Abstract
Cardiac biology and heart regeneration have been intensively investigated and debated in the last 15 years. Nowadays, the well-established and old dogma that the adult heart lacks of any myocyte-regenerative capacity has been firmly overturned by the evidence of cardiomyocyte renewal throughout the mammalian life as part of normal organ cell homeostasis, which is increased in response to injury. Concurrently, reproducible evidences from independent laboratories have convincingly shown that the adult heart possesses a pool of multipotent cardiac stem/progenitor cells (CSCs or CPCs) capable of sustaining cardiomyocyte and vascular tissue refreshment after injury. CSC transplantation in animal models displays an effective regenerative potential and may be helpful to treat chronic heart failure (CHF), obviating at the poor/modest results using non-cardiac cells in clinical trials. Nevertheless, the degree/significance of cardiomyocyte turnover in the adult heart, which is insufficient to regenerate extensive damage from ischemic and non-ischemic origin, remains strongly disputed. Concurrently, different methodologies used to detect CSCs in situ have created the paradox of the adult heart harboring more than seven different cardiac progenitor populations. The latter was likely secondary to the intrinsic heterogeneity of any regenerative cell agent in an adult tissue but also to the confusion created by the heterogeneity of the cell population identified by a single cell marker used to detect the CSCs in situ. On the other hand, some recent studies using genetic fate mapping strategies claimed that CSCs are an irrelevant endogenous source of new cardiomyocytes in the adult. On the basis of these contradictory findings, here we critically reviewed the available data on adult CSC biology and their role in myocardial cell homeostasis and repair.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Braunwald E (2015) The war against heart failure: the lancet lecture. Lancet 385:812–824
Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL (2013) ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 128:e240–e327
Lin Z, Pu WT (2014) Strategies for cardiac regeneration and repair. Sci Transl Med 6:239
Olson EN, Schneider MD (2003) Sizing up the heart: development redux in disease. Genes Dev 17:1937–1956
Tam SK, Gu W, Mahdavi V, Nadal-Ginard B (1995) Cardiac myocyte terminal differentiation. Potential for cardiac regeneration. Ann N Y Acad Sci 752:72–79
Später D, Hansson EM, Zangi L, Chien KR (2014) How to make a cardiomyocyte. Development 141:4418–4431
MacLellan WR, Garcia A, Oh H, Frenkel P, Jordan MC, Roos KP, Schneider MD (2005) Overlapping roles of pocket proteins in the myocardium are unmasked by germ line deletion of p130 plus heart-specific deletion of Rb. Mol Cell Biol 25:2486–2497
Burke A, Tavora F (2015) The 2015 WHO classification of tumors of the heart and pericardium. J Thorac Oncol 4:441–452
Ahuja P, Sdek P, MacLellan WR (2007) Cardiac myocyte cell cycle control in development, disease, and regeneration. Physiol Rev 87:521–544
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
Rumyantsev PP, Marakjan VO (1968) Reactive synthesis of DNA and mitotic division in atrial heart muscle cells following ventricle infarction. Experientia 24:1234–1235
Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabé-Heider F, Walsh S, Zupicich J, Alkass K, Buchholz BA, Druid H, Jovinge S, Frisén J (2009) Evidence for cardiomyocyte renewal in humans. Science 324:98–102
Hsieh PC, Segers VF, Davis ME, MacGillivray C, Gannon J, Molkentin JD, Robbins J, Lee RT (2007) Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nat Med 13:970–974
Hsueh YC, Wu JM, Yu CK, Wu KK, Hsieh PC (2014) Prostaglandin E promotes post-infarction cardiomyocyte replenishment by endogenous stem cells. EMBO Mol Med 6:496–503
Walsh S, Ponte NA, Fleischmann BK, Jovinge S (2010) Cardiomyocyte cell cycle control and growth estimation in vivo - an analysis based on cardiomyocyte nuclei. Cardiovasc Res 86:365–373
Nadal-Ginard B, Ellison GM, Torella D (2014b) The cardiac stem cell compartment is indispensable for myocardial cell homeostasis, repair and regeneration in the adult. Stem Cell Res 13:615–630
Bergmann O, Zdunek S, Felker A et al (2015) Dynamics of cell generation and turnover in the human heart. Cell 161(7):1566–1575
Nadal-Ginard B (1978) Commitment, fusion and biochemical differentiation of a myogenic cell line in the absence of DNA synthesis. Cell 15:855–864
Soonpaa MH, Field LJ (1997) Assessment of cardiomyocyte DNA synthesis in normal and injured adult mouse hearts. Am J Physiol Circ Physiol 272:H220–H226
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(6):763–776
Morrison SJ, Wandycz AM, Hemmati HD, Wright DE, Weissman IL (1997) Identification of a lineage of multipotent hematopoietic progenitors. Development 124:1929–1939
Martin CM, Meeson AP, Robertson SM, Hawke TJ, Richardson JA, Bates S, Goetsch SC, Gallardo TD, Garry DJ (2004) Persistent expression of the ATP-binding cassette transporter, Abcg2, identifies cardiac SP cells in the developing and adult heart. Dev Biol 265:262–275
Balsam LB, Wagers AJ, Christensen JL, Kofidis T, Weissman IL, Robbins RC (2004) Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 428:668–673
Vicinanza C, Aquila I, Scalise M, Cristiano F, Marino F, Cianflone E, Mancuso T, Marotta P, Sacco W, Lewis FC, Couch L, Shone V, Gritti G, Torella A, Smith AJ, Terracciano CM, Britti D, Veltri P, Indolfi C, Nadal-Ginard B, Ellison-Hughes GM, Torella D (2017) Adult cardiac stem cells are multipotent and robustly myogenic: c-kit expression is necessary but not sufficient for their identification. Cell Death Differ 24(12):2101–2116
