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• W2956154114 abstract "•Limited regeneration occurs in the neonatal mouse heart upon ventricular apex amputation•Progenitor cell differentiation from epicardium is very minimal during heart repair•New coronary vessels are generated through angiogenesis after injury The regeneration capacity of neonatal mouse heart is controversial. In addition, whether epicardial cells provide a progenitor pool for de novo heart regeneration is incompletely defined. Following apical resection of the neonatal mouse heart, we observed limited regeneration potential. Fate-mapping of Tbx18MerCreMer mice revealed that newly formed coronary vessels and a limited number of cardiomyocytes were derived from the T-box transcription factor 18 (Tbx18) lineage. However, further lineage tracing with SM-MHCCreERT2 and Nfactc1Cre mice revealed that the new smooth muscle and endothelial cells are in fact derivatives of pre-existing coronary vessels. Our data show that neonatal mouse heart can regenerate but that its potential is limited. Moreover, although epicardial cells are multipotent during embryogenesis, their contribution to heart repair through “stem” or “progenitor” cell conversion is minimal after birth. These observations suggest that early embryonic heart development and postnatal heart regeneration are distinct biological processes. Multipotency of epicardial cells is significantly decreased after birth. The regeneration capacity of neonatal mouse heart is controversial. In addition, whether epicardial cells provide a progenitor pool for de novo heart regeneration is incompletely defined. Following apical resection of the neonatal mouse heart, we observed limited regeneration potential. Fate-mapping of Tbx18MerCreMer mice revealed that newly formed coronary vessels and a limited number of cardiomyocytes were derived from the T-box transcription factor 18 (Tbx18) lineage. However, further lineage tracing with SM-MHCCreERT2 and Nfactc1Cre mice revealed that the new smooth muscle and endothelial cells are in fact derivatives of pre-existing coronary vessels. Our data show that neonatal mouse heart can regenerate but that its potential is limited. Moreover, although epicardial cells are multipotent during embryogenesis, their contribution to heart repair through “stem” or “progenitor” cell conversion is minimal after birth. These observations suggest that early embryonic heart development and postnatal heart regeneration are distinct biological processes. Multipotency of epicardial cells is significantly decreased after birth. Acute myocardial infarction from coronary artery occlusion and ischemia is a major cause of death worldwide. Lack of regeneration with fibrogenic response to the acute injury is the main obstacle in treatment of cardiovascular disease (Laflamme and Murry, 2011Laflamme M.A. Murry C.E. Heart regeneration.Nature. 2011; 473: 326-335Crossref PubMed Scopus (840) Google Scholar). Replacing the scarred tissue with new functional cardiac cells is a potential therapeutic strategy to patients with heart failure (Jopling et al., 2010Jopling C. Sleep E. Raya M. Martí M. Raya A. Izpisúa Belmonte J.C. Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation.Nature. 2010; 464: 606-609Crossref PubMed Scopus (880) Google Scholar, Poss et al., 2002Poss K.D. Wilson L.G. Keating M.T. Heart regeneration in zebrafish.Science. 