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

Giuseppe Taurino; Ruhi Deshmukh; Victor H Villar; Martina Chiu; Robin Shaw; Ann Hedley; Engy Shokry; David Sumpton; Erica Dander; Giovanna D'Amico; Ovidio Bussolati; Saverio Tardito

doi:10.1016/j.molmet.2022.101532

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

Giuseppe Taurino, Ruhi Deshmukh, Victor H Villar, Martina Chiu, Robin Shaw, Ann Hedley, Engy Shokry, David Sumpton, Erica Dander, Giovanna D'Amico, Ovidio Bussolati^*, Saverio Tardito^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	101532
Number of pages	10
Journal	Molecular Metabolism
Volume	63
Early online date	30 Jun 2022
DOIs	https://doi.org/10.1016/j.molmet.2022.101532
Publication status	Published - 1 Sept 2022

Keywords

Bone marrow cells
Citrates/metabolism
Glucose/metabolism
Glutamic Acid/metabolism
Humans
Mesenchymal stem cells/metabolism

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10.1016/j.molmet.2022.101532Licence: CC BY

Taurino_2023_MM_Mesenchymal-stromal_CC
Copyright © 2022 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Final published version, 2.68 MBLicence: CC BY

Mesenchymal stromal cells cultured in physiological conditions sustain citrate secretion with glutamate anaplerosis (dataset)
Villar, V. H. (Creator), BioStudies, 2022
https://www.ebi.ac.uk/biostudies/arrayexpress/studies/E-MTAB-11421?query=E-MTAB-11421
Dataset

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title = "Mesenchymal stromal cells cultured in physiological conditions sustain citrate secretion with glutamate anaplerosis",

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{\texttrademark}, 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.",

keywords = "Bone marrow cells, Citrates/metabolism, Glucose/metabolism, Glutamic Acid/metabolism, Humans, Mesenchymal stem cells/metabolism",

author = "Giuseppe Taurino and Ruhi Deshmukh and Villar, {Victor H} and Martina Chiu and Robin Shaw and Ann Hedley and Engy Shokry and David Sumpton and Erica Dander and Giovanna D'Amico and Ovidio Bussolati and Saverio Tardito",

note = "Funding: 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{\textquoteright}A. GT received an EMBO Short-Term Fellowship (STF_8177) and a research fellowship by MRH funded by Fondazione Cariparma Project “Parma Microbiota{"}.",

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T1 - Mesenchymal stromal cells cultured in physiological conditions sustain citrate secretion with glutamate anaplerosis

AU - Taurino, Giuseppe

AU - Deshmukh, Ruhi

AU - Villar, Victor H

AU - Chiu, Martina

AU - Shaw, Robin

AU - Hedley, Ann

AU - Shokry, Engy

AU - Sumpton, David

AU - Dander, Erica

AU - D'Amico, Giovanna

AU - Bussolati, Ovidio

AU - Tardito, Saverio

N1 - Funding: 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".

PY - 2022/9/1

Y1 - 2022/9/1

N2 - 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.

AB - 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.

KW - Bone marrow cells

KW - Citrates/metabolism

KW - Glucose/metabolism

KW - Glutamic Acid/metabolism

KW - Humans

KW - Mesenchymal stem cells/metabolism

U2 - 10.1016/j.molmet.2022.101532

DO - 10.1016/j.molmet.2022.101532

M3 - Article

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SN - 2212-8778

VL - 63

JO - Molecular Metabolism

JF - Molecular Metabolism

M1 - 101532

ER -

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

Abstract

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

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