Theranostics 2020; 10(20):9100-9112. doi:10.7150/thno.44281

Research Paper

Mydgf promotes Cardiomyocyte proliferation and Neonatal Heart regeneration

Yuyao Wang1,2✉*#, Yan Li1,2,#, Jie Feng2#, Weijing Liu1, Yandong Li2, Jun Liu1, Qianqian Yin2, Hong Lian2, Lihui Liu2, Yu Nie2✉*

1. Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan 030001, China.
2. State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
#These authors contributed equally to the study.
*Co-corresponding authors contributed equally to this study.

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Citation:
Wang Y, Li Y, Feng J, Liu W, Li Y, Liu J, Yin Q, Lian H, Liu L, Nie Y. Mydgf promotes Cardiomyocyte proliferation and Neonatal Heart regeneration. Theranostics 2020; 10(20):9100-9112. doi:10.7150/thno.44281. Available from https://www.thno.org/v10p9100.htm

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Abstract

Myeloid-derived growth factor (Mydgf), a paracrine protein secreted by bone marrow-derived monocytes and macrophages, was found to protect against cardiac injury following myocardial infarction (MI) in adult mice. We speculated that Mydgf might improve heart function via myocardial regeneration, which is essential for discovering the target to reverse heart failure.

Methods: Two genetic mouse lines were used: global Mydgf knockout (Mydgf-KO) and Mydgf-EGFP mice. Two models of cardiac injury, apical resection was performed in neonatal and MI was performed in adult mice. Quantitative reverse transcription-polymerase chain reaction, western blot and flow cytometry were performed to study the protein expression. Immunofluorescence was performed to detect the proliferation of cardiomyocytes. Heart regeneration and cardiac function were evaluated by Masson's staining and echocardiography, respectively. RNA sequencing was employed to identify the key involved in Mydgf-induced cardiomyocyte proliferation. Mydgf recombinant protein injection was performed as a therapy for cardiac repair post MI in adult mice.

Results: Mydgf expression could be significantly induced in neonatal mouse hearts after cardiac injury. Unexpectedly, we found that Mydgf was predominantly expressed by endothelial cells rather than macrophages in injured neonatal hearts. Mydgf deficiency impeded neonatal heart regeneration and injury-induced cardiomyocyte proliferation. Mydgf recombinant protein promoted primary mouse cardiomyocyte proliferation. Employing RNA sequencing and functional verification, we demonstrated that c-Myc/FoxM1 pathway mediated Mydgf-induced cardiomyocyte expansion. Mydgf recombinant protein improved cardiac function in adult mice after MI injury with inducing cardiomyocyte proliferation.

Conclusion: Mydgf promotes cardiomyocyte proliferation by activating c-Myc/FoxM1 pathway and improves heart regeneration both in neonatal and adult mice after cardiac injury, providing a potential target to reverse cardiac remodeling and heart failure.

Keywords: Mydgf, cardiomyocyte proliferation, heart regeneration, c-Myc, FoxM1