2002; 298: 2188-2190Crossref PubMed Scopus (1290) Google Scholar). Although the mammalian heart lacks sufficient regeneration capacity at adulthood, a few studies have shown that the neonatal mouse heart can fully regenerate after injury (Bryant et al., 2015Bryant D.M. O’Meara C.C. Ho N.N. Gannon J. Cai L. Lee R.T. A systematic analysis of neonatal mouse heart regeneration after apical resection.J. Mol. Cell. Cardiol. 2015; 79: 315-318Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, Haubner et al., 2012Haubner B.J. Adamowicz-Brice M. Khadayate S. Tiefenthaler V. Metzler B. Aitman T. Penninger J.M. Complete cardiac regeneration in a mouse model of myocardial infarction.Aging (Albany N.Y.). 2012; 4: 966-977Crossref PubMed Scopus (143) Google Scholar, Porrello et al., 2011Porrello E.R. Mahmoud A.I. Simpson E. Hill J.A. Richardson J.A. Olson E.N. Sadek H.A. Transient regenerative potential of the neonatal mouse heart.Science. 2011; 331: 1078-1080Crossref PubMed Scopus (1490) Google Scholar, Strungs et al., 2013Strungs E.G. Ongstad E.L. O’Quinn M.P. Palatinus J.A. Jourdan L.J. Gourdie R.G. Cryoinjury models of the adult and neonatal mouse heart for studies of scarring and regeneration.Methods Mol. Biol. 2013; 1037: 343-353Crossref PubMed Scopus (40) Google Scholar). Similar to the teleosts, injury-induced neonatal mouse heart regeneration is initiated with rapid clotting and inflammatory and epicardial activation (Han et al., 2015Han C. Nie Y. Lian H. Liu R. He F. Huang H. Hu S. Acute inflammation stimulates a regenerative response in the neonatal mouse heart.Cell Res. 2015; 25: 1137-1151Crossref PubMed Scopus (86) Google Scholar, Lepilina et al., 2006Lepilina A. Coon A.N. Kikuchi K. Holdway J.E. Roberts R.W. Burns C.G. Poss K.D. A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration.Cell. 2006; 127: 607-619Abstract Full Text Full Text PDF PubMed Scopus (605) Google Scholar, Porrello et al., 2011Porrello E.R. Mahmoud A.I. Simpson E. Hill J.A. Richardson J.A. Olson E.N. Sadek H.A. Transient regenerative potential of the neonatal mouse heart.Science. 2011; 331: 1078-1080Crossref PubMed Scopus (1490) Google Scholar, Uygur and Lee, 2016Uygur A. Lee R.T. Mechanisms of Cardiac Regeneration.Dev. Cell. 2016; 36: 362-374Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar). These observations revealed that within a short time window after birth, the mammalian hearts retain robust regeneration capacity (Haubner et al., 2012Haubner B.J. Adamowicz-Brice M. Khadayate S. Tiefenthaler V. Metzler B. Aitman T. Penninger J.M. Complete cardiac regeneration in a mouse model of myocardial infarction.Aging (Albany N.Y.). 2012; 4: 966-977Crossref PubMed Scopus (143) Google Scholar, Porrello et al., 2011Porrello E.R. Mahmoud A.I. Simpson E. Hill J.A. Richardson J.A. Olson E.N. Sadek H.A. Transient regenerative potential of the neonatal mouse heart.Science. 2011; 331: 1078-1080Crossref PubMed Scopus (1490) Google Scholar). However, arguments arose recently concerning this capacity (Andersen et al., 2014Andersen D.C. Ganesalingam S. Jensen C.H. Sheikh S.P. Do neonatal mouse hearts regenerate following heart apex resection?.Stem Cell Reports. 2014; 2: 406-413Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, Andersen et al., 2016Andersen D.C. Jensen C.H. Baun C. Hvidsten S. Zebrowski D.C. Engel F.B. Sheikh S.P. Persistent scarring and dilated cardiomyopathy suggest incomplete regeneration of the apex resected neonatal mouse myocardium--A 180 days follow up study.J. Mol. Cell. Cardiol. 2016; 90: 47-52Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, Bryant et al., 2015Bryant D.M. O’Meara C.C. Ho N.N. Gannon J. Cai L. Lee R.T. A systematic analysis of neonatal mouse heart regeneration after apical resection.J. Mol. Cell. Cardiol. 