Laboratory for Heart Regeneration (C.N., Y.S., A.S., W.K.), RIKEN Center for Biosystems Dynamics Research, Kobe, Japan.
Laboratory for Animal Resources and Genetic Engineering (M.K., H.K.), RIKEN Center for Biosystems Dynamics Research, Kobe, Japan.
Circulation. 2022 Jul 12;146(2):125-139. doi: 10.1161/CIRCULATIONAHA.121.055269. Epub 2022 May 26.
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.
We examined cardiomyocyte proliferation in neonates of the marsupial opossum () 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.
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.
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.
在出生后的短暂时间内，无论是大型哺乳动物还是小型哺乳动物的早期新生儿，都能够通过心肌细胞增殖来再生心肌。这种心肌再生能力与出生后几天内心肌细胞退出细胞周期的速度平行下降。迄今为止，没有发现任何一种哺乳动物在出生后 1 周后能够对心肌损伤产生有意义的再生反应。
我们通过在出生后不同时间点进行免疫染色，检查了有袋动物负鼠的心肌细胞增殖情况。在出生后 14 天或 29 天，通过心尖切除或诱导心肌梗死评估了新生负鼠心肌的再生能力，而在出生后 7 天，通过心肌梗死评估了新生小鼠心肌的再生能力。应用生物信息学数据分析、免疫荧光染色以及药理学和遗传学干预来确定 AMPK（5'-AMP 激活的蛋白激酶）信号在调节哺乳动物心肌细胞周期中的作用。
发现负鼠新生儿在出生后至少 2 周内表现出心肌细胞增殖，其频率与早期新生小鼠相似。此外，出生后 14 天的负鼠心脏在心尖切除和心肌梗死损伤后都表现出显著的再生能力，而这种能力在出生后 29 天已经减弱。转录组学和免疫荧光分析表明，AMPK 信号在负鼠和小鼠的新生心肌细胞中均被激活。药理学或遗传学抑制 AMPK 信号足以延长新生小鼠和负鼠的心肌细胞增殖以及新生小鼠的心脏再生的出生后窗口期。
有袋动物负鼠在出生后至少 2 周内保持心肌细胞增殖和心肌再生的能力。就我们所知，这是迄今为止检查过的哺乳动物中最长的出生后持续时间。AMPK 信号被认为是调节哺乳动物出生后心肌细胞增殖的一种进化保守的调节剂。
