Evidence for hormonal control of heart regenerative capacity during endothermy acquisition

Hirose, Kentaro; Payumo, Alexander Y.; Cutie, Stephen; Hoang, Alison; Zhang, Hao; Guyot, Romain; Lunn, Dominic; Bigley, Rachel B.; Yu, Hongyao; Wang, Jiajia; Smith, Megan; Gillett, Ellen; Muroy, Sandra E; Schmid, Tobias; Wilson, Emily; Field, Kenneth A.; Reeder, Dee Ann M.; Maden, Malcom; Yartsev, Michael M.; Wolfgang, Michael J.; Grützner, Frank; Scanlan, Thomas S.; Szweda, Luke I.; Buffenstein, Rochelle; Hu, Guang; Flamant, Frédéric; Olgin, Jeffrey E.; Huang, Guo N.

doi:10.1126/science.aar2038

Cited by 291 publications

(372 citation statements)

References 55 publications

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“…These include maturation of cardiac fibroblasts, activity of macrophages and other immune cells, ECM composition and rigidity, as well as physiological hypoxia and hormonal regulation. 14,28,41,42 Investigating the discordance in timing of cardiac maturation and regenerative capacity in pigs could be useful to define relative contributions of multiple cell types and physiological factors in heart regeneration. Here, we show that ECM remodeling is significant by P7 in pigs, contributing to increased rigidity of the matrix, while maturational collagen remodeling continues to 6mo.…”

Section: What Dictates Postnatal Regenerative Capacity Of the Mammalimentioning

confidence: 99%

Cardiomyocyte cell cycling, maturation, and growth by multinucleation in postnatal swine

Velayutham

Alfieri

Agnew

et al. 2019

Preprint

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words)Aims: Cardiomyocyte (CM) cell cycle arrest, decline of mononucleated-diploid CMs, sarcomeric maturation, and extracellular matrix remodeling are implicated in loss of cardiac regenerative potential in mice after birth. Recent studies show a 3-day neonatal regenerative capacity in pig hearts similar to mice, but postnatal pig CM growth dynamics are unknown. We examined cardiac maturation in postnatal pigs and mice, to determine the relative timing of developmental events underlying heart growth and regenerative potential in large and small mammals. Methods and Results:Left ventricular tissue from White Yorkshire-Landrace pigs at postnatal day (P)0 to 6 months (6mo) was analyzed to span birth, weaning, and adolescence in pigs, compared to similar physiological timepoints in mice. Collagen remodeling increases by P7 in postnatal pigs, but sarcomeric and gap junctional maturation only occur at 2mo. Also, there is no postnatal transition to beta-oxidation metabolism in pig hearts. Mononucleated CMs, predominant at birth, persist to 2mo in swine, with over 50% incidence of mononucleated-diploid CMs at P7-P15. Extensive multinucleation with 4-16 nuclei per CM occurs beyond P30. Pigs also exhibit increased CM length relative to multinucleation, preceding increase in CM width at 2mo-6mo. Further, robust CM mitotic nuclear pHH3 activity and cardiac cell cycle gene expression is apparent in pig left ventricles up to 2mo. By contrast, in mice, these maturational events occur concurrently in the first two postnatal weeks alongside loss of cardiac regenerative capacity. Conclusions:Cardiac maturation occurs over a 6mo postnatal period in pigs, despite a similar early-neonatal heart regenerative window as mice. Postnatal pig CM growth includes increase in CM length alongside multinucleation, with CM cell cycle arrest and loss of mononucleated-diploid CMs occurring at 2mo-6mo. These CM characteristics are important to consider for pig preclinical studies and may offer opportunities to study aspects of heart regeneration unavailable in other models.

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Section: What Dictates Postnatal Regenerative Capacity Of the Mammalimentioning

confidence: 99%

Cardiomyocyte cell cycling, maturation, and growth by multinucleation in postnatal swine

Velayutham

Alfieri

Agnew

et al. 2019

Preprint

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“…3B-D). The heart weight to body weight ratio did not significantly differ between Myh6-Cre;Vdr f/f knockout mice We recently showed that TH signaling regulates CM proliferative potential, but mice with deficiency in TH receptor activation in CMs have ~30% mononuclear CMs at P14, implicating the existence of other pathways that contribute to CM binucleation in the neonatal period 11 . We next investigated whether loss of GR or VDR signaling affect CM proliferative potential in combination with loss of TH signaling.…”

Section: Resultsmentioning

confidence: 91%

“…dosed with propylthiouracil (PTU) -a potent inhibitor of TH synthesis -from birth through postnatal day 14 (P14) show significantly increased mononuclear CM percentage and CM proliferation 11 . These mononuclear CMs and CM proliferation phenotypes are also observed in mutant mice in which TH signaling is specifically inactivated in CMs 11 . These mutant mouse hearts also display enhanced recovery after MI as indicated by cardiac contractile functions and fibrosis one month post-surgery.…”

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confidence: 99%

In vitro and in vivo roles of glucocorticoid and vitamin D receptors in the control of cardiomyocyte proliferative potential

