FoxO3 controls cardiomyocyte proliferation and heart regeneration by regulating Sfrp2 expression in postnatal mice

Jing-Bo Xia ^1,2, Kun Liu ^1,3, Xiao-Lin Lin ¹

¹Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Department of Developmental & Regenerative Biology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China.
²Department of Cardiology, The Affiliated Guangdong Second Provincial General Hospital, Jinan University, Guangzhou, 510317, China.
³Department of Cardiology, Zhongshan Torch Development Zone People's Hospital, Zhongshan, 528437, China.
⁴Department of Cardiology, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, 510220, China.
⁵Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, 523808, China.
⁶Key Laboratory of Regenerative Medicine of Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
⁷Department of Physiology, Wonju College of Medicine, Yonsei University, Wonju, Gangwon, 220-701, Korea.
⁸School of Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Science, Jinan, 250117, China.
⁹Department of Cardiology, The Affiliated Guangdong Second Provincial General Hospital, Jinan University, Guangzhou, 510317, China. bean9350@sina.com.
¹⁰Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Department of Developmental & Regenerative Biology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China. tdongbme@jnu.edu.cn.
¹¹Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Department of Developmental & Regenerative Biology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China. zhenyuju2016@jnu.edu.cn.
¹²Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Department of Developmental & Regenerative Biology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China. qixufeng@jnu.edu.cn.
¹³Department of Cardiology, The Affiliated Guangdong Second Provincial General Hospital, Jinan University, Guangzhou, 510317, China. qixufeng@jnu.edu.cn.

⁰Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Department of Developmental & Regenerative Biology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China.

Nature Communications +

|

March 15, 2025

View abstract on PubMed

Summary

Forkhead box O3 (FoxO3) deficiency enhances heart repair and regeneration in mice by promoting cardiomyocyte proliferation. This occurs via suppression of secreted frizzled-related protein 2 (Sfrp2) and activation of Wnt/β-catenin signaling.

Area Of Science

Cardiovascular Biology
Developmental Biology
Molecular Cardiology

Background

The transcription factor Forkhead box O3 (FoxO3) is vital for adult heart growth.
Its precise function in postnatal cardiac repair and regeneration is not fully understood.

Purpose Of The Study

To investigate the role of FoxO3 in cardiomyocyte proliferation, cardiac function, and heart regeneration in postnatal mice.
To elucidate the molecular mechanisms by which FoxO3 influences cardiac repair.

Main Methods

FoxO3 deficiency models in postnatal mice.
Assessment of cardiomyocyte proliferation and cardiac function.
Analysis of heart regeneration following injury.
Investigation of gene expression, including Sfrp2 and Wnt/β-catenin signaling pathways.

Main Results

FoxO3 deficiency increased cardiomyocyte proliferation and improved cardiac function in adult mice.
Loss of FoxO3 accelerated heart regeneration after injury in both regenerative and non-regenerative stages.
FoxO3 directly upregulates secreted frizzled-related protein 2 (Sfrp2) expression, inhibiting Wnt/β-catenin signaling.
Sfrp2 overexpression counteracted the pro-regenerative effects of FoxO3 deficiency.

Conclusions

FoxO3 acts as a negative regulator of cardiomyocyte proliferation and heart regeneration in postnatal mice.
This regulation is mediated, at least in part, through the promotion of Sfrp2 expression and subsequent Wnt/β-catenin pathway inactivation.

Related Concept Videos

Formation of Muscle Fibers from Myoblasts

De novo myogenesis, or the formation of muscle fibers, begins during the early embryonic stages. The skeletal muscle is formed from somites– blocks of embryonic cell layers. The somites are further divided into dermatomes, myotomes, sclerotomes, and syndetomes. Among these, the myotomes give rise to muscle fibers.
Muscle progenitor cells (MPCs) are formed from the myotomes. MPCs express genes that encode the transcription factors Pax3 and Pax7. Along with Pax 3/7, other transcription...