Bearzi C, Rota M, Hosoda T, Tillmanns J, Nascimbene A, De Angelis A, Yasuzawa-Amano S, Trofimova I, Siggins RW, Lecapitaine N, Cascapera S, Beltrami AP, D’Alessandro DA, Zias E, Quaini F, Urbanek K, Michler RE, Bolli R, Kajstura J, Leri A, Anversa P (2007) Human cardiac stem cells. Proc Natl Acad Sci U S A 104(35):14068–14073
Ellison GM, Torella D, Dellegrottaglie S, Perez-Martinez C, Perez de Prado A, Vicinanza C, Purushothaman S, Galuppo V, Iaconetti C, Waring CD, Smith A, Torella M, Cuellas Ramon C, Gonzalo-Orden JM, Agosti V, Indolfi C, Galiñanes M, Fernandez-Vazquez F, Nadal-Ginard B (2011) Endogenous cardiac stem cell activation by insulin-like growth factor-1/hepatocyte growth factor intracoronary injection fosters survival and regeneration of the infarcted pig heart. J Am Coll Cardiol 58(9):977–986
Hou X, Appleby N, Fuentes T, Longo LD, Bailey LL, Hasaniya N, Kearns-Jonke M (2012) Isolation, characterization, and spatial distribution of cardiac progenitor cells in the sheep heart. J Clin Exp Cardiolog S6:004
Smith AJ, Lewis FC, Aquila I, Waring CD, Nocera A, Agosti V, Nadal-Ginard B, Torella D, Ellison GM (2014) Isolation and characterization of resident endogenous c-kit+ cardiac stem cells from the adult mouse and rat heart. Nat Protoc 9:1662–1681
Chimenti I, Gaetani R, Barile L, Forte E, Ionta V, Angelini F, Frati G, Messina E, Giacomello A (2012) Isolation and expansion of adult cardiac stem/progenitor cells in the form of cardiospheres from human cardiac biopsies and murine. Methods Mol Biol 879:327–338
Messina E, De Angelis L, Frati G, Morrone S, Chimenti S, Fiordaliso F, Salio M, Battaglia M, Latronico MV, Coletta M, Vivarelli E, Frati L, Cossu G, Giacomello A (2004) Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ Res 95(9):911–921
Bollini S, Vieira JM, Howard S, Dubè KN, Balmer GM, Smart N, Riley PR (2014) Re-activated adult epicardial progenitor cells are a heterogeneous population molecularly distinct from their embryonic counterparts. Stem Cells Dev 23(15):1719–1730
Smart N, Bollini S, Dubé KN, Vieira JM, Zhou B, Davidson S, Yellon D, Riegler J, Price AN, Lythgoe MF (2011) De novo cardiomyocytes from within the activated adult heart after injury. Nature 474:640–644
Pfister O, Mouquet F, Jain M, Summer R, Helmes M, Fine A, Colucci WS, Liao R (2005) CD31- but not CD31+ cardiac side population cells exhibit functional cardiomyogenic differentiation. Circ Res 97:52–61
Sandstedt J, Jonsson M, Kajic K, Sandstedt M, Lindahl A, Dellgren G, Jeppsson A, Asp J (2012) Left atrium of the human adult heart contains a population of side population cells. Basic Res Cardiol 107:255
Oh H, Bradfute SB, Gallardo TD, Nakamura T, Gaussin V, Mishina Y, Pocius J, Michael LH, Behringer RR, Garry DJ, Entman ML, Schneider MD (2003) Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc Natl Acad Sci 100:12313–12318
Smits AM, van Vliet P, Metz CH, Korfage T, Sluijter JP, Doevendans PA, Goumans MJ (2009) Human cardiomyocyte progenitor cell transplantation preserves long-term function of the infarcted mouse myocardium. Cardiovasc Res 83:527–535
van Vliet P, Roccio M, Smits AM, van Oorschot AAM, Metz CHG, van Veen TAB, Sluijter JPG, Doevendans PA, Goumans MJ (2008) Progenitor cells isolated from the human heart: potential cell source for regenerative therapy. Neth Heart J 16(5):163–169
Bu L, Jiang X, Martin-Puig S, Caron L, Zhu S, Shao Y, Roberts DJ, Huang PL, Domian IJ, Chien KR (2009) Human ISL1 heart progenitors generate diverse multipotent cardiovascular cell lineages. Nature 460:113–117
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 (2005) Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 433:647–653
Noseda M, Harada M, McSweeney S, Leja T, Belian E, Stuckey DJ, Paiva MSA, Habib J, Macaulay I, de Smith AJ, al-Beidh F, Sampson R, Lumbers RT, Rao P, Harding SE, Blakemore AIF, Jacobsen SE, Barahona M, Schneider MD (2015) PDGFRα demarcates the cardiogenic clonogenic Sca1+ stem/progenitor cell in adult murine myocardium. Nat Commun 6:6930
Cai CL, Liang X, Shi Y, Chu PH, Pfaff SL, Chen J, Evans S (2003) Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell 5(6):877–889
Weissman IL (2000) Translating stem and progenitor cell biology to the clinic: barriers and opportunities. Science 287(5457):1442–1446
Besmer P, Manova K, Duttlinger R, Huang EJ, Packer A, Gyssler C, Bachvarova RF (1993) The kit-ligand (steel factor) and its receptor c-kit/W: pleiotropic roles in gametogenesis and melanogenesis. Dev Suppl 1993:125–137
Hesse M, Fleischmann BK, Kotlikoff MI (2014) Concise review: the role of C-kit expressing cells in heart repair at the neonatal and adult stage. Stem Cells 32(7):1701–1712
Meininger CJ, Yano H, Rottapel R, Bernstein A, Zsebo KM, Zetter BR (1992) The c-kit receptor ligand functions as a mast cell chemoattractant. Blood 79(4):958–963
Ogawa M, Matsuzaki Y, Nishikawa S, Hayashi S, Kunisada T, Sudo T, Kina T, Nakauchi H, Nishikawa S (1991) Expression and function of c-kit in hemopoietic progenitor cells. J Exp Med 174(1):63–71
Ray P, Krishnamoorthy N, Ray A (2008) Emerging functions of c-kit and its ligand stem cell factor in dendritic cells: regulators of T cell differentiation. Cell Cycle 7(18):2826–2832
