, Biondi A, Alamanni F, Capogrossi MC, Agrifoglio M, Pesce M, C-kit+ cardiac progenitors exhibit mesenchymal markers and preferential cardiovascular commitment. Cardiovasc Res 2011; 89: 362-373. doi: 10.1093/cvr/cvq292.
73. Smith RR, Barile L, Cho HC, Leppo MK, Hare JM, Messina E, Giacomello A, Abraham MR, Marbán E, Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation 2007; 115: 896-908. doi: 10.1161/CIRCULATIONAHA.106.655209.
74. Malliaras K, Li TS, Luthringer D, Terrovitis J, Cheng K, Chakravarty T, Galang G, Zhang Y, Schoenhoff F, Van Eyk J, Marbán L, Marbán E, Safety and efficacy of allogeneic cell therapy in infarcted rats transplanted with mismatched cardiosphere-derived cells. Circulation 2012; 125: 100-112. doi: 10.1161/CIRCULATIONAHA.111.042598.
75. Li TS, Cheng K, Malliaras K, Smith RR, Zhang Y, Sun B, Matsushita N, Blusztajn A, Terrovitis J, Kusuoka H, Marbán L, Marbán E, Direct comparison of different stem cell types and subpopulations reveals superior paracrine potency and myocardial repair efficacy with cardiosphere-derived cells. J Am Coll Cardiol 2012; 59: 942-953. doi: 10.1016/j.jacc.2011.11.029.
76. Li TS, Cheng K, Lee ST, Matsushita S, Davis D, Malliaras K, Zhang Y, Matsushita N, Smith RR, Marbán E, Cardiospheres recapitulate a niche-like microenvironment rich in stemness and cell-matrix interactions, rationalizing their enhanced functional potency for myocardial repair. Stem Cells 2010; 28: 2088-2098. doi: 10.1002/stem.532.
77. Itzhaki-Alfia A, Leor J, Raanani E, Sternik L, Spiegelstein D, Netser S, Holbova R, Pevsner-Fischer M, Lavee J, Barbash IM, Patient characteristics and cell source determine the number of isolated human cardiac progenitor cells. Circulation 2009; 120: 2559-2566. doi: 10.1161/CIRCULATIONAHA.109.849588.
78. Cheng K, Malliaras K, Smith RR, Human cardiosphere-derived cells from advanced heart failure patients exhibit augmented functional potency in myocardial repair. JACC Heart Fail 2014; 2: 49-61. doi: 10.1016/j.jchf.2013.08.008.
79. Smith AJ, Lewis FC, Aquila I, Waring CD, Nocera A, Agosti V, Nadal-Ginard B, Torella D, Ellison GM, Isolation and characterization of resident endogenous c-Kit+ cardiac stem cells from the adult mouse and rat heart. Nat Protoc 2014; 9: 1662-1681. doi: 10.1038/nprot.2014.113.
80. Guan K, Hasenfuss G, Cardiac resident progenitor cells: evidence and functional significance. Eur Heart J 2013; 34: 2784-2787. doi: 10.1093/eurheartj/ehs208.
81. Gagari E, Rand MK, Tayari L, Vastardis H, Sharma P, Hauschka PV, Damoulis PD, Expression of stem cell factor and its receptor, c-kit, in human oral mesenchymal cells. Eur J Oral Sci 2006; 114: 409-415. doi: 10.1111/j.1600-0722.2006.00388.x.
82. Blazquez-Martinez A, Chiesa M, Arnalich F, Fernandez-Delgado J, Nistal M, De Miguel MP, c-Kit identifies a subpopulation of mesenchymal stem cells in adipose tissue with higher telomerase expression and differentiation potential. Differentiation 2014; 87: 147-160. doi: 10.1016/j.diff.2014.02.007.
83. Singh MK, Epstein JA, Epicardium-derived cardiac mesenchymal stem cells: expanding the outer limit of heart repair. Circ Res 2012; 110: 904-906. doi: 10.1161/RES.0b013e31825332a3.
84. Crigler L, Kazhanie A, Yoon TJ, Zakhari J, Anders J, Taylor B, Virador VM, Isolation of a mesenchymal cell population from murine dermis that contains progenitors of multiple cell lineages. FASEB J 2007; 21: 2050-2063. doi: 10.1096/fj.06-5880com.
85. Nagaya N, Fujii T, Iwase T, Ohgushi H, Itoh T, Uematsu M, Yamagishi M, Mori H, Kangawa K, Kitamura S, 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 2004 287 H2670 H2676. doi: 10.1152/ajpheart.01071.2003.
86. Nagaya N, Kangawa K, Itoh T, Iwase T, Murakami S, Miyahara Y, Fujii T, Uematsu M, Ohgushi H, Yamagishi M, Tokudome T, Mori H, Miyatake K, Kitamura S, Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy. Circulation 2005; 112: 1128-1135. doi: 10.1161/CIRCULATIONAHA.104.500447.
87. Nadal-Ginard B, Ellison GM, Torella D, The absence of evidence is not evidence of absence: the pitfalls of cre knock-ins in the c-kit locus. Circ Res 2014; 115(4) 415-418. doi: 10.1161/CIRCRESAHA.114.304676.
88. Nygren JM, Jovinge S, Breitbach M, Säwén P, Röll W, Hescheler J, Taneera J, Fleischmann BK, Jacobsen SE, Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nat Med 2004; 10: 494-501. doi: 10.1038/nm1040.
