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  3. Single-cell RNA sequencing reveals that BMPR2 mutation regulates right ventricular function via ID genes

Single-cell RNA sequencing reveals that BMPR2 mutation regulates right ventricular function via ID genes

  • Eur Respir J. 2022 Jul 7;60(1):2100327. doi: 10.1183/13993003.00327-2021.
Mingxia Du 1 2,  Haibin Jiang 1 2,  Hongxian Liu 1 2,  Xin Zhao 1 2,  Yu Zhou 3,  Fang Zhou 2,  Chunmei Piao 4,  Guoqiang Xu 5,  Feng Ma 6,  Jianan Wang 7,  Frederic Perros 8,  Nicholas W Morrell 9,  Hong Gu 4,  Jun Yang 10
Affiliations

Affiliations

  • 1 Dept of Physiology, and Dept of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China.
  • 3 Dept of General Intensive Care Unit, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
  • 4 Dept of Pediatric Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
  • 5 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
  • 6 Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Chengdu, China.
  • 7 Dept of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 8 Université Paris-Saclay, AP-HP, INSERM UMR_S 999, Service de Pneumologie et Soins Intensifs Respiratoires, Hôpital de Bicêtre, Le Kremlin Bicêtre, France.
  • 9 Dept of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK.
  • 10 Dept of Physiology, and Dept of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China yang_jun@zju.edu.cn.
PMID: 34857612 DOI: 10.1183/13993003.00327-2021
Abstract

Background: Mutations in bone morphogenetic protein type II receptor (BMPR2) have been found in patients with congenital heart disease-associated pulmonary arterial hypertension (CHD-PAH). Our study aimed to clarify whether deficient BMPR2 signalling acts through downstream effectors, inhibitors of DNA-binding proteins (IDs) during heart development to contribute to the progress of PAH in CHD patients.

Methods: To confirm that IDs are downstream effectors of BMPR2 signalling in cardiac mesoderm progenitors (CMPs) and contribute to PAH, we generated cardiomyocyte-specific Id 1/3 knockout mice (Ids cDKO), and 12 out of 25 developed mild PAH with altered haemodynamic indices and pulmonary vascular remodelling. Moreover, we generated ID1 and ID3 double-knockout (IDs KO) human embryonic stem cells that recapitulated the BMPR2 signalling deficiency of CHD-PAH induced pluripotent stem cells (iPSCs).

Results: Cardiomyocytes differentiated from iPSCs derived from CHD-PAH patients with BMP Receptor mutations exhibited dysfunctional cardiac differentiation and reduced calcium (CA2+) transients, as evidenced by confocal microscopy experiments. Smad1/5 phosphorylation and ID1 and ID3 expression were reduced in CHD-PAH iPSCs and in Bmpr2 +/- rat right ventricles. Moreover, ultrasound revealed that 33% of Ids cDKO mice had detectable defects in their ventricular septum and pulmonary regurgitation. Cardiomyocytes isolated from mouse right ventricles also showed reduced CA2+ transients and shortened sarcomeres. Single-cell RNA Sequencing analysis revealed impaired differentiation of CMPs and downregulated USP9X expression in IDs KO cells compared with wild-type cells.

Conclusion: We found that BMPR2 signals through IDs and USP9X to regulate cardiac differentiation, and the loss of ID1 and ID3 expression contributes to cardiomyocyte dysfunction in CHD-PAH patients with BMPR2 mutations.

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