Yoshinaga K, Nishikawa S, Ogawa M, Hayashi S, Kunisada T, Fujimoto T, Nishikawa S (1991) Role of c-kit in mouse spermatogenesis: identification of spermatogonia as a specific site of c-kit expression and function. Development 113(2):689–699
Fransioli J, Bailey B, Gude NA, Cottage CT, Muraski JA, Emmanuel G, Wu W, Alvarez R, Rubio M, Ottolenghi S, Schaefer E, Sussman MA (2008) Evolution of the c-kit-positive cell response to pathological challenge in the myocardium. Stem Cells 26(5):1315–1324
Linke A, Müller P, Nurzynska D, Casarsa C, Torella D, Nascimbene A, Castaldo C, Cascapera S, Böhm M, Quaini F, Urbanek K, Leri A, Hintze TH, Kajstura J, Anversa P (2005) Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function. Proc Natl Acad Sci U S A 102(25):8966–8971
Arsalan M, Woitek F, Adams V, Linke A, Barten MJ, Dhein S, Walther T, Mohr FW, Garbade J (2012) Distribution of cardiac stem cells in the human heart. ISRN Cardiol 2012:483407
Torella D, Ellison GM, Karakikes I, Galuppo V, De Serio D, Onorati F, Mastroroberto P, Renzulli A, Indolfi C, Nadal-Ginard B (2006) Biological properties and regenerative potential, in vitro and in vivo, of human cardiac stem cells isolated from each of the four chamber of the adult human heart. Circulation 114:87
Torella D, Ellison GM, Karakikes I, Nadal-Ginard B (2007b) Resident cardiac stem cells. Cell Mol Life Sci 64(6):661–673
Vincent SD, Buckingham ME (2010) How to make a heart: the origin and regulation of cardiac progenitor cells. Curr Top Dev Biol 90:1–41
Chong JJH, Chandrakanthan V, Xaymardan M, Asli NS, Li J, Ahmed I, Heffernan C, Menon MK, Scarlett CJ, Rashidianfar A, Biben C, Zoellner H, Colvin EK, Pimanda JE, Biankin AV, Zhou B, Pu WT, Prall OW, Harvey RP (2011) Adult cardiac-resident MSC-like stem cells with a proepicardial origin. Cell Stem Cell 9:527–540
Torella D, Ellison GM, Karakikes I, Nadal-Ginard B (2007a) Growth-factor-mediated cardiac stem cell activation in myocardial regeneration. Nat Clin Pract Cardiovasc Med 4(Suppl 1):S46–S51
Ellison GM, Galuppo V, Vicinanza C, Aquila I, Waring CD, Leone A, Indolfi C, Torella D (2010) Cardiac stem and progenitor cell identification: different markers for the same cell? Front Biosci (Schol Ed) 2:641–652
Miyamoto S, Kawaguchi N, Ellison GM, Matsuoka R, Shin’oka T, Kurosawa H (2010) Characterization of long-term cultured c-kit+ cardiac stem cells derived from adult rat hearts. Stem Cells Dev 19(1):105–116
Mercola M, Ruiz-Lozano P, Schneider MD (2011) Cardiac muscle regeneration: lessons from development. Genes Dev 25(4):299–309
Noseda M, Peterkin T, Simões FC, Patient R, Schneider MD (2011) Cardiopoietic factors: extracellular signals for cardiac lineage commitment. Circ Res 108(1):129–152
Cianflone E, Aquila I, Scalise M, Marotta P, Torella M, Nadal-Ginard B, Torella D (2018) Molecular basis of functional myogenic specification of Bona fide multipotent adult cardiac stem cells. Cell Cycle 17(8):927–946
David R, Brenner C, Stieber J, Schwarz F, Brunner S, Vollmer M, Mentele E, Müller-Höcker J, Kitajima S, Lickert H, Rupp R, Franz WM (2008) MesP1 drives vertebrate cardiovascular differentiation through Dkk-1-mediated blockade of Wnt-signalling. Nat Cell Biol 10(3):338–345
High FA, Jain R, Stoller JZ, Antonucci NB, Lu MM, Loomes KM, Kaestner KH, Pear WS, Epstein JA (2009) Murine Jagged1/notch signaling in the second heart field orchestrates Fgf8 expression and tissue-tissue interactions during outflow tract development. J Clin Invest 119(7):1986–1996
Koyanagi M, Bushoven P, Iwasaki M, Urbich C, Zeiher AM, Dimmeler S (2007) Notch signaling contributes to the expression of cardiac markers in human circulating progenitor cells. Circ Res 101(11):1139–1145
Rochais F, Mesbah K, Kelly RG (2009) Signaling pathways controlling second heart field development. Circ Res 104(8):933–942
Kattman SJ, Witty AD, Gagliardi M, Dubois NC, Niapour M, Hotta A, Ellis J, Keller G (2011) Stage-specific optimization of activin/nodal and BMP signaling promotes cardiac differentiation of mouse and human pluripotent stem cell lines. Cell Stem Cell 8(2):228–240
Klaus A, Müller M, Schulz H, Saga Y, Martin JF, Birchmeier W (2012) Wnt/β-catenin and Bmp signals control distinct sets of transcription factors in cardiac progenitor cells. Proc Natl Acad Sci U S A 109(27):10921–10926
Qyang Y, Martin-Puig S, Chiravuri M, Chen S, Xu H, Bu L, Jiang X, Lin L, Granger A, Moretti A, Caron L, Wu X, Clarke J, Taketo MM, Laugwitz KL, Moon RT, Gruber P, Evans SM, Ding S, Chien KR (2007) The renewal and differentiation of Isl1+ cardiovascular progenitors are controlled by a Wnt/beta-catenin pathway. Cell Stem Cell 1(2):165–179
Morrison SJ, Spradling AC (2008) Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 132(4):598–611
Mohsin S, Siddiqi S, Collins B, Sussman MA (2011) Empowering adult stem cells for myocardial regeneration. Circ Res 109(12):1415–1412
Waring CD, Vicinanza C, Papalamprou A, Smith AJ, Purushothaman S, Goldspink DF, Nadal-Ginard B, Torella D, Ellison GM (2014) The adult heart responds to increased workload with physiologic hypertrophy, cardiac stem cell activation, and new myocyte formation. Eur Heart J 35(39):2722–2731
Ellison GM, Torella D, Karakikes I, Purushothaman S, Curcio A, Gasparri C, Indolfi C, Cable NT, Goldspink DF, Nadal-Ginard B et al (2007) Acute beta-adrenergic overload produces damage through calcium leakage from the ryanodine receptor 2 but spares cardiac stem cells. J Biol Chem 282(15):11397–11409