2015; 79: 315-318Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, Kotlikoff et al., 2014Kotlikoff M.I. Hesse M. Fleischmann B.K. Comment on “Do neonatal mouse hearts regenerate following heart apex resection”?.Stem Cell Reports. 2014; 3: 2Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, Polizzotti et al., 2016Polizzotti B.D. Ganapathy B. Haubner B.J. Penninger J.M. Kühn B. A cryoinjury model in neonatal mice for cardiac translational and regeneration research.Nat. Protoc. 2016; 11: 542-552Crossref PubMed Scopus (32) Google Scholar, Polizzotti et al., 2015Polizzotti B.D. Ganapathy B. Walsh S. Choudhury S. Ammanamanchi N. Bennett D.G. dos Remedios C.G. Haubner B.J. Penninger J.M. Kühn B. Neuregulin stimulation of cardiomyocyte regeneration in mice and human myocardium reveals a therapeutic window.Sci. Transl. Med. 2015; 7: 281ra45Crossref PubMed Scopus (137) Google Scholar), as they conversely reported that neonatal mouse hearts lack regeneration potential following apical resection or cryoinjury. Despite the regeneration capacity of neonatal mouse heart, stimulation renewal of adult cardiac muscles remains challenging (Cai et al., 2003Cai C.L. Liang X. Shi Y. Chu P.H. Pfaff S.L. Chen J. Evans S. Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart.Dev. Cell. 2003; 5: 877-889Abstract Full Text Full Text PDF PubMed Scopus (1208) Google Scholar, Laflamme and Murry, 2011Laflamme M.A. Murry C.E. Heart regeneration.Nature. 2011; 473: 326-335Crossref PubMed Scopus (840) Google Scholar, Leferovich et al., 2001Leferovich J.M. Bedelbaeva K. Samulewicz S. Zhang X.M. Zwas D. Lankford E.B. Heber-Katz E. Heart regeneration in adult MRL mice.Proc. Natl. Acad. Sci. USA. 2001; 98: 9830-9835Crossref PubMed Scopus (222) Google Scholar, Poss et al., 2002Poss K.D. Wilson L.G. Keating M.T. Heart regeneration in zebrafish.Science. 2002; 298: 2188-2190Crossref PubMed Scopus (1290) Google Scholar). Thus, identifying an optimal source of cardiac stem cells that can differentiate into different types of cardiac cells has been deemed an alternative approach for heart repair (Beltrami et al., 2003Beltrami A.P. Barlucchi L. Torella D. Baker M. Limana F. Chimenti S. Kasahara H. Rota M. Musso E. Urbanek K. et al.Adult cardiac stem cells are multipotent and support myocardial regeneration.Cell. 2003; 114: 763-776Abstract Full Text Full Text PDF PubMed Scopus (2912) Google Scholar, Dawn et al., 2005Dawn B. Stein A.B. Urbanek K. Rota M. Whang B. Rastaldo R. Torella D. Tang X.L. Rezazadeh A. Kajstura J. et al.Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function.Proc. Natl. Acad. Sci. USA. 2005; 102: 3766-3771Crossref PubMed Scopus (414) Google Scholar, Orlic et al., 2001Orlic D. Kajstura J. Chimenti S. Jakoniuk I. Anderson S.M. Li B. Pickel J. McKay R. Nadal-Ginard B. Bodine D.M. et al.Bone marrow cells regenerate infarcted myocardium.Nature. 2001; 410: 701-705Crossref PubMed Scopus (4617) Google Scholar). Epicardial cells are multipotent cardiac progenitor cells during embryonic development (Cai et al., 2008Cai C.L. Martin J.C. Sun Y. Cui L. Wang L. Ouyang K. Yang L. Bu L. Liang X. Zhang X. et al.A myocardial lineage derives from Tbx18 epicardial cells.Nature. 2008; 454: 104-108Crossref PubMed Scopus (578) Google Scholar, Limana et al., 2007Limana F. Zacheo A. Mocini D. Mangoni A. Borsellino G. Diamantini A. De Mori R. Battistini L. Vigna E. Santini M. et al.Identification of myocardial and vascular precursor cells in human and mouse epicardium.Circ. Res. 2007; 101: 1255-1265Crossref PubMed Scopus (190) Google Scholar, Zhou et al., 2008Zhou B. Ma Q. Rajagopal S. Wu S.M. Domian I. Rivera-Feliciano J. Jiang D. von Gise A. Ikeda S. Chien K.R. Pu W.T. Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart.Nature. 2008; 454: 109-113Crossref PubMed Scopus (740) Google Scholar). In zebrafish and mice, a fetal epicardial gene expression program is immediately activated following cardiac injury (Han et al., 2015Han C. Nie Y. Lian H. Liu R. He F. Huang H. Hu S. Acute inflammation stimulates a regenerative response in the neonatal mouse heart.Cell Res. 2015; 25: 1137-1151Crossref PubMed Scopus (86) Google Scholar, Lepilina et al., 2006Lepilina A. Coon A.N. Kikuchi K. Holdway J.E. Roberts R.W. Burns C.G. Poss K.D. A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration.Cell. 2006; 127: 607-619Abstract Full Text Full Text PDF PubMed Scopus (605) Google Scholar, Limana et al., 2010Limana F. Bertolami C. Mangoni A. Di Carlo A. Avitabile D. Mocini D. Iannelli P. De Mori R. Marchetti C. Pozzoli O. et al.Myocardial infarction induces embryonic reprogramming of epicardial c-kit(+) cells: role of the pericardial fluid.J. Mol. Cell. Cardiol. 2010; 48: 609-618Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, Limana et al., 2007Limana F. Zacheo A. Mocini D. Mangoni A. Borsellino G. Diamantini A. De Mori R. Battistini L. Vigna E. Santini M. et al.Identification of myocardial and vascular precursor cells in human and mouse epicardium.Circ. Res. 2007; 101: 1255-1265Crossref PubMed Scopus (190) Google Scholar, Porrello et al., 2011Porrello E.R. Mahmoud A.I. Simpson E. Hill J.A. Richardson J.A. Olson E.N. Sadek H.A. Transient regenerative potential of the neonatal mouse heart.Science. 2011; 331: 1078-1080Crossref PubMed Scopus (1490) Google Scholar, Uygur and Lee, 2016Uygur A. Lee R.T. Mechanisms of Cardiac Regeneration.Dev. Cell. 2016; 36: 362-374Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar). However, it failed to identify epicardium-derived cardiomyocytes during heart regeneration in zebrafish (Kikuchi et al., 2011Kikuchi K. Gupta V. Wang J. Holdway J.E. Wills A.A. Fang Y. Poss K.D. tcf21+ epicardial cells adopt non-myocardial fates during zebrafish heart development and regeneration.Development. 2011; 138: 2895-2902Crossref PubMed Scopus (201) Google Scholar). In mice, it is not fully determined whether postnatal epicardial cells can differentiate into different cardiac lineages after injury. With Wilms tumor suppressor 1 (Wt1) lineage tracing of the adult epicardial cells, van Wijk et al., 2012van Wijk B. Gunst Q.D. Moorman A.F. van den Hoff M.J. Cardiac regeneration from activated epicardium.PLoS ONE. 2012; 7: e44692Crossref PubMed Scopus (126) Google Scholar detected myocardial cells derived from epicardial mesenchyme post-infarction. Smart et al., 2011Smart N. Bollini S. Dubé K.N. Vieira J.M. Zhou B. Davidson S. Yellon D. Riegler J. Price A.N. Lythgoe M.F. et al.De novo cardiomyocytes from within the activated adult heart after injury.Nature. 2011; 474: 640-644Crossref PubMed Scopus (500) Google Scholar also identified epicardial differentiation into cardiomyocytes, and this differentiation potential is enhanced upon thymosin β4 treatment. In contrast, Zhou et al., 2011Zhou B. Honor L.B. He H. Ma Q. Oh J.H. Butterfield C. Lin R.Z. Melero-Martin J.M. Dolmatova E. Duffy H.S. et al.Adult mouse epicardium modulates myocardial injury by secreting paracrine factors.J. Clin. Invest. 