Mesenchymal stromal cells cultured in physiological conditions sustain citrate secretion with glutamate anaplerosis

Taurino, G. et al. (2022) Mesenchymal stromal cells cultured in physiological conditions sustain citrate secretion with glutamate anaplerosis. Molecular Metabolism, 63, 101532. (doi: 10.1016/j.molmet.2022.101532) (PMID:35752287) (PMCID:PMC9254159)

Abstract

Bone marrow mesenchymal stromal cells (MSCs) have immunomodulatory and regenerative potential. However, culture conditions govern their metabolic processes and therapeutic efficacy. Here we show that culturing donor-derived MSCs in Plasmax™, a physiological medium with the concentrations of nutrients found in human plasma, supports their proliferation and stemness, and prevents the nutritional stress induced by the conventional medium DMEM. The quantification of the exchange rates of metabolites between cells and medium, untargeted metabolomics, stable isotope tracing and transcriptomic analysis, performed at physiologically relevant oxygen concentrations (1%O2), reveal that MSCs rely on a high rate of glucose to lactate conversion, coupled with parallel anaplerotic fluxes from glutamine and glutamate to support citrate synthesis and secretion. These distinctive traits of MSCs shape the metabolic microenvironment of the bone marrow niche and can influence nutrient cross-talks under physiological and pathological conditions.

• Item Type: Articles
• Additional Information: The authors thank the Core Services and Advanced Technologies at the Cancer Research UK Beatson Institute (C596/A17196 and A31287), and particularly the Metabolomics, Biological Services Unit, and Molecular Technologies. The authors acknowledge Catherine Winchester for the research integrity checks and her comments on the manuscript, all members of the Oncometabolism lab and Metabolomics facility for constructive discussion. This work was funded by Cancer Research UK award A17196 and A31287 (CRUK Beatson Institute), and Cancer Research UK award A23982 (ST). This work was supported by Associazione Italiana Ricerca sul Cancro (project number IG 2019 Id.23354) to G. D’A. GT received an EMBO Short-Term Fellowship (STF_8177) and a research fellowship by MRH funded by Fondazione Cariparma Project “Parma Microbiota".
• Keywords: Glutamate, Stable isotope tracing, Glutamine, Mesenchymal stromal cells, Primary cells, Physiological medium, Plasmax, Metabolism, Citrate, Hypoxia
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Tardito, Dr Saverio
• Authors: Taurino, G., Deshmukh, R., Villar, V. H., Chiu, M., Shaw, R., Hedley, A., Shokry, E., Sumpton, D., Dander, E., D'Amico, G., Bussolati, O., and Tardito, S.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Molecular Metabolism
• Publisher: Elsevier
• ISSN: 2212-8778
• ISSN (Online): 2212-8778
• Published Online: 22 June 2022
• Copyright Holders: Copyright © 2022 The Author(s)
• First Published: First published in Molecular Metabolism 63: 101532
• Publisher Policy: Reproduced under a Creative Commons licence