Dedifferentiation, Proliferation, and Redifferentiation of Adult Mammalian Cardiomyocytes After Ischemic Injury.
Dedifferentiation, Proliferation, and Redifferentiation of Adult Mammalian Cardiomyocytes After Ischemic Injury.
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成年哺乳动物心肌细胞缺血性损伤后的去分化、增殖和再分化
DOI：
10.1161/circulationaha.116.024307
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发表时间：
2017-08-29
期刊：
影响因子：
37.8
通讯作者：
Zeng C
中科院分区：
文献类型：
--
作者：
Wang WE;Li L;Xia X;Fu W;Liao Q;Lan C;Yang D;Chen H;Yue R;Zeng C;Zhou L;Zhou B;Duan DD;Chen X;Houser SR;Zeng C
背景：成年哺乳动物心脏产生新的心肌细胞的能力有限。现有的成年心肌细胞(ACM)的增殖是新的心肌细胞的潜在来源。了解ACM增殖的基础生物学对治疗心肌梗死(MI)具有重要的临床意义。我们的目的是了解ACM增殖的过程和调节，以及它在MI后小鼠心脏新的心肌细胞形成中的作用。方法：用&BGR；-肌动蛋白-绿色荧光蛋白转基因小鼠和命运定位MYH6-MerCreMer-tdTomato/LacZ小鼠追踪ACM的命运。在与新生大鼠心室肌细胞共培养体系中，ACM的增殖被记录下来，并通过时间推移成像观察到明显的胞质分裂。用细胞周期标记物和5-乙炔基-2-脱氧尿苷掺入法检测心肌梗死后成年小鼠心肌细胞的增殖。超声心动图用于测量心功能，组织学检查用于确定梗塞范围。结果：在体外，单核和双核/多核细胞在共培养条件下的增殖率相似(7.0%)。去分化伴随着ACM的增殖，然后是再分化。再分化是赋予子代细胞心肌收缩功能所必需的。收缩的新生大鼠心室肌细胞内的钙离子向ACM子细胞的细胞内增殖需要激活激活的T细胞信号通路中钙依赖的钙调神经磷酸酶-核因子来诱导ACM的再分化。新生大鼠心肌细胞钙瞬变特性影响ACM再分化的速度。缺氧通过使缝隙连接蛋白43去磷酸化来损害缝隙连接的功能，连接蛋白43是细胞间钙离子在心肌细胞间传播的主要媒介，从而损害ACM的再分化。在体内，ACM的增殖主要发生在心肌梗死交界区。一个耐缺血的连接蛋白43突变体促进了急性心肌梗死后ACM来源的新心肌细胞的再分化，并改善了心功能。结论：成熟的急性心肌细胞可通过去分化、增殖和再分化3个步骤重新进入细胞周期并形成新的心肌细胞。来自相邻功能心肌细胞的细胞间钙信号通过缝隙连接诱导再分化过程。这种新的机制有助于在哺乳动物心肌梗死后的心脏中形成新的心肌细胞。
Background: Adult mammalian hearts have a limited ability to generate new cardiomyocytes. Proliferation of existing adult cardiomyocytes (ACMs) is a potential source of new cardiomyocytes. Understanding the fundamental biology of ACM proliferation could be of great clinical significance for treating myocardial infarction (MI). We aim to understand the process and regulation of ACM proliferation and its role in new cardiomyocyte formation of post-MI mouse hearts. Methods: &bgr;-Actin-green fluorescent protein transgenic mice and fate-mapping Myh6-MerCreMer-tdTomato/lacZ mice were used to trace the fate of ACMs. In a coculture system with neonatal rat ventricular myocytes, ACM proliferation was documented with clear evidence of cytokinesis observed with time-lapse imaging. Cardiomyocyte proliferation in the adult mouse post-MI heart was detected by cell cycle markers and 5-ethynyl-2-deoxyuridine incorporation analysis. Echocardiography was used to measure cardiac function, and histology was performed to determine infarction size. Results: In vitro, mononucleated and bi/multinucleated ACMs were able to proliferate at a similar rate (7.0%) in the coculture. Dedifferentiation proceeded ACM proliferation, which was followed by redifferentiation. Redifferentiation was essential to endow the daughter cells with cardiomyocyte contractile function. Intercellular propagation of Ca2+ from contracting neonatal rat ventricular myocytes into ACM daughter cells was required to activate the Ca2+-dependent calcineurin-nuclear factor of activated T-cell signaling pathway to induce ACM redifferentiation. The properties of neonatal rat ventricular myocyte Ca2+ transients influenced the rate of ACM redifferentiation. Hypoxia impaired the function of gap junctions by dephosphorylating its component protein connexin 43, the major mediator of intercellular Ca2+ propagation between cardiomyocytes, thereby impairing ACM redifferentiation. In vivo, ACM proliferation was found primarily in the MI border zone. An ischemia-resistant connexin 43 mutant enhanced the redifferentiation of ACM-derived new cardiomyocytes after MI and improved cardiac function. Conclusions: Mature ACMs can reenter the cell cycle and form new cardiomyocytes through a 3-step process: dedifferentiation, proliferation, and redifferentiation. Intercellular Ca2+ signal from neighboring functioning cardiomyocytes through gap junctions induces the redifferentiation process. This novel mechanism contributes to new cardiomyocyte formation in post-MI hearts in mammals.