Postnatal expression of cell cycle promoter Fam64a causes heart dysfunction by inhibiting cardiomyocyte differentiation through repression of Klf15.
Postnatal expression of cell cycle promoter Fam64a causes heart dysfunction by inhibiting cardiomyocyte differentiation through repression of Klf15.
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DOI：
10.1016/j.isci.2022.104337
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发表时间：
2022-05-20
期刊：
影响因子：
5.8
通讯作者：
Mohri, Satoshi
中科院分区：
文献类型：
--
作者：
Hashimoto, Ken;Kodama, Aya;Ohira, Momoko;Kimoto, Misaki;Nakagawa, Reiko;Usui, Yuu;Ujihara, Yoshihiro;Hanashima, Akira;Mohri, Satoshi
将胎儿细胞周期基因引入受损的成年心脏已成为刺激有丝分裂后成年心肌细胞增殖和再生的有前途的策略。我们最近发现 Fam64a 是心肌细胞中胎儿特异性的细胞周期启动子。在这里，我们分析了当内源表达被消除时仍保持心肌细胞特异性的 Fam64a 出生后表达的转基因小鼠。尽管心肌细胞增殖增强，但这些小鼠在出生后发育过程中表现出心肌细胞分化受损，导致晚年心脏功能障碍。从机制上讲，Fam64a 通过抑制 Klf15 抑制心肌细胞分化，导致未分化心肌细胞的积累。相比之下，在分化的成年野生型心脏中引入 Fam64a 可以改善损伤后的功能恢复，细胞周期延长，并且心肌细胞不会去分化。这些数据表明，Fam64a 在早期发育过程中抑制心肌细胞分化，但不会诱导分化后的心肌细胞去分化，说明 Fam64a 作为细胞周期促进剂实现心脏再生的巨大潜力。心肌细胞中细胞周期启动子 Fam64a 的过度表达导致心力衰竭 Fam64a 通过抑制 Klf15 抑制发育过程中的心肌细胞分化 Fam64a 在成人心脏中的瞬时和局部诱导可改善损伤后的恢复 Fam64a 激活心肌细胞细胞周期，损伤后不去分化细胞生物学；干细胞研究
Introduction of fetal cell cycle genes into damaged adult hearts has emerged as a promising strategy for stimulating proliferation and regeneration of postmitotic adult cardiomyocytes. We have recently identified Fam64a as a fetal-specific cell cycle promoter in cardiomyocytes. Here, we analyzed transgenic mice maintaining cardiomyocyte-specific postnatal expression of Fam64a when endogenous expression was abolished. Despite an enhancement of cardiomyocyte proliferation, these mice showed impaired cardiomyocyte differentiation during postnatal development, resulting in cardiac dysfunction in later life. Mechanistically, Fam64a inhibited cardiomyocyte differentiation by repressing Klf15, leading to the accumulation of undifferentiated cardiomyocytes. In contrast, introduction of Fam64a in differentiated adult wildtype hearts improved functional recovery upon injury with augmented cell cycle and no dedifferentiation in cardiomyocytes. These data demonstrate that Fam64a inhibits cardiomyocyte differentiation during early development, but does not induce de-differentiation in once differentiated cardiomyocytes, illustrating a promising potential of Fam64a as a cell cycle promoter to attain heart regeneration. Overexpression of cell cycle promoter Fam64a in cardiomyocytes causes heart failure Fam64a inhibits cardiomyocyte differentiation during development by repressing Klf15 Transient and local induction of Fam64a in adult hearts improves recovery upon injury Fam64a activates cardiomyocyte cell cycle without dedifferentiation upon injury Biological sciences; Cell biology; Stem cells research
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影响因子：
21.3
作者：
D'Uva, Gabriele;Aharonov, Alla;Tzahor, Eldad
通讯作者：
Tzahor, Eldad
影响因子：
16.6
作者：
Katanosaka, Yuki;Iwasaki, Keiichiro;Ujihara, Yoshihiro;Takatsu, Satomi;Nishitsuji, Koki;Kanagawa, Motoi;Sudo, Atsushi;Toda, Tatsushi;Katanosaka, Kimiaki;Mohri, Satoshi;Naruse, Keiji
通讯作者：
Naruse, Keiji
影响因子：
4.6
作者：
Hashimoto K;Kodama A;Honda T;Hanashima A;Ujihara Y;Murayama T;Nishimatsu SI;Mohri S
通讯作者：
Mohri S
影响因子：
16.6
作者：
Han, Sean (Shuxin);Zhang, Rongli;Jain, Rajan;Shi, Hong;Zhang, Lilei;Zhou, Guangjin;Sangwung, Panjamaporn;Tugal, Derin;Atkins, G. Brandon;Prosdocimo, Domenick A.;Lu, Yuan;Han, Xiaonan;Tso, Patrick;Liao, Xudong;Epstein, Jonathan A.;Jain, Mukesh K.
通讯作者：
Jain, Mukesh K.
DOI：
10.1016/j.bbamcr.2013.02.004
发表时间：
2013-05-01
影响因子：
5.1
作者：
Archangelo, Leticia Froehlich;Greif, Philipp A.;Olalla Saad, Sara Teresinha
通讯作者：
Olalla Saad, Sara Teresinha