2011; 121: 1894-1904Crossref PubMed Scopus (362) Google Scholar showed that epicardial cells only benefit heart repair through paracrine effects. Besides these unsolved critical issues regarding the epicardial myogenic potential, it is still uncertain whether postnatal epicardial cells sustain their potency and provide precursors for neovascularization during heart repair (Cai et al., 2008Cai C.L. Martin J.C. Sun Y. Cui L. Wang L. Ouyang K. Yang L. Bu L. Liang X. Zhang X. et al.A myocardial lineage derives from Tbx18 epicardial cells.Nature. 2008; 454: 104-108Crossref PubMed Scopus (578) Google Scholar, Katz et al., 2012Katz T.C. Singh M.K. Degenhardt K. Rivera-Feliciano J. Johnson R.L. Epstein J.A. Tabin C.J. Distinct compartments of the proepicardial organ give rise to coronary vascular endothelial cells.Dev. Cell. 2012; 22: 639-650Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, Limana et al., 2007Limana F. Zacheo A. Mocini D. Mangoni A. Borsellino G. Diamantini A. De Mori R. Battistini L. Vigna E. Santini M. et al.Identification of myocardial and vascular precursor cells in human and mouse epicardium.Circ. Res. 2007; 101: 1255-1265Crossref PubMed Scopus (190) Google Scholar, Mikawa and Fischman, 1992Mikawa T. Fischman D.A. Retroviral analysis of cardiac morphogenesis: discontinuous formation of coronary vessels.Proc. Natl. Acad. Sci. USA. 1992; 89: 9504-9508Crossref PubMed Scopus (325) Google Scholar, Mikawa and Gourdie, 1996Mikawa T. Gourdie R.G. Pericardial mesoderm generates a population of coronary smooth muscle cells migrating into the heart along with ingrowth of the epicardial organ.Dev. Biol. 1996; 174: 221-232Crossref PubMed Scopus (508) Google Scholar, Zhou et al., 2008Zhou B. Ma Q. Rajagopal S. Wu S.M. Domian I. Rivera-Feliciano J. Jiang D. von Gise A. Ikeda S. Chien K.R. Pu W.T. Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart.Nature. 2008; 454: 109-113Crossref PubMed Scopus (740) Google Scholar). In this study, to define the regeneration potential and epicardial “progenitor” or “stem” activity in the injured neonatal mouse heart, we scrutinized the heart with apical resection. Through an inducible Tbx18-MerCreMer (Tbx18MerCreMer/+) knockin allele that labels epicardial cells, we observed that although the neonatal hearts can regrow, their regenerative potential is restricted. We further uncovered that smooth muscle cells within the newly formed coronary vessels are derived from transcription factor T-box 18 (Tbx18) and smooth muscle myosin heavy chain (SM-MHC) cells through angiogenesis. The new coronary endothelial cells are also derivatives of the pre-existing cardiac endothelium. While Tbx18 epicardial cells can give rise to cardiomyocytes, the number is exceedingly low and appears not to substantially contribute to a functional heart repair. To investigate neonatal mouse heart regeneration, we resected the lower portion of ventricular apex (∼10% of the heart) at postnatal day 1 (P1) (Porrello et al., 2011Porrello E.R. Mahmoud A.I. Simpson E. Hill J.A. Richardson J.A. Olson E.N. Sadek H.A. Transient regenerative potential of the neonatal mouse heart.Science. 2011; 331: 1078-1080Crossref PubMed Scopus (1490) Google Scholar). After amputation, the blood clotted immediately and the entire apex was sealed 3 hours after injury (Figure S1). Criteria to determine heart regeneration were based on several key factors including smoothness and thickness of apex, apical shape (curved or flat), and the presence of fibrotic tissues in the injured area. We first examined the hearts at 7 days post-surgery (dps). Scars with rugged edges were observed (Figure S2). Haemotoxylin & Eosin (H&E) and trichrome staining were performed to determine how neonatal heart