89. Kouris NA, Schaefer JA, Hatta M, Freeman BT, Kamp TJ, Kawaoka Y, Ogle BM, Directed Fusion of Mesenchymal Stem Cells with Cardiomyocytes via VSV-G Facilitates Stem Cell Programming. Stem Cells Int 2012 2012 414038. doi: 10.1155/2012/414038.
90. Acquistapace A, Bru T, Lesault PF, Figeac F, Coudert AE, le Coz O, Christov C, Baudin X, Auber F, Yiou R, Dubois-Randé JL, Rodriguez AM, Human mesenchymal stem cells reprogram adult cardiomyocytes toward a progenitor-like state through partial cell fusion and mitochondria transfer. Stem Cells 2011; 29: 812-824. doi: 10.1002/stem.632.
91. Noiseux N, Gnecchi M, Lopez-Ilasaca M, Zhang L, Solomon SD, Deb A, Dzau VJ, Pratt RE, Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Mol Ther 2006; 14: 840-850. doi: 10.1016/j.ymthe.2006.05.016.
92. Rota M, Padin-Iruegas ME, Misao Y, Local activation or implantation of cardiac progenitor cells rescues scarred infarcted myocardium improving cardiac function. Circ Res 2008; 103: 107-116. doi: 10.1161/CIRCRESAHA.108.178525.
93. Zaglia T, Dedja A, Candiotto C, Cozzi E, Schiaffino S, Ausoni S, Cardiac interstitial cells express GATA4 and control dedifferentiation and cell cycle re-entry of adult cardiomyocytes. J Mol Cell Cardiol 2009; 46: 653-662. doi: 10.1016/j.yjmcc.2008.12.010.
94. Watt AJ, Battle MA, Li J, Duncan SA, GATA4 is essential for formation of the proepicardium and regulates cardiogenesis. Proc Natl Acad Sci U S A 2004; 101: 12573-12578. doi: 10.1073/pnas.0400752101.
95. Kajioka S, Takahashi-Yanaga F, Shahab N, Endogenous cardiac troponin T modulates Ca(2+)-mediated smooth muscle contraction. Sci Rep 2012 2 979. doi: 10.1038/srep00979.
96. Miyamoto S, Kawaguchi N, Ellison GM, Matsuoka R, Shin'oka T, Kurosawa H, Characterization of long-term cultured c-kit+ cardiac stem cells derived from adult rat hearts. Stem Cells Dev 2010; 19: 105-116. doi: 10.1089/scd.2009.0041.
97. Oskouei BN, Lamirault G, Joseph C, Treuer AV, Landa S, Da Silva J, Hatzistergos K, Dauer M, Balkan W, McNiece I, Hare JM, Increased potency of cardiac stem cells compared with bone marrow mesenchymal stem cells in cardiac repair. Stem Cells Transl Med 2012; 1: 116-124. doi: 10.5966/sctm.2011-0015.
98. Koninckx R, Daniëls A, Windmolders S, Carlotti F, Mees U, Steels P, Rummens JL, Hendrikx M, Hensen K, Mesenchymal stem cells or cardiac progenitors for cardiac repair? A comparative study. Cell Mol Life Sci 2011; 68: 2141-2156. doi: 10.1007/s00018-010-0560-y.
99. Pirozzi G, Tirino V, Camerlingo R, Franco R, La Rocca A, Liguori E, Martucci N, Paino F, Normanno N, Rocco G, Epithelial to mesenchymal transition by TGFβ-1 induction increases stemness characteristics in primary non small cell lung cancer cell line. PLoS One 2011 6 e21548. doi: 10.1371/journal.pone.0021548.
100. Tang YL, Fan YL, Jiang J, Li KD, Zheng M, Chen W, Ma XR, Geng N, Chen QM, Chen Y, Liang XH, C-kit induces epithelial-mesenchymal transition and contributes to salivary adenoid cystic cancer progression. Oncotarget 2014 5 1491 1501
101. Fioret BA, Heimfeld JD, Paik DT, Hatzopoulos AK, Endothelial cells contribute to generation of adult ventricular myocytes during cardiac homeostasis. Cell Rep 2014; 8: 229-241. doi: 10.1016/j.celrep.2014.06.004.
102. Tallini YN, Greene KS, Craven M, Spealman A, Breitbach M, Smith J, Fisher PJ, Steffey M, Hesse M, Doran RM, Woods A, Singh B, Yen A, Fleischmann BK, Kotlikoff MI, c-kit expression identifies cardiovascular precursors in the neonatal heart. Proc Natl Acad Sci U S A 2009; 106: 1808-1813. doi: 10.1073/pnas.0808920106.
103. Jesty SA, Steffey MA, Lee FK, Breitbach M, Hesse M, Reining S, Lee JC, Doran RM, Nikitin AY, Fleischmann BK, Kotlikoff MI, c-kit+ precursors support postinfarction myogenesis in the neonatal, but not adult, heart. Proc Natl Acad Sci U S A 2012; 109: 13380-13385. doi: 10.1073/pnas.1208114109.
104. Craven M, Kotlikoff MI, Nadworny AS, C-kit expression identifies cardiac precursor cells in neonatal mice. Methods Mol Biol 2012; 843: 177-189. doi: 10.1007/978-1-61779-523-7-17.
105. Becker K, Becker M, Schwarz JH., String Theory and m-Theory: A Modern Introduction 2007 Cambridge; New York Cambridge University Press
106. Andersen DC, Ganesalingam S, Jensen CH, Sheikh SP, Do neonatal mouse hearts regenerate following heart apex resection? Stem Cell Reports 2014; 2: 406-413. doi: 10.1016/j.stemcr.2014.02.008.