Integrated single-cell RNA-seq analysis reveals mitochondrial calcium signaling as a modulator of endothelial-to-mesenchymal transition.
2 UNITO - Università degli studi di Torino = University of Turin
3 Universität Heidelberg [Heidelberg] = Heidelberg University
4 CRCI2NA - Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers
5 Helmholtz Diabetes Center [Munich]
6 PHYCELL - Laboratoire de Physiologie Cellulaire - U 1003
7 INFINITE - Institute for Translational Research in Inflammation - U 1286
8 Temple University [Philadelphia]
9 Wake Forest University
10 Robarts Research Institute [Canada]
11 LKI - Leuven Cancer Institute [Leuven, Belgium]
12 UMG - University Medical Center Göttingen
13 DZHK - German Center for Cardiovascular Research
14 Aarhus University [Aarhus]
15 University of Texas Health Science Center at San Antonio [San Antonio, Tx, USA]
16 TUM - Technische Universität Munchen = Technical University Munich = Université Technique de Munich
17 HMGU - Helmholtz Zentrum München = German Research Center for Environmental Health
18 SyNergy - Munich Cluster for systems neurology [Munich]
19 CANTHER - Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277
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Résumé
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.
Domaines
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