Ellison GM, Vicinanza C, Smith AJ, Aquila I, Leone A, Waring CD, Henning BJ, Stirparo GG, Papait R, Scarfò M, Agosti V, Viglietto G, Condorelli G, Indolfi C, Ottolenghi S, Torella D, Nadal-Ginard B (2013) Adult c-kitpos cardiac stem cells are necessary and sufficient for functional cardiac regeneration and repair. Cell 154:827–842
Aquila I, Cianflone E, Scalise M, Marino F, Mancuso T, Filardo A, Smith AJ, Cappetta D, De Angelis A, Urbanek K, Isidori AM, Torella M, Agosti V, Viglietto G, Nadal-Ginard B, Ellison-Hughes GM, Torella D (2019) c-kit Haploinsufficiency impairs adult cardiac stem cell growth, myogenicity and myocardial regeneration. Cell Death Dis 10(6):436
Torella D, Rota M, Nurzynska D, Musso E, Monsen A, Shiraishi I, Zias E, Walsh K, Rosenzweig A, Sussman MA, Urbanek K, Nadal-Ginard B, Kajstura J, Anversa P, Leri A (2004) Cardiac stem cell and myocyte aging, heart failure, and insulin-like growth factor-1 overexpression. Circ Res 94(4):514–524
Urbanek K, Quaini F, Tasca G, Torella D, Castaldo C, Nadal-Ginard B, Leri A, Kajstura J, Quaini E, Anversa P (2011) Intense myocyte formation from cardiac stem cells in human cardiac hypertrophy. Proc Natl Acad Sci 100(18):10440–10445
Tateishi K, Ashihara E, Takehara N, Nomura T, Honsho S, Nakagami T, Morikawa S, Takahashi T, Ueyama T, Matsubara H, Oh H (2007) Clonally amplified cardiac stem cells are regulated by Sca-1 signaling for efficient cardiovascular regeneration. J Cell Sci 120:1791–1800
Matsuura K, Nagai T, Nishigaki N, Oyama T, Nishi J, Wada H, Sano M, Toko H, Akazawa H, Sato T, Nakaya H, Kasanuki H, Komuro I (2004) Adult cardiac sca-1-positive cells differentiate into beating cardiomyocytes. J Biol Chem 279:11384–11391
Ye J, Boyle A, Shih H, Sievers RE, Zhang Y, Prasad M, Su H, Zhou Y, Grossman W, Bernstein HS, Yeghiazarians Y (2012) Sca-1+ cardiosphere-derived cells are enriched for Isl1- expressing cardiac precursors and improve cardiac function after myocardial injury. PLoS One 7(1):e30329
Takamiya M, Haider KH, Ashraf M (2011) Identification and characterization of a novel multipotent sub-population of sca-1+ cardiac progenitor cells for myocardial regeneration. PLoS One 6:e25265
Wang X, Hu Q, Nakamura Y, Lee J, Zhang G, From AH, Zhang J (2006) The role of the sca-1+/CD31- cardiac progenitor cell population in postinfarction left ventricular remodeling. Stem Cells 24(7):1779–1788
Goumans MJ, de Boer TP, Smits AM, van Laake LW, van Vliet P, Metz CH, Korfage TH, Kats KP, Hochstenbach R, Pasterkamp G, Verhaar MC, van der Heyden MA, de Kleijn D, Mummery CL, van Veen TA, Sluijter JP, Doevendans PA (2008) TGF-β1 induces efficient differentiation of human cardiomyocyte progenitor cells into functional cardiomyocytes in vitro. Stem Cell Res 1:138–149
Bailey B, Fransioli J, Gude NA, Alvarez R Jr, Zhang X, Gustafsson ÅB, Sussman MA (2012) Sca-1 knockout impairs myocardial and cardiac progenitor cell function. Circ Res 111:750–760
Uchida S, De Gaspari P, Kostin S, Jenniches K, Kilic A, Izumiya Y, Shiojima I, Grosse Kreymborg K, Renz H, Walsh K, Braun T (2013) Sca1-derived cells are a source of myocardial renewal in the murine adult heart. Stem Cell Reports 1:397–410
Vagnozzi RJ, Sargent MA, Lin SJ, Palpant NJ, Murry CE, Molkentin JD (2018) Genetic lineage tracing of Sca-1+ cells reveals endothelial but not myogenic contribution to the murine heart. Circulation 138(25):2931–2939
Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC (1996) Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 183(4):1797–1806
Zhou S, Schurtz JD, Burting KD et al (2001) The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med 7(9):1028–1034
Doyle L, Ross DD (2003) Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene 22(47):7340–7358
Asakura A, Rudnicki MA (2002) Side population cells from diverse adult tissues are capable of in vitro hematopoietic differentiation. Exp Hematol 30(11):1339–1345
Hierlihy AM, Seale P, Lobe CG, Rudnicki MA, Megeney LA (2002) The post-natal heart contains a myocardial stem cell population. FEBS Lett 530(1–3):239–243
Yamahara K, Fukushima S, Coppen SR, Felkin LE, Varela-Carver A, Barton PJ, Yacoub MH, Suzuki K (2008) Heterogeneic nature of adult cardiac side population cells. Biochem Biophys Res Commun 371:615–620
Oyama T, Nagai T, Wada H, Naito AT, Matsuura K, Iwanaga K, Takahashi T, Goto M, Mikami Y, Yasuda N, Akazawa H, Uezumi A, Takeda S, Komuro I (2007) Cardiac side population cells have a potential to migrate and differentiate into cardiomyocytes in vitro and in vivo. J Cell Biol 176:329–341
Dey D, Han L, Bauer M, Sanada F, Oikonomopoulos A, Hosoda T, Unno K, De Almeida P, Leri A, Wu JC (2013) Dissecting the molecular relationship among various cardiogenic progenitor cells. Circ Res 112:1253–1262
Martin CM, Ferdous A, Gallardo T, Humphries C, Sadek H, Caprioli A, Garcia JA, Szweda LI, Garry MG, Garry DJ (2008) Hypoxia-inducible factor-2α transactivates Abcg2 and promotes cytoprotection in cardiac side population cells. Circ Res 102:1075–1081
Mouquet F, Pfister O, Jain M, Oikonomopoulos A, Ngoy S, Summer R, Fine A, Liao R (2005) Restoration of cardiac progenitor cells after myocardial infarction by self-proliferation and selective homing of bone marrow-derived stem cells. Circ Res 97:1090–1092
Emmert MY, Emmert LS, Martens A, Ismail I, Schmidt-Richter I, Gawol A, Seifert B, Haverich A, Martin U, Gruh I (2013) Higher frequencies of BCRP+ cardiac resident cells in ischaemic human myocardium. Eur Heart J 34:2830–2838
Meissner K, Heydrich B, Jedlitschky G, Meyer Zu Schwabedissen H, Mosyagin I, Dazert P, Eckel L, Vogelgesang S, Warzok RW, Böhm M, Lehmann C, Wendt M, Cascorbi I, Kroemer HK (2006) The ATP-binding cassette transporter ABCG2 (BCRP), a marker for side population stem cells, is expressed in human heart. J Histochem Cytochem 54:215–221
