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

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 <i>Mcu</i> 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.

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Publication Details

Journal
Science Advances
Published
2024-08-09
DOI
https://doi.org/10.1126/sciadv.adp6182
Citations
14
Primary Topic
Congenital heart defects research
Type
article
Field-Weighted Citation Impact
3.27

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article

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

Bart Staels, David Dombrowicz, Dhanendra Tomar, Cyril Robil et al.
14 citations
Science Advances
Congenital heart defects research
3.27
article

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

Bart Staels, David Dombrowicz, Dhanendra Tomar, Cyril Robil, Giorgia Chinigò, Muniswamy Madesh, Hilda Carolina Delgado-De la Herrán, Vance Gao, Raj Kishore, Loïc Lemonnier, J. Geoffrey Pickering, Lucas Treps, Lena‐Christin Conradi, Mathilde Lebas, Yonglun Luo, Dimitra Gkika, Valérie Gouyer, Elisabeth M. Zeisberg, Alina Errerd, Fabiana Perocchi, Laurent L’homme, Anna Rita Cantelmo, Jean‐Luc Desseyn, Hao Yin, Stefan Vinckier, Mohamed Chamlali, Venkata Naga Srikanth Garikipati, Alicia Mayeuf-Louchart, Louay Bettaieb, Hajime Fukui, Alessandra Fiorio, Aleksandar Beatovic, Fabiola Silva, Fabrice Infanti, Jermaine Goveia, Camille Dejos, Mauro Vedelago, Lin Lin, Anneke Stolte, Evan Courmont, Amani Machmouchi, Job Van Kerckhove
article en
14 citations

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 <i>Mcu</i> 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.

Science AdvancesVol. 10(32)
Western University (CA), Centre National de la Recherche Scientifique (FR), Inserm (FR), The University of Texas at San Antonio Health Science Center (US), German Cancer Research Center (DE), Aarhus University (DK), Heidelberg University (DE), Université de Lille (FR), Institut Pasteur de Lille (FR), Helmholtz Zentrum München (DE), Centre Hospitalier Universitaire de Lille (FR), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers (FR), VIB-KU Leuven Center for Cancer Biology (BE), National Cerebral and Cardiovascular Center (JP), Munich Cluster for Systems Neurology (DE), Universitätsmedizin Göttingen (DE), German Centre for Cardiovascular Research (DE), Wake Forest University (US), University of Turin (IT), Technical University of Munich (DE), University of Göttingen (DE), Temple University (US), Nantes Université (FR)
Université de Lille, Agence Nationale de la Recherche, KU Leuven, Ligue Contre le Cancer, Région Hauts-de-France
Good health and well-being
Openalex Percentile: Top 7%
Congenital heart defects research
3.27
DOIOpen Access PDFOpenAlex
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