In vitro and in vivo roles of glucocorticoid and vitamin D receptors in the control of neonatal cardiomyocyte proliferative potential
In vitro and in vivo roles of glucocorticoid and vitamin D receptors in the control of neonatal cardiomyocyte proliferative potential
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DOI：
10.1016/j.yjmcc.2020.04.013
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发表时间：
2020-05-01
影响因子：
5
通讯作者：
Huang, Guo N.
中科院分区：
文献类型：
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作者：
Cutie, Stephen;Payumo, Alexander Y.;Huang, Guo N.
心肌细胞（CM）的增殖潜力在不同物种之间存在很大差异。虽然低等脊椎动物和新生哺乳动物保留了强大的 CM 增殖能力，但成年哺乳动物 CM 由于细胞周期退出和多倍化而失去了增殖潜力，无法在心脏损伤后启动增殖反应来再生丢失的 CM。小鼠 CM 增殖潜力的下降发生在新生儿期，此时内分泌系统为适应宫外生活而发生剧烈变化。我们最近证明，甲状腺激素 (TH) 信号传导是驱动脊椎动物 CM 增殖潜力丧失的主要因素。其他激素途径是否控制这一过程在很大程度上仍有待探索。在这里，我们发现糖皮质激素受体 (GR) 和维生素 D 受体 (VDR) 激动剂可抑制新生儿 CM 增殖。接下来，我们检查了CM中缺乏GR或VDR的新生突变小鼠的CM成核和增殖，但我们在出生后第14天观察到突变体和对照同窝小鼠之间没有差异。此外，我们生成了缺乏GR或VDR并在其CM中表达显性失活TH受体α的复合突变小鼠，并且类似地观察到与单独显性失活TH受体α小鼠相比，CM增殖潜力没有增加。因此，尽管GR和VDR激活足以抑制CM增殖，但它们对于新生儿CM细胞周期退出和体内多倍化似乎是可有可无的。此外，鉴于最近有报道称斑马鱼中的 VDR 激活可促进 CM 增殖和组织再生，我们的结果表明 VDR 在斑马鱼和啮齿动物 CM 细胞周期调节中具有独特的作用。
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. We next examined CM nucleation and proliferation in neonatal mutant mice lacking GR or VDR specifically in CMs, but we observed no difference between mutant and control littermates at postnatal day 14. 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 is sufficient to inhibit CM proliferation, they seem to be dispensable for neonatal CM cell-cycle exit and polyploidization 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.