Smith RR, Barile L, Cho HC, Leppo MK, Hare JM, Messina E, Giacomello A, Abraham MR, Marban E (2007) Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation 115:896–908
Davis DR, Zhang Y, Smith RR, Cheng K, Terrovitis J, Malliaras K, Li TS, White A, Makkar R, Marbán E (2009) Validation of the cardiosphere method to culture cardiac progenitor cells from myocardial tissue. PLoS One 4(9):e7195
Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255(5052):1707–1710
Bartosh TJ, Wang Z, Rosales AA, Dimitrijevich SD, Roque RS (2008) 3D-model of adult cardiac stem cells promotes cardiac differentiation and resistance to oxidative stress. J Cell Biochem 105(2):612–623
Martens A, Gruh I, Dimitroulis D, Rojas SV, Schmidt-Richter I, Rathert C, Khaladj N, Gawol A, Chikobava MG, Martin U, Haverich A, Kutschka I (2011) Rhesus monkey cardiosphere derived cells for myocardial restoration. Cytotherapy 13(7):864–872
Mishra R, Vijayan K, Colletti EJ, Harrington DA, Matthiesen TS, Simpson D, Goh SK, Walker BL, Almeida-Porada G, Wang D, Backer CL, Dudley SC Jr, Wold LE, Kaushal S (2011) Characterization and functionality of cardiac progenitor cells in congenital heart patients. Circulation 123(4):364–373
White AJ, Smith RR, Matsushita S, Chakravarty T, Czer LS, Burton K, Schwarz ER, Davis DR, Wang Q, Reinsmoen NL, Forrester JS, Marbán E, Makkar R (2013) Intrinsic cardiac origin of human cardiosphere-derived cells. Eur Heart J 34(1):68–75
Andersen DC, Andersen P, Schneider M, Jensen HB, Sheikh SP (2009) Murine “cardiospheres” are not a source of stem cells with cardiomyogenic potential. Stem Cells 27(7):1571–1581
Lee ST, White AJ, Matsushita S, Malliaras K, Steenbergen C, Zhang Y, Li TS, Terrovitis J, Yee K, Simsir S, Makkar R, Marbán E (2011) Intramyocardial injection of autologous cardiospheres or cardiosphere-derived cells preserves function and minimizes adverse ventricular remodeling in pigs with heart failure post-myocardial infarction. J Am Coll Cardiol 57(4):455–465
Li TS, Cheng K, Lee ST, Matsushita S, Davis D, Malliaras K, Zhang Y, Matsushita N, Smith RR, Marbán E (2010) Cardiospheres recapitulate a niche-like microenvironment rich in stemness and cell-matrix interactions, rationalizing their enhanced functional potency formyocardial repair. Stem Cells 28(11):2088–2098
Chimenti I, Smith RR, Li TS, Gerstenblith G, Messina E, Giacomello A, Marbán E (2010) Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cells transplanted into infarcted mice. Circ Res 106(5):971–980
Johnston PV, Sasano T, Mills K, Evers R, Lee ST, Smith RR, Lardo AC, Lai S, Steenbergen C, Gerstenblith G, Lange R, Marbán E (2009) Engraftment, differentiation, and functional benefits of autologous cardiosphere-derived cells in porcine ischemic cardiomyopathy. Circulation 120(12):1075–1083
Li Z, Lee A, Huang M, Chun H, Chung J, Chu P, Hoyt G, Yang P, Rosenberg J, Robbins RC, Wu JC (2009) Imaging survival and function of transplanted cardiac resident stem cells. J Am Coll Cardiol 53:1229–1240
Makkar RR, Smith RR, Cheng K, Malliaras K, Thomson LE, Berman D, Czer LS, Marban L, Mendizabal A, Johnston PV, Russell SD, Schuleri KH, Lardo AC, Gerstenblith G, Marban E (2012) Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet 379:895–904
Malliaras K, Makkar RR, Smith RR, Cheng K, Wu E, Bonow RO, Marban L, Mendizabal A, Cingolani E, Johnston PV, Gerstenblith G, Schuleri KH, Lardo AC, Marban E (2014) Intracoronary cardiosphere-derived cells after myocardial infarction: evidence of therapeutic regeneration in the final 1-year results of the CADUCEUS trial (CArdiosphere-derived aUtologous stem CElls to reverse ventricUlar dySfunction). J Am Coll Cardiol 63:110–122
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(4):393–403
Dimarino AM, Caplan AI, Bonfield TL (2013) Mesenchymal stem cells in tissue repair. Front Immunol 4:201
Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop DJ, Horwitz E (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8(4):315–317
Chong JJH, Reinecke H, Iwata M, Torok-Storb B, Stempien-Otero A, Murry CE (2013) Progenitor cells identified by PDGFR-alpha expression in the developing and diseased human heart. Stem Cells Dev 22:1932–1943
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
Navarro-Betancourt JR, Hernández S (2015) On the existence of cardiomesenchymal stem cells. Med Hypotheses 84(5):511–515
Beltrami AP, Cesselli D, Bergamin N, Marcon P, Rigo S, Puppato E, D’Aurizio F, Verardo R, Piazza S, Pignatelli A, Poz A, Baccarani U, Damiani D, Fanin R, Mariuzzi L, Finato N, Masolini P, Burelli S, Belluzzi O, Schneider C, Beltrami CA (2007) Multipotent cells can be generated in vitro from several adult human organs (heart, liver, and bone marrow). Blood 110(9):3438–3446
Santini MP, Forte E, Harvey RP, Kovacic JC (2016) Developmental origin and lineage plasticity of endogenous cardiac stem cells. Development 143:1242–1258
Zhang Y, Sivakumaran P, Newcomb AE, Hernandez D, Harris N, Khanabdali R, Liu GS, Kelly DJ, Pébay A, Hewitt AW, Boyle A, Harvey R, Morrison WA, Elliott DA, Dusting GJ, Lim SY (2015) Cardiac repair with a novel population of mesenchymal stem cells resident in the human heart. Stem Cells 33(10):3100–3113
Cohen ED, Wang Z, Lepore JJ, Lu MM, Taketo MM, Epstein DJ, Morrisey EE (2007) Wnt/beta-catenin signaling promotes expansion of Isl-1-positive cardiac progenitor cells through regulation of FGF signaling. J Clin Invest 117(7):1794–1804