Cutie

Lunn

Huang

2019

Preprint

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Cardiomyocyte (CM) proliferative potential varies considerably across species. While lower vertebrates and neonatal mammals retain robust capacities for CM proliferation, adult mammalian CMs lose proliferative potential due to cell-cycle withdrawal and polyploidization, failing to mount a proliferative response to regenerate lost CMs after cardiac injury. The decline of murine CM proliferative potential occurs in the neonatal period when the endocrine system undergoes drastic changes for adaptation to extrauterine life. We recently demonstrated that thyroid hormone (TH) signaling functions as a primary factor driving CM proliferative potential loss in vertebrates. Whether other hormonal pathways govern this process remains largely unexplored. Here we showed that agonists of glucocorticoid receptor (GR) and vitamin D receptor (VDR) suppressed neonatal CM proliferation in vitro. We next examined CM nucleation and proliferation in mutant mice lacking GR or VDR specifically in CMs, but we observed no difference between mutant and control littermates. Additionally, we generated compound mutant mice that lack GR or VDR and express dominant-negative TH receptor alpha in their CMs, and similarly observed no increase in CM proliferative potential compared to dominant-negative TH receptor alpha mice alone. Thus, although GR and VDR activation in cultured CMs is sufficient to inhibit CM proliferation, they seem to be dispensable for CM cell-cycle exit and binucleation in vivo. In addition, given the recent report that VDR activation in zebrafish promotes CM proliferation and tissue regeneration, our results suggest distinct roles of VDR in zebrafish and rodent CM cell-cycle regulation. BACKGROUNDCardiovascular disease is the leading killer in the United States, mostly due to heart failure after myocardial infarction (MI) 1,2 . After ischemic injury like MI induces CM death in the hearts of adult mammals, lost CMs are not replenished and fibrotic tissue permanently replaces previously functional cardiac muscle. However, lower vertebrates like zebrafish (Danio rerio), newts (Notophthalmus viridescens), and axolotls (Ambystoma mexicanum) display robust CM proliferation and myocardial regeneration after cardiac injury 2-4 . Intriguingly, neonatal mammals also transiently possess considerable CM proliferative potential. Ischemic heart injury induced in newborn mice at P0 or P1 resolves as fibrosis-free, fully-regenerated cardiac muscle by 21 days post-injury, mediated by existing CMs that proliferate to reconstitute the lost myocardium 5,6 . This transient CM proliferative potential is lost in mice after the first week as neonatal CMs binucleate and permanently exit the cell cycle 7 . Because the regeneration-competent hearts of lower vertebrates and neonatal mammals consist predominantly of mononuclear diploid CMs while the non-regenerative hearts of adult mammals consist primarily of polyploid CMs, this developmental polyploidization -documented in both mice and humans -is implicated as a critical inhibitor of CM proliferative...

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“…To test if thyroid hormone signaling is necessary for Coq10a expression in the heart, we analyzed its transcript levels in mice that express a dominant negative form of thyroid hormone receptor alpha (Thra DN ) to suppress thyroid hormone signaling specifically in cardiomyocytes (Myh6-Cre;Thra DN ), recently generated by our laboratory (19). RNA-seq analyses of Myh6-Cre;Thra DN hearts at P14 demonstrated that the gene expression of Coq10a was reduced to one-third compared to control hearts ( Figure 2B).…”

Section: Thyroid Hormone Signaling Activates Coq10a Gene Expressionmentioning

confidence: 99%

“…Mice procedures were conducted in accordance with the Institutional Animal Care and Use Committee (IACUC) of the University of California, San Francisco. CD-1 (Charles River) and against Thra-GFP were described in our previous paper (19).…”

Section: Animalsmentioning

confidence: 99%

Loss of a novel striated muscle-enriched mitochondrial protein Coq10a enhances postnatal cardiac hypertrophic growth

Hirose

Chang

et al. 2019

Preprint

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Postnatal mammalian cardiomyocytes undergo a major transition from hyperplasia (increases in cell numbers) to hypertrophy (expansion in cell size). This process is accompanied by rapid mitochondrial biogenesis and metabolic switches to meet the demand of increased cardiac output.Although most mitochondrial components express ubiquitously, recent transcriptomic and proteomic analyses have discovered numerous tissue-specific mitochondrial proteins whose physiological functions are largely unknown. Here we report that a highly evolutionarily conserved mitochondrial protein Coq10a is predominantly expressed in mammalian cardiac and skeletal muscles, and is highly up-regulated around birth in a thyroid hormone-dependent manner. Deletion of Coq10a by CRISPR/Cas9 leads to enhanced cardiac growth after birth. Surprisingly, adult Coq10a mutant mice maintain the hypertrophic heart phenotype with increased levels of coenzyme Q (CoQ) per cardiomyocyte, preserved cardiac contractile function and mitochondrial respiration, which contrasts with reported mice and humans with mutations in other Coq family genes. Further RNA-seq analysis and mitochondrial characterization suggest an increase of mitochondrial biogenesis in the Coq10a

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Evidence for hormonal control of heart regenerative capacity during endothermy acquisition

Cited by 291 publications

References 55 publications

Cardiomyocyte cell cycling, maturation, and growth by multinucleation in postnatal swine

Cardiomyocyte cell cycling, maturation, and growth by multinucleation in postnatal swine

In vitro and in vivo roles of glucocorticoid and vitamin D receptors in the control of cardiomyocyte proliferative potential

Loss of a novel striated muscle-enriched mitochondrial protein Coq10a enhances postnatal cardiac hypertrophic growth

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