文章基本信息

标题：Postnatal expression of cell cycle promoter Fam64a causes heart dysfunction by inhibiting cardiomyocyte differentiation through repression of Klf15
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作者：Ken Hashimoto ; Aya Kodama ; Momoko Ohira 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：5
页码：1-26
DOI：10.1016/j.isci.2022.104337
语种：English
出版社：Elsevier
摘要：SummaryIntroduction 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.Graphical abstractDisplay OmittedHighlights•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 injuryBiological sciences; Cell biology; Stem cells research