Integrated single-cell RNA-seq analysis reveals mitochondrial calcium signaling as a modulator of endothelial-to-mesenchymal transition-Reference-Cited by-同舟云学术

Integrated single-cell RNA-seq analysis reveals mitochondrial calcium signaling as a modulator of endothelial-to-mesenchymal transition

Published:2024-08-09 Issue:32 Volume:10 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Lebas Mathilde¹^ORCID,Chinigò Giorgia²^ORCID,Courmont Evan¹^ORCID,Bettaieb Louay¹^ORCID,Machmouchi Amani¹^ORCID,Goveia Jermaine³,Beatovic Aleksandar³,Van Kerckhove Job³^ORCID,Robil Cyril¹^ORCID,Angulo Fabiola Silva¹,Vedelago Mauro¹^ORCID,Errerd Alina¹⁴^ORCID,Treps Lucas⁵^ORCID,Gao Vance¹^ORCID,Delgado De la Herrán Hilda C.⁶^ORCID,Mayeuf-Louchart Alicia¹^ORCID,L’homme Laurent¹^ORCID,Chamlali Mohamed¹^ORCID,Dejos Camille⁷^ORCID,Gouyer Valérie⁸^ORCID,Garikipati Venkata Naga Srikanth⁹,Tomar Dhanendra¹⁰^ORCID,Yin Hao¹¹^ORCID,Fukui Hajime¹²^ORCID,Vinckier Stefan¹³^ORCID,Stolte Anneke¹⁴^ORCID,Conradi Lena-Christin¹⁴^ORCID,Infanti Fabrice¹⁵,Lemonnier Loic⁷^ORCID,Zeisberg Elisabeth¹⁶¹⁷,Luo Yonglun¹⁸^ORCID,Lin Lin¹⁸^ORCID,Desseyn Jean-Luc⁸^ORCID,Pickering J.¹¹¹⁹^ORCID,Kishore Raj²⁰²¹^ORCID,Madesh Muniswamy²²^ORCID,Dombrowicz David¹^ORCID,Perocchi Fabiana⁶²³²⁴,Staels Bart¹^ORCID,Pla Alessandra Fiorio²⁷^ORCID,Gkika Dimitra²⁵^ORCID,Cantelmo Anna Rita¹^ORCID

Affiliation:

1. Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France.

2. Department of Life Sciences and Systems Biology, University of Torino, 10123 Torino, Italy.

3. Unicle Biomedical Data Science, Leuven, Belgium.

4. Molecular Biosciences/Cancer Biology Program, Heidelberg University and German Cancer Research Center (DKFZ), Heidelberg, Germany.

5. Nantes Université, INSERM UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA, F-44000 Nantes, France.

6. Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, Munich, Germany.

7. INSERM, U1003 - PHYCEL - Physiologie Cellulaire, Université de Lille, F-59000 Lille, France.

8. Université de Lille, Inserm, CHU Lille, U1286 Infinite, F-59000 Lille, France.

9. Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.

10. Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157 USA.

11. Robarts Research Institute, Western University, London, Canada.

12. National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 564-8565, Japan.

13. Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology (CCB), VIB and Department of Oncology, Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium.

14. Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Robert-Koch-Straβe 40, 37075 Göttingen, Germany.

15. 4 Science Consulting, F-59000 Lille, France.

16. Department of Cardiology and Pneumology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.

17. DZHK German Center for Cardiovascular Research, Partner Site Lower Saxony, Göttingen, Germany.

18. Department of Biomedicine, Aarhus University, Aarhus, Denmark.

19. Department of Medicine, Biochemistry, and Medical Biophysics, Western University, London, Canada.

20. Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.

21. Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140 USA.

22. Department of Medicine, Center for Mitochondrial Medicine, Division of Cardiology, University of Texas Health San Antonio, San Antonio, TX 78229 USA.

23. Institute of Neuronal Cell Biology, Technical University of Munich, Munich, Germany.

24. Munich Cluster for Systems Neurology, Munich, Germany.

25. Université de Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France.

Abstract

Endothelial cells (ECs) are highly plastic, capable of differentiating into various cell types. Endothelial-to-mesenchymal transition (EndMT) is crucial during embryonic development and contributes substantially to vascular dysfunction in many cardiovascular diseases (CVDs). While targeting EndMT holds therapeutic promise, understanding its mechanisms and modulating its pathways remain challenging. Using single-cell RNA sequencing on three in vitro EndMT models, we identified conserved gene signatures. We validated original regulators in vitro and in vivo during embryonic heart development and peripheral artery disease. EndMT induction led to global expression changes in all EC subtypes rather than in mesenchymal clusters. We identified mitochondrial calcium uptake as a key driver of EndMT; inhibiting mitochondrial calcium uniporter (MCU) prevented EndMT in vitro, and conditional Mcu deletion in ECs blocked mesenchymal activation in a hind limb ischemia model. Tissues from patients with critical limb ischemia with EndMT features exhibited significantly elevated endothelial MCU. These findings highlight MCU as a regulator of EndMT and a potential therapeutic target.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adp6182

Reference86 articles.

1. The molecular basis of endothelial cell plasticity

2. In Brief: Endothelial-to-mesenchymal transition

3. Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination

4. Endothelial-to-mesenchymal transition compromises vascular integrity to induce Myc-mediated metabolic reprogramming in kidney fibrosis

5. Transforming growth factor beta 1 promotes the differentiation of endothelial cells into smooth muscle-like cells in vitro