Karlsson O, Thor S, Norberg T, Ohlsson H, Edlund T (1990) Insulin gene enhancer binding protein Isl-1 is a member of a novel class of proteins containing both a homeo- and a Cys- His domain. Nature 344:879–882
Tsuchida T, Ensini M, Morton SB, Baldassare M, Edlund T, Jessell TM, Pfaff SL (1994) Topographic organization of embryonic motor neurons defined by expression of LIM homeobox genes. Cell 79:957–970
Franco D, Campione M, Kelly R, Zammit PS, Buckingham M, Lamers WH, Moorman AF (2000) Multiple transcriptional domains, with distinct left and right components, in the atrial chambers of the developing heart. Circ Res 87:984–991
Kubalak SW, Miller-Hance WC, OBrien TX, Dyson E, Chien KR (1994) Chamber specification of atrial myosin light chain-2 expression precedes septation during murine cardiogenesis. J Biol Chem 269:16961–16970
Milgrom-Hoffman M, Harrelson Z, Ferrara N, Zelzer E, Evans SM, Tzahor E (2011) The heart endocardium is derived from vascular endothelial progenitors. Development 138(21):4777–4787
Zhou B, von Gise A, Ma Q, Rivera-Feliciano J, Pu WT (2008b) Nkx2-5- and Isl1-expressing cardiac progenitors contribute to proepicardium. Biochem Biophys Res Commun 375(3):450–453
Engleka KA, Manderfield LJ, Brust RD, Li L, Cohen A, Dymecki SM, Epstein JA (2012) Islet1 derivatives in the heart are of both neural crest and second heart field origin. Circ Res 110(7):922–926
Bondue A, Tännler S, Chiapparo G, Chabab S, Ramialison M, Paulissen C, Beck B, Harvey R, Blanpain C (2011) Defining the earliest step of cardiovascular progenitor specification during embryonic stem cell differentiation. J Cell Biol 192(5):751–765
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 (2006) Multipotent embryonic Isl1+ progenitor cells lead to cardiac, smooth muscle, and endothelial cell diversification. Cell 127:1151–1165
Amir G, Ma X, Reddy VM, Hanley FL, Reinhartz O, Ramamoorthy C, Riemer RK (2008) Dynamics of human myocardial progenitor cell populations in the neonatal period. Ann Thorac Surg 86(4):1311–1319
Genead R, Fischer H, Hussain A, Jaksch M, Andersson AB, Ljung K, Bulatovic I, Cereceda AF, Elsheikh E, Corbascio M, Smith CIE, Sylvén C, Grinnemo KH (2012) Ischemiareperfusion injury and pregnancy initiate time-dependent and robust signs of upregulation of cardiac progenitor cells. PLoS One 7:e36804
Genead R, Danielsson C, Andersson AB, Corbascio M, Franco-Cereceda A, Sylvén C, Grinnemo KH (2010) Islet-1 cells are cardiac progenitors present during the entire lifespan: from the embryonic stage to adulthood. Stem Cells Dev 19(10):1601–1615
Smart N, Dubè KN, Riley PR et al (2010) Identification of thymosin ß4 as an effector of Hand1-mediated vascular development. Nat Commun 1:46
Weinberger F, Mehrkens D, Friedrich FW, Stubbendorff M, Hua X, Muller JC, Schrepfer S, Evans SM, Carrier L, Eschenhagen T (2012) Localization of Islet-1-positive cells in the healthy and infarcted adult murine heart. Circ Res 110:1303–1310
Limana F, Zacheo A, Mocini D, Mangoni A, Borsellino G, Diamantini A, De Mori R, Battistini L, Vigna E, Santini M, Loiaconi V, Pompilio G, Germani A, Capogrossi MC (2007) Identification of myocardial and vascular precursor cells in human and mouse epicardium. Circ Res 101(12):1255–1265
Zhou B, Ma Q, Rajagopal S, Wu SM, Domian I, Rivera-Feliciano J, Jiang D, von Gise A, Ikeda S, Chien KR, Pu WT (2008a) Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart. Nature 454(7200):109–113
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 (2008) A myocardial lineage derives from Tbx18 epicardial cells. Nature 454(7200):104–108
Kikuchi K, Gupta V, Wang J, Holdway JE, Wills AA, Fang Y, Poss KD (2011) tcf21+ epicardial cells adopt non-myocardial fates during zebrafish heart development and regeneration. Development 138(14):2895–2902
MacNeill C, French R, Evans T, Wessels A, Burch JB (2000) Modular regulation of cGATA-5 gene expression in the developing heart and gut. Dev Biol 217(1):62–76
Vrancken Peeters MP, Mentink MM, Poelmann RE, Gittenberger-de Groot AC (1995) Cytokeratins as a marker for epicardial formation in the quail embryo. Anat Embryol (Berl) 191(6):503–508
Smits AM, Dronkers E, Goumans MJ (2018) The epicardium as a source of multipotent adult cardiac progenitor cells: their origin, role and fate. Pharmacol Res 127:129–140
Carmona R, González-Iriarte M, Pérez-Pomares JM, Muñoz-Chápuli R (2001) Localization of the Wilm’s tumour protein WT1 in avian embryos. Cell Tissue Res 303(2):173–186
Van Den Akker NM, Lie-Venema H, Maas S, Eralp I, DeRuiter MC, Poelmann RE, Gittenberger-De Groot AC (2005) Platelet-derived growth factors in the developing avian heart and maturating coronary vasculature. Dev Dyn 233(4):1579–1588
Gittenberger-de Groot AC, Vrancken Peeters MP, Bergwerff M, Mentink MM, Poelmann RE (2000) Epicardial outgrowth inhibition leads to compensatory mesothelial outflow tract collar and abnormal cardiac septation and coronary formation. Circ Res 87(11):969–971
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(7016):466–472
Smart N, Risebro CA, Melville AA, Moses K, Schwartz RJ, Chien KR, Riley PR (2007) Thymosin beta-4 is essential for coronary vessel development and promotes neovascularization via adult epicardium. Ann N Y Acad Sci 1112:171–188
Bollini S, Riley PR, Smart N (2015) Thymosin β4: multiple functions in protection, repair and regeneration of the mammalian heart. Expert Opin Biol Ther 15(Suppl 1):S163–S174
