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

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

doi:10.1016/j.molmet.2022.101532

Cited by 4 publications

(5 citation statements)

References 49 publications

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“…A direct toxic effect of transport inhibitors on MSCs is unlikely since their viability is not altered at all by either GluγHA or V‐9302. Indeed, although ASCT2 and SNAT5 are expressed by MSCs, 39 these cells are not apparently endowed with Asn uptake from the extra‐cellular compartment when cultured in complete growth medium, 40 indicating that they satisfy their needs through intracellular synthesis. A similar selective cytotoxicity was described in murine models of acute myeloid leukaemia, where either the knockout or the pharmacological inhibition of ASCT2 caused mild to moderate effects on normal blood cell development while markedly hindered malignant cells 36 …”

Section: Discussionmentioning

confidence: 99%

Asparagine transport through SLC1A5/ASCT2 and SLC38A5/SNAT5 is essential for BCP‐ALL cell survival and a potential therapeutic target

Taurino,

Dander,

Chiu

et al. 2024

Br J Haematol

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SummaryB‐cell precursor acute lymphoblastic leukaemia (BCP‐ALL) blasts strictly depend on the transport of extra‐cellular asparagine (Asn), yielding a rationale for L‐asparaginase (ASNase) therapy. However, the carriers used by ALL blasts for Asn transport have not been identified yet. Exploiting RS4;11 cells as BCP‐ALL model, we have found that cell Asn is lowered by either silencing or inhibition of the transporters ASCT2 or SNAT5. The inhibitors V‐9302 (for ASCT2) and GluγHA (for SNAT5) markedly lower cell proliferation and, when used together, suppress mTOR activity, induce autophagy and cause a severe nutritional stress, leading to a proliferative arrest and a massive cell death in both the ASNase‐sensitive RS4;11 cells and the relatively ASNase‐insensitive NALM‐6 cells. The cytotoxic effect is not prevented by coculturing leukaemic cells with primary mesenchymal stromal cells. Leukaemic blasts of paediatric ALL patients express ASCT2 and SNAT5 at diagnosis and undergo marked cytotoxicity when exposed to the inhibitors. ASCT2 expression is positively correlated with the minimal residual disease at the end of the induction therapy. In conclusion, ASCT2 and SNAT5 are the carriers exploited by ALL cells to transport Asn, and ASCT2 expression is associated with a lower therapeutic response. ASCT2 may thus represent a novel therapeutic target in BCP‐ALL.

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Section: Discussionmentioning

confidence: 99%

Asparagine transport through SLC1A5/ASCT2 and SLC38A5/SNAT5 is essential for BCP‐ALL cell survival and a potential therapeutic target

Taurino,

Dander,

Chiu

et al. 2024

Br J Haematol

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“…Thus, cancer cell culture in physiological medium results in vast alterations in cell metabolism and behavior ( 9 – 11 , 17 ). Despite these recent developments, to date, only one study has compared the effects of physiological versus standard media in noncancerous cells ( 12 ).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, cancer cell culture in physiological medium results in vast alterations in cell metabolism and behavior (9)(10)(11)17). Despite these recent developments, to date, only one study has compared the effects of physiological versus standard media in noncancerous cells (12). Plasmax is a chemically defined medium formulated using nutrients, metabolites at concentrations reported for plasma from healthy adult humans (9).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies comparing cells cultured with physiological media versus standard media (e.g., DMEM-F12) revealed profound differences in metabolism (9)(10)(11). Although these media have been mainly employed for studies with cancer cells, which characteristically exhibit altered metabolism, a recent report have demonstrated that physiological media support the proliferation of primary mesenchymal stromal cells (12).…”

Section: Introductionmentioning

confidence: 99%

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Physiologically relevant culture medium Plasmax improves human placental trophoblast stem cell function

Avellino

Deshmukh

Rogers

et al. 2023

American Journal of Physiology-Cell Physiology

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Human trophoblast cultures provide powerful tools to model key processes of placental development. In vitro trophoblast studies to date have relied on commercial media which contains non-physiological levels of nutrients, and the impact of these conditions on trophoblast metabolism and function is unknown. Here we show that the physiological medium (Plasmaxä) with nutrient and metabolite concentrations recapitulating human plasma improves human trophoblast stem cell (hTSC) proliferation and differentiation compared to standard medium (DMEM-F12). hTSCs cultured in Plasmax-based medium also show altered glycolytic and mitochondrial metabolism, as well as reduced S-adenosylmethionine/S-adenosyl-homosysteine ratio compared to DMEM-F12-based medium. These findings demonstrate the importance of the nutritional environment for phenotyping cultured human trophoblasts.

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“…With these data one can assume that citrate, present in HPLM and Plasmax, can not only support fatty acid biosynthesis due to production of AcCoA by ACLY in the cytoplasm but also give rise to OAA in mitochondria. However, a report from Tardito’s group demonstrated that mesenchymal stem cells in Plasmax as well as in DMEM produce and secrete lactate ( 91 ). They also showed that a majority of citrate produced from AcCoA is exported to the cytoplasm, thus supporting evidence for a “Finley cycle.” However, one should note that such a phenotype could be a feature of stemness, and its occurrence in differentiated cells remains to be examined in future.…”

Section: Differences In Cell Metabolism Between Cells Cultivated In C...mentioning

confidence: 99%

Plasma-Like Culture Medium for the Study of Viruses

Golikov

Bartosch

Smirnova

et al. 2023

mBio

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

Cited by 4 publications

References 49 publications

Asparagine transport through SLC1A5/ASCT2 and SLC38A5/SNAT5 is essential for BCP‐ALL cell survival and a potential therapeutic target

Asparagine transport through SLC1A5/ASCT2 and SLC38A5/SNAT5 is essential for BCP‐ALL cell survival and a potential therapeutic target

Physiologically relevant culture medium Plasmax improves human placental trophoblast stem cell function

Plasma-Like Culture Medium for the Study of Viruses

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