responds to amputation. Deposition of extracellular matrix was evident in the injured area at an early stage (Figure 1D2). After 7 dps, progressive repair with myocardial restoration was detected in the apex (Figure 1, 14–60 dps). However, by examining 59 hearts at 21 dps, we found that the time needed for repair was much longer than that which was previously reported (Porrello et al., 2011Porrello E.R. Mahmoud A.I. Simpson E. Hill J.A. Richardson J.A. Olson E.N. Sadek H.A. Transient regenerative potential of the neonatal mouse heart.Science. 2011; 331: 1078-1080Crossref PubMed Scopus (1490) Google Scholar). Of 32 representative hearts, 28 (87.5%) still had substantial fibrotic tissues in the apex (Figure 1D4 and Figures 2A, B, and E), suggesting most hearts were not fully regenerated by 21 dps, in contrast to that which was suggested previously (Porrello et al., 2011Porrello E.R. Mahmoud A.I. Simpson E. Hill J.A. Richardson J.A. Olson E.N. Sadek H.A. Transient regenerative potential of the neonatal mouse heart.Science. 2011; 331: 1078-1080Crossref PubMed Scopus (1490) Google Scholar).Figure 2Limited Potential of Neonatal Heart RegenerationShow full caption(A–D) Transverse sections of representative hearts at 21 dps (A and B) and 60 dps (C and D), suggesting that the repairing process takes longer than 21 days. A significant portion of hearts (46.2%) cannot be fully regenerated at 60 dps (C4 and C5). Asterisks indicate injured regions and incomplete repair.(E) Quantification of repair degree at 21 dps and 60 dps determined by apex shape and fibrotic tissues.(F–H) Global view of hearts in sham (F) and surgery (G) groups. Ventricular morphology is quantitated by the ratio of maximal horizontal width (w) to maximal vertical height (h) (H).∗∗p < 0.01 versus the sham control. Scale bar, 1 mm.See also Figures S1 and S2.View Large Image Figure ViewerDownload Hi-res image Download (PPT) (A–D) Transverse sections of representative hearts at 21 dps (A and B) and 60 dps (C and D), suggesting that the repairing process takes longer than 21 days. A significant portion of hearts (46.2%) cannot be fully regenerated at 60 dps (C4 and C5). Asterisks indicate injured regions and incomplete repair. (E) Quantification of repair degree at 21 dps and 60 dps determined by apex shape and fibrotic tissues. (F–H) Global view of hearts in sham (F) and surgery (G) groups. Ventricular morphology is quantitated by the ratio of maximal horizontal width (w) to maximal vertical height (h) (H). ∗∗p < 0.01 versus the sham control. Scale bar, 1 mm. See also Figures S1 and S2. We then examined the injured hearts at later stages. In 108 hearts collected at 60 dps, 26 were subjected to further histological analysis. Although 53.8% of them (14/26; Figure 2E) showed reconstruction with residual fibrotic tissues (Figure 1D6 and Figures 2C1, 2C2, 2D1, and 2D2; Figure S2B6), a large number (46.2%, 12/26; Figure 2E) still did not exhibit full regeneration. Damage to this group seems permanent because their apical shape did not retrieve (Figures 2C3–2C5 and 2D3–2D5; Figure S2B6). Substantial fibrotic tissues were persistently present in the injured region of these hearts when we examined at 90–180 dps and later (data not shown). Moreover, when we inspected the “regenerated” group hearts at 60 dps by comparing them with the sham group, it showed that although the apical edge of hearts in this group was relatively smooth with minimal fibrotic tissues, the global morphology was altered to a more “rounded” shape, characterized by significantly increased ventricular horizontal width to vertical height ratio (Figures 2F–2H). Mammalian myocardial cells progressively decrease their proliferation activity after birth, with <1% turnover rate per year at adulthood (Bergmann et al., 2009Bergmann O. Bhardwaj R.D. Bernard S. Zdunek S. Barnabé-Heider F. Walsh S. Zupicich J. Alkass K. Buchholz B.A. Druid H. et al.Evidence for cardiomyocyte renewal in humans.Science. 