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 (2007) Epicardial cells of human adults can undergo an epithelial-to-mesenchymal transition and obtain characteristics of smooth muscle cells in vitro. Stem Cells 25(2):271–278
Winter EM, Grauss RW, Hogers B et al (2007) Preservation of left ventricular function and attenuation of remodeling after transplantation of human epicardiumderived cells into the infarcted mouse heart. Circulation 116(8):917–927
Lin SL, Kisseleva T, Brenner DA, Duffield JS (2008) Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney. Am J Pathol 173:1617–1627
Mederacke I, Hsu CC, Troeger JS, Huebener P, Mu X, Dapito DH, Pradere JP, Schwabe RF (2013) Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun 4:2823
Wong SP, Rowley JE, Redpath AN, Tilman JD, Fellous TG, Johnson JR (2015) Pericytes, mesenchymal stem cells and their contributions to tissue repair. Pharmacol Ther 151:107–120
Díaz-Flores L, Gutiérrez R, Madrid JF, Varela H, Valladares F, Acosta E, Martín-Vasallo P, Díaz-Flores L Jr (2009) Pericytes. Morphofunction, interactions and pathology in a quiescent and activated mesenchymal cell niche. Histol Histopathol 24:909–969
Kunisaki Y, Bruns I, Scheiermann C, Ahmed J, Pinho S, Zhang D, Mizoguchi T, Wei Q, Lucas D, Ito K, Mar JC, Bergman A, Frenette PS (2013) Arteriolar niches maintain haematopoietic stem cell quiescence. Nature 502(7473):637–643
Nayak RC, Berman AB, George KL, Eisenbarth GS, King GL (1988) A monoclonal antibody (3G5)-defined ganglioside antigen is expressed on the cell surface of microvascular pericytes. J Exp Med 167(3):1003–1015
Zannettino AC, Paton S, Arthur A, Khor F, Itescu S, Gimble JM, Gronthos S (2008) Multipotential human adipose-derived stromal stem cells exhibit a perivascular phenotype in vitro and in vivo. J Cell Physiol 214(2):413–421
Fujimoto T, Singer SJ (1987) Immunocytochemical studies of desmin and vimentin in pericapillary cells of chicken. J Histochem Cytochem 35(10):1105–1115
Dellavalle A, Maroli G, Covarello D, Azzoni E, Innocenzi A, Perani L, Antonini S, Sambasivan R, Brunelli S, Tajbakhsh S, Cossu G (2011) Pericytes resident in postnatal skeletal muscle differentiate into muscle fibres and generate satellite cells. Nat Commun 2:499
Dellavalle A, Sampaolesi M, Tonlorenzi R, Tagliafico E, Sacchetti B, Perani L, Innocenzi A, Galvez BG, Messina G, Morosetti R, Li S, Belicchi M, Peretti G, Chamberlain JS, Wright WE, Torrente Y, Ferrari S, Bianco P, Cossu G (2007) Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells. Nat Cell Biol 9(3):255–267
Crisan M, Corselli M, Chenc WCW, Péaul B (2012) Perivascular cells for regenerative medicine. J Cell Mol Med 16(12):2851–2860
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, Péault B (2008) A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3(3):301–313
Armulik A, Abramsson A, Betsholtz C (2005) Endothelial/pericyte interactions. Circ Res 97:512–523
Gale NW, Baluk P, Pan L, Kwan M, Holash J, DeChiara TM, McDonald DM, Yancopoulos GD (2001) Ephrin-B2 selectively marks arterial vessels and neovascularization sites in the adult, with expression in both endothelial and smooth-muscle cells. Dev Biol 230(2):151–160
Christia P, Bujak M, Gonzalez-Quesada C, Chen W, Dobaczewski M, Reddy A, Frangogiannis NG (2013) Systematic characterization of myocardial inflammation, repair, and remodeling in a mouse model of reperfused myocardial infarction. J Histochem Cytochem 61:555–570
Deb A, Ubil E (2014) Cardiac fibroblast in development and wound healing. J Mol Cell Cardiol 70:47–55
Uezumi A, Ito T, Morikawa D, Shimizu N, Yoneda T, Segawa M, Yamaguchi M, Ogawa R, Matev MM, Miyagoe-Suzuki Y, Takeda S, Tsujikawa K, Tsuchida K, Yamamoto H, Fukada S (2011) Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle. J Cell Sci 124(Pt 21):3654–3664
Baum O, Gübeli J, Frese S, Torchetti E, Malik C, Odriozola A, Graber F, Hoppeler H, Tschanz SA (2015) Angiogenesis-related ultrastructural changes to capillaries in human skeletal muscle in response to endurance exercise. J Appl Physiol 119(10):1118–1126
Zammit PS, Partridge TA, Yablonka-Reuveni Z (2006) The skeletal muscle satellite cell: the stem cell that came in from the cold. J Histochem Cytochem 54(11):1177–1191
Mikawa T, Gourdie RG (1996) Pericardial mesoderm generates a population of coronary smooth muscle cells migrating into the heart along with ingrowth of the epicardial organ. Dev Biol 174:221–232
Beltrami AP, Madeddu P (2018) Pericytes and cardiac stem cells: common features and peculiarities. Pharmacol Res 127:101–109
Pelekanos RA, Li J, Gongora M, Chandrakanthan V, Scown J, Suhaimi N, Brooke G, Christensen ME, Doan T, Rice AM, Osborne GW, Grimmond SM, Harvey RP, Atkinson K, Little MH (2012) Comprehensive transcriptome and immunophenotype analysis of renal and cardiac MSC-like populations supports strong congruence with bone marrow MSC despite maintenance of distinct identities. Stem Cell Res 8(1):58–73
Avolio E, Meloni M, Spencer HL, Riu F, Katare R, Mangialardi G, Oikawa A, Rodriguez-Arabaolaza I, Dang Z, Mitchell K, Reni C, Alvino VV, Rowlinson J, Livi U, Cesselli D, Angelini G, Emanueli C, Beltrami AP, Madeddu P (2015a) Combined intramyocardial delivery of human pericytes and cardiac stem cells additively improves the healing of mouse infarcted hearts through stimulation of vascular and muscular repair. Circ Res 116(10):e81–e94
