Journal Article

DKFZ-2024-01634

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Integrated single-cell RNA-seq analysis reveals mitochondrial calcium signaling as a modulator of endothelial-to-mesenchymal transition.

Lebas, M. ; Chinigò, G. ; Courmont, E. ; Bettaieb, L. ; Machmouchi, A. ; Goveia, J. ; Beatovic, A. ; Van Kerckhove, J. ; Robil, C. ; Angulo, F. S. ; Vedelago, M. ; Errerd, A.DKFZ* ; Treps, L. ; Gao, V. ; Delgado De la Herrán, H. C. ; Mayeuf-Louchart, A. ; L'homme, L. ; Chamlali, M. ; Dejos, C. ; Gouyer, V. ; Garikipati, V. N. S. ; Tomar, D. ; Yin, H. ; Fukui, H. ; Vinckier, S. ; Stolte, A. ; Conradi, L.-C. ; Infanti, F. ; Lemonnier, L. ; Zeisberg, E. ; Luo, Y. ; Lin, L. ; Desseyn, J.-L. ; Pickering, J. ; Kishore, R. ; Madesh, M. ; Dombrowicz, D. ; Perocchi, F. ; Staels, B. ; Pla, A. F. ; Gkika, D. ; Cantelmo, A. R.

2024
Assoc. Washington, DC [u.a.]

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Please use a persistent id in citations: doi:10.1126/sciadv.adp6182

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.

Keyword(s): Animals (MeSH) ; Single-Cell Analysis (MeSH) ; Calcium Signaling (MeSH) ; Humans (MeSH) ; Mitochondria: metabolism (MeSH) ; RNA-Seq: methods (MeSH) ; Mice (MeSH) ; Endothelial Cells: metabolism (MeSH) ; Epithelial-Mesenchymal Transition: genetics (MeSH) ; Calcium Channels: metabolism (MeSH) ; Calcium Channels: genetics (MeSH) ; Ischemia: metabolism (MeSH) ; Ischemia: pathology (MeSH) ; Calcium: metabolism (MeSH) ; Single-Cell Gene Expression Analysis (MeSH) ; Calcium Channels ; mitochondrial calcium uniporter ; Calcium

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Contributing Institute(s):

1. Lehrveranstaltungen (W071)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2024

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