2009; 324: 98-102Crossref PubMed Scopus (2076) Google Scholar, Li et al., 1996Li F. Wang X. Capasso J.M. Gerdes A.M. Rapid transition of cardiac myocytes from hyperplasia to hypertrophy during postnatal development.J. Mol. Cell. Cardiol. 1996; 28: 1737-1746Abstract Full Text PDF PubMed Scopus (604) Google Scholar, Mollova et al., 2013Mollova M. Bersell K. Walsh S. Savla J. Das L.T. Park S.Y. Silberstein L.E. Dos Remedios C.G. Graham D. Colan S. Kühn B. Cardiomyocyte proliferation contributes to heart growth in young humans.Proc. Natl. Acad. Sci. USA. 2013; 110: 1446-1451Crossref PubMed Scopus (441) Google Scholar, Naqvi et al., 2014Naqvi N. Li M. 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Jovinge S. Cardiomyocyte cell cycle control and growth estimation in vivo--an analysis based on cardiomyocyte nuclei.Cardiovasc. Res. 2010; 86: 365-373Crossref PubMed Scopus (198) Google Scholar, Zhang and Kühn, 2014Zhang C.H. Kühn B. Muscling up the heart: a preadolescent cardiomyocyte proliferation contributes to heart growth.Circ. Res. 2014; 115: 690-692Crossref PubMed Scopus (3) Google Scholar). In mice, cardiomyocytes maintain their cell cycle till 21 days after birth, and it showed that the neonatal heart fully regenerated with myocardial turnover by 21 dps (Porrello et al., 2011Porrello E.R. Mahmoud A.I. Simpson E. Hill J.A. Richardson J.A. Olson E.N. Sadek H.A. Transient regenerative potential of the neonatal mouse heart.Science. 2011; 331: 1078-1080Crossref PubMed Scopus (1490) Google Scholar). We decided to assess the course of myocardial repair after 21 dps (Figures 2C–2E), given the improved repair rate or degree at 21–60 dps (Figure 2E). A 5-ethynyl-2'-deoxyuridine (EdU) pulse-chase assay was conducted to determine if myocardial proliferation continually contribute to heart repair after 21 dps. Mice were injected intraperitoneally with EdU at P21/P28 and P32/39, respectively (Figure 3A). Proliferative myocardial cells were identified by co-localization of EdU, cardiac troponin T (cTnT), and DAPI at 32 dps and 43 dps. Compared with the sham group, an increased number of EdU-positive (EdU+) cells were detected in the apex and remote region of injured hearts (32 dps: ∼34.5 cells and ∼26.1 cells/100× field in apex and remote region versus ∼11.0 cells and ∼10.7 cells/100× field in the sham apex and remote region; 43 dps: ∼34.9 cells and ∼23.7 cells/100× field in the injured apex and remote region versus ∼12.1 cells and ∼12.5 cells/100× field in the sham apex and remote region, Figures 3B–J), suggesting that the apical injury promotes global cardiac cell proliferation at 21–43 dps, although most of them are non-cardiomyocytes (cTnT–; Figures 3C2 and 3G2). Further evaluation revealed an increased number of EdU+ cardiomyocytes in the injured apex border zone at 32 dps and 43 dps (∼3.0 cells and ∼2.3 cells/100× field, respectively) (Figures 3C1, 3G1, and 3K), and the number was significantly higher than that of the sham-operated controls (∼0.2 cells and ∼0.07 cells/100× field at 32 dps and 43 dps, respectively) (Figures 3E1, 3I1, and 3K). The plasma membrane marker wheat germ agglutinin (WGA) was used to identify the true proliferation of