Avolio E, Rodriguez-Arabaolaza I, Spencer HL, Riu F, Mangialardi G, Slater SC, Rowlinson J, Alvino VV, Idowu OO, Soyombo S, Oikawa A, Swim MM, Kong CH, Cheng H, Jia H, Ghorbel MT, Hancox JC, Orchard CH, Angelini G, Emanueli C, Caputo M, Madeddu P (2015b) Expansion and characterization of neonatal cardiac pericytes provides a novel cellular option for tissue engineering in congenital heart disease. J Am Heart Assoc 4(6):e002043
Katare R, Riu F, Mitchell K, Gubernator M, Campagnolo P, Cui Y, Fortunato O, Avolio E, Cesselli D, Beltrami AP, Angelini G, Emanueli C, Madeddu P (2011) Transplantation of human pericyte progenitor cells improves the repair of infarcted heart through activation of an angiogenic program involving micro-rna-132. Circ Res 109(8):894–906
O’Farrell FM, Mastitskaya S, Hammond-Haley M, Freitas F, Wah WR, Attwell D (2017) Capillary pericytes mediate coronary no-reflow after myocardial ischaemia. elife 6:pii: e29280
Costa MA, Paiva AE, Andreotti JP, Cardoso MV, Cardoso CD, Mintz A, Birbrair A (2018) Pericytes constrict blood vessels after myocardial ischemia. J Mol Cell Cardiol 116:1–4
Kanisicak O, Vagnozzi RJ, Molkentin JD (2017) Identity crisis for regenerative cardiac cKit+cells. Circ Res 121:1130–1132
Keith MCL, Bolli R (2015) “String Theory” of c-kit pos cardiac cells. Circ Res 116:1216–1230
Liu Q, Yang R, Huang X, Zhang H, He L, Zhang L, Tian X, Nie Y, Hu S, Yan Y, Zhang L, Qiao Z, Wang QD, Lui KO, Zhou B (2016) Genetic lineage tracing identifies in situ Kit-expressing cardiomyocytes. Cell Res 26:119–130
Sultana N, Zhang L, Yan J, Chen J, Cai W, Razzaque S, Jeong D, Sheng W, Bu L, Xu M, Huang GY, Hajjar RJ, Zhou B, Moon A, Cai CL (2015) Resident c-kit+ cells in the heart are not cardiac stem cells. Nat Commun 6:8701
Van Berlo JH, Kanisicak O, Maillet M, Vagnozzi RJ, Karch J, Lin SCJ, Middleton RC, Marbán E, Molkentin JD (2014) C-kit+ cells minimally contribute cardiomyocytes to the heart. Nature 509:337–341
Cianflone E, Torella M, Chimenti C, De Angelis A, Beltrami AP, Urbanek K, Torella D (2019) Adult cardiac stem cell aging: a reversible stochastic phenomenon? Oxid Med Cell Longev 2019:5813147
Lennartsson J, Rönnstrand L (2012) Stem cell factor receptor/c-kit: from basic science to clinical implications. Physiol Rev 92:1619–1649
van Berlo JH, Molkentin JD (2014) An emerging consensus on cardiac regeneration. Nat Med 20:1386–1393
van Berlo JH, Molkentin JD (2016) Most of the dust has settled. Circ Res 118:17–19
Zaruba MM, Soonpaa M, Reuter S, Field LJ (2010) Cardiomyogenic potential of C-Kit+−expressing cells derived from neonatal and adult mouse hearts. Circulation 121:1992–2000
Jesty SA, Steffey MA, Lee FK, Breitbach M, Hesse M, Reining S, Lee JC, Doran RM, Nikitin AY, Fleischmann BK et al (2012) c-kit+ precursors support postinfarction myogenesis in the neonatal, but not adult, heart. Proc Natl Acad Sci 109:13380–13385
Aquila I, Marino F, Cianflone E, Marotta P, Torella M, Mollace V, Indolfi C, Nadal-Ginard B, Torella D (2018) The use and abuse of Cre/Lox recombination to identify adult cardiomyocyte renewal rate and origin. Pharmacol Res 127:116–128
Nadal-Ginard B, Ellison GM, Torella D (2014a) Absence of evidence is not evidence of absence: pitfalls of cre knock-ins in the c-kit locus. Circ Res 115:415–418
Fazel S, Cimini M, Chen L, Li S, Angoulvant D, Fedak P, Verma S, Weisel RD, Keating A, Li R-K (2006) Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines. J Clin Invest 116:1865–1877
Bernex F, De Sepulveda P, Kress C, Elbaz C, Delouis C, Panthier JJ (1996) Spatial and temporal patterns of c-kit-expressing cells in WlacZ/+ and WlacZ/WlacZ mouse embryos. Development 122:3023–3033
Bernstein A, Chabot B, Dubreuil P, Reith A, Nocka K, Majumder S, Ray P, Besmer P (1990) The mouse W/c-kit locus. Ciba Found Symp 148:158–166
Reith AD, Rottapel R, Giddens E, Brady C, Forrester L, Bernstein A (1990) W mutant mice with mild or severe developmental defects contain distinct point mutations in the kinase domain of the c-kit receptor. Genes Dev 4:390–400
Schmidt-Supprian M, Rajewsky K (2007) Vagaries of conditional gene targeting. Nat Immunol 8:665–668
Shin JY, Hu W, Naramura M, Park CY (2014) High c-Kit expression identifies hematopoietic stem cells with impaired self-renewal and megakaryocytic bias. J Exp Med 211:217–231
Vicinanza C, Aquila I, Cianflone E, Scalise M, Marino F, Mancuso T, Fumagalli F, Giovannone ED, Cristiano F, Iaccino E, Marotta P, Torella A, Latini R, Agosti V, Veltri P, Urbanek K, Isidori AM, Saur D, Indolfi C, Nadal-Ginard B, Torella D (2018) Kitcre knock-in mice fail to fate-map cardiac stem cells. Nature 555(7697):E1–E5
Di Siena S, Gimmelli R, Nori SL et al (2016) Activated c-Kit receptor in the heart promotes cardiac repair and regeneration after injury. Cell Death Dis 7(7):e2317
Torella D, Indolfi C, Goldspink FD, Ellison GM (2008) Cardiac stem cell-based myocardial regeneration: towards a translational approach. Cardiovasc Hematol Agents Med Chem 6:53–59
Wu SM, Fujiwara Y, Cibulsky SM, Clapham DE, Lien CL, Schultheiss TM, Orkin SH (2006) Developmental origin of a bipotential myocardial and smooth muscle cell precursor in the mammalian heart. Cell 127(6):1137–1150
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Scalise, M. et al. (2019). Heterogeneity of Adult Cardiac Stem Cells. In: Birbrair, A. (eds) Stem Cells Heterogeneity in Different Organs. Advances in Experimental Medicine and Biology, vol 1169. Springer, Cham. https://doi.org/10.1007/978-3-030-24108-7_8
Download citation
DOI: https://doi.org/10.1007/978-3-030-24108-7_8
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-24107-0
Online ISBN: 978-3-030-24108-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)