Prolonged Myocardial Regenerative Capacity in Neonatal Opossum
Prolonged Myocardial Regenerative Capacity in Neonatal Opossum
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DOI：
10.1161/circulationaha.121.055269
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发表时间：
2022-05
期刊：
影响因子：
37.8
通讯作者：
C. Nishiyama;Yuichi Saito;Akane Sakaguchi;M. Kaneko;H. Kiyonari;Yuqing Xu;Y. Arima;Hideki Uosaki;Wataru Kimura
中科院分区：
文献类型：
--
作者：
C. Nishiyama;Yuichi Saito;Akane Sakaguchi;M. Kaneko;H. Kiyonari;Yuqing Xu;Y. Arima;Hideki Uosaki;Wataru Kimura
背景资料：大型和小型哺乳动物的早期新生儿都能够在出生后的短时间内通过心肌细胞增殖再生心肌。这种心肌再生能力的下降与出生后最初几天心肌细胞从细胞周期中退出平行。迄今为止，没有发现任何哺乳动物物种能够在出生后1周内对心肌损伤产生有意义的再生反应。研究方法：我们研究了心肌细胞增殖的新生儿的有袋负鼠（Monodelphis arctica）在出生后的不同时间免疫染色。在出生后第14或29天进行心尖切除或诱导心肌梗死后评估出生后负鼠心肌的再生能力，而在出生后第7天进行心肌梗死后评估出生后小鼠心肌的再生能力。采用生物信息学数据分析、免疫荧光染色、药理学和遗传学干预等方法，研究AMPK（5′-AMP活化蛋白激酶）信号通路在哺乳动物心肌细胞周期调控中的作用。结果如下：负鼠新生儿出生后至少2周内出现心肌细胞增殖，其频率与早期新生小鼠相似。此外，负鼠的心脏在出生后第14天表现出实质性的再生能力后，心尖切除和心肌梗死损伤，而这种能力已经减少了出生后第29天。转录组学和免疫荧光分析表明，AMPK信号在负鼠和小鼠出生后的心肌细胞中被激活。AMPK信号的药理学或遗传学抑制足以延长小鼠和负鼠新生儿心肌细胞增殖以及新生小鼠心脏再生的出生后窗口。结论：有袋负鼠在出生后至少2周内保持心肌细胞增殖和心肌再生能力。据我们所知，这是迄今为止所研究的哺乳动物中这种能力在出生后持续时间最长的。AMPK信号转导被认为是哺乳动物出生后心肌细胞增殖的进化保守调节因子。
Background: Early neonates of both large and small mammals are able to regenerate the myocardium through cardiomyocyte proliferation for only a short period after birth. This myocardial regenerative capacity declines in parallel with withdrawal of cardiomyocytes from the cell cycle in the first few postnatal days. No mammalian species examined to date has been found capable of a meaningful regenerative response to myocardial injury later than 1 week after birth. Methods: We examined cardiomyocyte proliferation in neonates of the marsupial opossum (Monodelphis domestica) by immunostaining at various times after birth. The regenerative capacity of the postnatal opossum myocardium was assessed after either apex resection or induction of myocardial infarction at postnatal day 14 or 29, whereas that of the postnatal mouse myocardium was assessed after myocardial infarction at postnatal day 7. Bioinformatics data analysis, immunofluorescence staining, and pharmacological and genetic intervention were applied to determine the role of AMPK (5′-AMP–activated protein kinase) signaling in regulation of the mammalian cardiomyocyte cell cycle. Results: Opossum neonates were found to manifest cardiomyocyte proliferation for at least 2 weeks after birth at a frequency similar to that apparent in early neonatal mice. Moreover, the opossum heart at postnatal day 14 showed substantial regenerative capacity both after apex resection and after myocardial infarction injury, whereas this capacity had diminished by postnatal day 29. Transcriptomic and immunofluorescence analyses indicated that AMPK signaling is activated in postnatal cardiomyocytes of both opossum and mouse. Pharmacological or genetic inhibition of AMPK signaling was sufficient to extend the postnatal window of cardiomyocyte proliferation in both mouse and opossum neonates as well as of cardiac regeneration in neonatal mice. Conclusions: The marsupial opossum maintains cardiomyocyte proliferation and a capacity for myocardial regeneration for at least 2 weeks after birth. As far as we are aware, this is the longest postnatal duration of such a capacity among mammals examined to date. AMPK signaling was implicated as an evolutionarily conserved regulator of mammalian postnatal cardiomyocyte proliferation.