cardiomyocytes as opposed to binucleation (Figure S3). These observations indicate that severe injury can induce myocardial proliferation after 21 dps. The transcription factor Tbx18 is expressed in the epicardium across species in vertebrates (Haenig and Kispert, 2004Haenig B. Kispert A. Analysis of TBX18 expression in chick embryos.Dev. Genes Evol. 2004; 214: 407-411Crossref PubMed Scopus (37) Google Scholar, Kraus et al., 2001Kraus F. Haenig B. Kispert A. Cloning and expression analysis of the mouse T-box gene Tbx18.Mech. Dev. 2001; 100: 83-86Crossref PubMed Scopus (137) Google Scholar). Previous studies suggested that epicardial cells are cardiac progenitors and give rise to multiple cardiac lineages, including coronary smooth muscle cells (cSMCs), endothelium, fibroblasts, and cardiomyocytes, during embryonic heart formation (Cai et al., 2008Cai C.L. Martin J.C. Sun Y. Cui L. Wang L. Ouyang K. Yang L. Bu L. Liang X. Zhang X. et al.A myocardial lineage derives from Tbx18 epicardial cells.Nature. 2008; 454: 104-108Crossref PubMed Scopus (578) Google Scholar, Katz et al., 2012Katz T.C. Singh M.K. Degenhardt K. Rivera-Feliciano J. Johnson R.L. Epstein J.A. Tabin C.J. Distinct compartments of the proepicardial organ give rise to coronary vascular endothelial cells.Dev. Cell. 2012; 22: 639-650Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, Mikawa and Fischman, 1992Mikawa T. Fischman D.A. Retroviral analysis of cardiac morphogenesis: discontinuous formation of coronary vessels.Proc. Natl. Acad. Sci. USA. 1992; 89: 9504-9508Crossref PubMed Scopus (325) Google Scholar, Mikawa and Gourdie, 1996Mikawa T. Gourdie R.G. Pericardial mesoderm generates a population of coronary smooth muscle cells migrating into the heart along with ingrowth of the epicardial organ.Dev. Biol. 1996; 174: 221-232Crossref PubMed Scopus (508) Google Scholar, Zhou et al., 2008Zhou B. Ma Q. Rajagopal S. Wu S.M. Domian I. Rivera-Feliciano J. Jiang D. von Gise A. Ikeda S. Chien K.R. Pu W.T. Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart.Nature. 2008; 454: 109-113Crossref PubMed Scopus (740) Google Scholar). To determine the potential de novo contribution of epicardial progenitor cells through differentiation in heart repair, we performed apical resection on Tbx18H2B-GFP/+ mice at P1. H2B-GFP in Tbx18H2B-GFP/+ knockin reporter mice recapitulates endogenous Tbx18 expression (Cai et al., 2008Cai C.L. Martin J.C. Sun Y. Cui L. Wang L. Ouyang K. Yang L. Bu L. Liang X. Zhang X. et al.A myocardial lineage derives from Tbx18 epicardial cells.Nature. 2008; 454: 104-108Crossref PubMed Scopus (578) Google Scholar), and the mice carrying heterozygous null for Tbx18 are normal in heart formation and function (Wu et al., 2013Wu S.P. Dong X.R. Regan J.N. Su C. Majesky M.W. Tbx18 regulates development of the epicardium and coronary vessels.Dev. Biol. 2013; 383: 307-320Crossref PubMed Scopus (57) Google Scholar). Upon surgical amputation, massive Tbx18H2B-GFP-positive cells accumulated in the ventricular apex at 3 dps (Figures 4A1 , 4B1, and 4C1). Density of these GFP+ cells was high at 1–21 dps (Figures 4A1–4A4, 4B1–4B4, and 4C1–4C4) and slowly decreased after 30 dps (Figures 4A5, 4A6, 4B5, 4B6, 4C5, and 4C6). To determine the cause of reduction of Tbx18+ cells during heart repair, we performed TUNEL" @default.
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• W2956154114 title "Limited Regeneration Potential with Minimal Epicardial Progenitor Conversions in the Neonatal Mouse Heart after Injury" @default.
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