FoxO3 controls cardiomyocyte proliferation and heart regeneration by regulating Sfrp2 expression in postnatal mice
The Forkhead box O3 (FoxO3) transcription factor is crucial to controlling heart growth in adulthood, but its exact role in cardiac repair and regeneration in postnatal mice remains unclear. Here, we show that FoxO3 deficiency promotes cardiomyocyte proliferation in postnatal mice and improves cardiac function in homeostatic adult mice. Moreover, FoxO3 deficiency accelerates heart regeneration following injury in postnatal mice at the regenerative and non-regenerative stages. We reveal that FoxO3 directly promotes the expression of secreted frizzled-related protein 2 (Sfrp2) and suppresses the activation of canonical Wnt/β-catenin signaling during heart regeneration. The increased activation of β-catenin in FoxO3-deficient cardiomyocytes can be blocked by Sfrp2 overexpression. In addition, Sfrp2 overexpression suppressed cardiomyocyte proliferation and heart regeneration in FoxO3-deficient mice. These findings suggest that FoxO3 negatively controls cardiomyocyte proliferation and heart regeneration in postnatal mice at least in part by promoting Sfrp2 expression, which leading to the inactivation of canonical Wnt/β-catenin signaling.
Authors
- Chi‐Qian Liang
- Xufeng Qi (ORCID: https://orcid.org/0000-0002-5911-071X)
- Hongji Li (ORCID: https://orcid.org/0000-0002-9783-6845)
- Kyu‐Sang Park (ORCID: https://orcid.org/0000-0003-0322-9807)
- Zhaofu Liao (ORCID: https://orcid.org/0000-0001-9433-851X)
- Yan Cao (ORCID: https://orcid.org/0000-0003-4902-2297)
- Hui Zhao (ORCID: https://orcid.org/0000-0001-8160-6415)
- Kun Liu (ORCID: https://orcid.org/0000-0003-3512-4516)
- Zhenyu Ju (ORCID: https://orcid.org/0009-0007-4550-4543)
- Guohua Song (ORCID: https://orcid.org/0000-0002-3799-8420)
- Z. Ye
- Dongqing Cai (ORCID: https://orcid.org/0000-0002-6014-5362)
- Li Li (ORCID: https://orcid.org/0000-0003-2342-3658)
- Jun‐Fang Lin (ORCID: https://orcid.org/0000-0002-2981-5188)
- Xiaolin Lin (ORCID: https://orcid.org/0000-0001-7457-9017)
- Na Wen (ORCID: https://orcid.org/0000-0001-5439-0444)
- Jingbo Xia (ORCID: https://orcid.org/0000-0003-3293-4812)
Institutions
- Jinan University (CN)
- Guangdong Medical College (CN)
- Chinese University of Hong Kong (HK)
- Yonsei University (KR)
- Second Affiliated Hospital of Guangzhou Medical University (CN)
- Zhongshan People's Hospital (CN)
- Regenerative Medicine Institute (MX)
- Shandong First Medical University (CN)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-14
- DOI
- https://doi.org/10.1038/s41467-025-57962-9
- Citations
- 10
- Primary Topic
- FOXO transcription factor regulation
- Type
- article
- Field-Weighted Citation Impact
- 8.06