2. Academic Validation
  3. SMYD1 modulates the proliferation of multipotent cardiac progenitor cells derived from human pluripotent stem cells during myocardial differentiation through GSK3β/β-catenin&ERK signaling

SMYD1 modulates the proliferation of multipotent cardiac progenitor cells derived from human pluripotent stem cells during myocardial differentiation through GSK3β/β-catenin&ERK signaling

  • Stem Cell Res Ther. 2024 Oct 8;15(1):350. doi: 10.1186/s13287-024-03899-7.
Yun Chang # 1,  Rui Bai # 2,  Yongshuai Zhang # 1,  Wen-Jing Lu 3,  Shuhong Ma 2,  Min Zhu 1,  Feng Lan 4 5,  Youxu Jiang 6 7
Affiliations

Affiliations

  • 1 Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College/National Center for Cardiovascular Diseases, Beijing, China.
  • 2 Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, Shenzhen Key Laboratory of Cardiovascular Disease, State Key Laboratory of Cardiovascular Disease, Key Laboratory of Pluripotent Stem Cells in Cardiac Repair and Regeneration, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China.
  • 3 Beijing Laboratory for Cardiovascular Precision Medicine, The Key Laboratory of Biomedical Engineering for Cardiovascular Disease Research, Ministry of Education, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China.
  • 4 Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, Shenzhen Key Laboratory of Cardiovascular Disease, State Key Laboratory of Cardiovascular Disease, Key Laboratory of Pluripotent Stem Cells in Cardiac Repair and Regeneration, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China. fenglan@ccmu.edu.cn.
  • 5 National Health Commission Key Laboratory of Cardiovascular Regenerative Medicine, Fuwai Central-China Hospital, Central-China Branch of National Center for Cardiovascular Diseases, Zhengzhou, China. fenglan@ccmu.edu.cn.
  • 6 Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College/National Center for Cardiovascular Diseases, Beijing, China. corner1987@126.com.
  • 7 Department of Cardiology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China. corner1987@126.com.
  • # Contributed equally.
PMID: 39380045 DOI: 10.1186/s13287-024-03899-7
Abstract

Background: The histone-lysine N-methyltransferase SMYD1, which is specific to striated muscle, plays a crucial role in regulating early heart development. Its deficiency has been linked to the occurrence of congenital heart disease. Nevertheless, the precise mechanism by which SMYD1 deficiency contributes to congenital heart disease remains unclear.

Methods: We established a SMYD1 knockout pluripotent stem cell line and a doxycycline-inducible SMYD1 expression pluripotent stem cell line to investigate the functions of SMYD1 utilizing an in vitro-directed myocardial differentiation model.

Results: Cardiomyocytes lacking SMYD1 displayed drastically diminished differentiation efficiency, concomitant with heightened proliferation capacity of cardiac progenitor cells during the early cardiac differentiation stage. These cellular phenotypes were confirmed through experiments inducing the re-expression of SMYD1. Transcriptome Sequencing and small molecule inhibitor intervention suggested that the GSK3β/β-catenin&ERK signaling pathway was involved in the proliferation of cardiac progenitor cells. Chromatin immunoprecipitation demonstrated that SMYD1 acted as a transcriptional activator of GSK3β through histone H3 lysine 4 trimethylation. Additionally, dual-luciferase analyses indicated that SMYD1 could interact with the promoter region of GSK3β, thereby augmenting its transcriptional activity. Moreover, administering Insulin and Insulin-like growth factor 1 can enhance the efficacy of myocardial differentiation in SMYD1 knockout cells.

Conclusions: Our research indicated that the participation of SMYD1 in the GSK3β/β-catenin&ERK signaling cascade modulated the proliferation of cardiac progenitor cells during myocardial differentiation. This process was partly reliant on the transcription of GSK3β. Our research provided a novel insight into the genetic modification effect of SMYD1 during early myocardial differentiation. The findings were essential to the molecular mechanism and potential interventions for congenital heart disease.

Keywords

GSK3β; Histone modification; Human pluripotent stem cells; Myocardial differentiation; SMYD1.

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