Postnatal expression of cell cycle promoter Fam64a causes heart dysfunction by inhibiting cardiomyocyte differentiation through repression of Klf15

Ken Hashimoto; Aya Kodama; Momoko Ohira; Misaki Kimoto; Reiko Nakagawa; Yuu Usui; Yoshihiro Ujihara; Akira Hanashima; Satoshi Mohri

doi:10.1016/j.isci.2022.104337

Postnatal expression of cell cycle promoter Fam64a causes heart dysfunction by inhibiting cardiomyocyte differentiation through repression of Klf15

iScience. 2022 Apr 30;25(5):104337. doi: 10.1016/j.isci.2022.104337. eCollection 2022 May 20.

Authors

Ken Hashimoto¹, Aya Kodama¹, Momoko Ohira¹, Misaki Kimoto¹, Reiko Nakagawa², Yuu Usui¹, Yoshihiro Ujihara³, Akira Hanashima¹, Satoshi Mohri¹

Affiliations

¹ First Department of Physiology, Kawasaki Medical School, Kurashiki 701-0192, Japan.
² Laboratory for Phyloinformatics, RIKEN Center for Biosystems Dynamics Research (BDR), Kobe 650-0047, Japan.
³ Department of Electrical and Mechanical Engineering, Nagoya Institute of Technology, Nagoya 466-8555, Japan.

Abstract

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.

Keywords: Biological sciences; Cell biology; Stem cells research.