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Open AccessFeature PaperArticle

Citrate Mediates Crosstalk between Mitochondria and the Nucleus to Promote Human Mesenchymal Stem Cell In Vitro Osteogenesis

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Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy
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Laboratorio per le Tecnologie delle Terapie Avanzate (LTTA), University of Ferrara, 44121 Ferrara, Italy
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Maria Cecilia Hospital, GVM Care & Research, Via Corriera 1, Cotignola, 48033 Ravenna, Italy
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Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland
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Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology, University of Ferrara, 44121 Ferrara, Italy
*
Authors to whom correspondence should be addressed.
Cells 2020, 9(4), 1034; https://doi.org/10.3390/cells9041034
Received: 18 March 2020 / Revised: 7 April 2020 / Accepted: 19 April 2020 / Published: 21 April 2020
(This article belongs to the Section Stem Cells)
Citrate, generated in the mitochondria, is a key metabolite that might link metabolism with signaling, chromatin structure and transcription to orchestrate mesenchymal stem cells (MSCs) fate determination. Based on a detailed morphological analysis of 3D reconstruction of mitochondria and nuclei in single cells, we identified contact sites between these organelles that drastically increase in volume and number during the early stage of mesenchymal stem cell differentiation. These contact sites create a microdomain that facilitates exchange of signals from mitochondria to the nucleus. Interestingly, we found that the citrate derived from mitochondria is necessary for osteogenic lineage determination. Indeed, inhibition of the citrate transporter system dramatically affected osteogenesis, reduced citrate levels that could be converted in α-ketoglutarate, and consequently affected epigenetic marker H3K9me3 associated with the osteogenesis differentiation process. These findings highlight that mitochondrial metabolites play key regulatory roles in the MSCs differentiation process. Further in-depth investigation is needed to provide novel therapeutic strategies in the field of regenerative medicine. View Full-Text
Keywords: osteogenesis; citrate; α-ketoglutarate; mitochondrial metabolism; mesenchymal stem cells; mitochondria-nucleus communication osteogenesis; citrate; α-ketoglutarate; mitochondrial metabolism; mesenchymal stem cells; mitochondria-nucleus communication
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MDPI and ACS Style

Morganti, C.; Bonora, M.; Marchi, S.; Ferroni, L.; Gardin, C.; Wieckowski, M.R.; Giorgi, C.; Pinton, P.; Zavan, B. Citrate Mediates Crosstalk between Mitochondria and the Nucleus to Promote Human Mesenchymal Stem Cell In Vitro Osteogenesis. Cells 2020, 9, 1034.

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