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Metabolites can regulate stem cell behavior through the STAT3/AKT pathway in a similar trend to that under hypoxic conditions.

ABSTRACT: Stem cell therapy has long been considered a promising mode of treatment for many incurable diseases. Human mesenchymal stem cells (hMSCs) have provided the most promising results to date for regenerative medicine. Nevertheless, due to several obstacles such as difficulty in sourcing and characterizing hMSCs, they remain largely unavailable for clinical use. The signaling requirements for maintaining stem cell function have been studied widely, but little is known about how metabolism contributes to stem cell function. hMSCs have been shown to promote therapeutic efficacy in hypoxic conditions through metabolic conversion. According to published studies, certain metabolites are able to convert stem cell metabolism from oxidative phosphorylation to glycolysis. In this study, we selected several metabolites (fructose-1,6-bisphosphate (FBP), Phosphoenolpyruvic acid (PEP) and sodium oxalate (OXA)) to examine the relation between metabolites and stem cell functions. In addition, we investigated the ability of selected metabolites to induce rapid expansion of this cell population. Our results indicate that selected metabolites stimulate stem cell proliferation by induce glycolytic metabolism via AKT/STAT signaling.

SUBMITTER: Jeong GJ

PROVIDER: S-EPMC6468014 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Metabolites can regulate stem cell behavior through the STAT3/AKT pathway in a similar trend to that under hypoxic conditions.

Jeong Gun-Jae GJ Kang Donglim D Kim Ae-Kyeong AK Han Kyu-Hyun KH Jeon Hye Ran HR Kim Dong-Ik DI

Scientific reports 20190416 1

Stem cell therapy has long been considered a promising mode of treatment for many incurable diseases. Human mesenchymal stem cells (hMSCs) have provided the most promising results to date for regenerative medicine. Nevertheless, due to several obstacles such as difficulty in sourcing and characterizing hMSCs, they remain largely unavailable for clinical use. The signaling requirements for maintaining stem cell function have been studied widely, but little is known about how metabolism contribute ...[more]

PMID: 30992510

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Project description:Hypoxia plays a crucial role in acute and chronic renal injury, which is attributable to renal tubular and glomerular cell damage. Some studies provide evidence that hypoxia-dependent upregulation of the mitochondrial enzyme arginase type-II (Arg-II) in tubular cells promotes renal tubular injury. It is, however, not known whether Arg-II is also expressed in glomerular cells, particularly podocytes under hypoxic conditions, contributing to hypoxia-induced podocyte injury. The effects of hypoxia on human podocyte cells (AB8/13) in cultures and on isolated kidneys from wild-type (wt) and arg-ii gene-deficient (arg-ii-/-) mice ex vivo, as well as on mice of the two genotypes in vivo, were investigated, respectively. We found that the Arg-II levels were enhanced in cultured podocytes in a time-dependent manner over 48 h, which was dependent on the stabilization of hypoxia-inducible factor 1α (HIF1α). Moreover, a hypoxia-induced derangement of cellular actin cytoskeletal fibers, a decrease in podocin, and an increase in mitochondrial ROS (mtROS) generation-as measured by MitoSOX-were inhibited by adenoviral-mediated arg-ii gene silencing. These effects of hypoxia on podocyte injury were mimicked by the HIFα stabilizing drug DMOG, which inhibits prolyl hydroxylases (PHD), the enzymes involved in HIFα degradation. The silencing of arg-ii prevented the detrimental effects of DMOG on podocytes. Furthermore, the inhibition of mtROS generation by rotenone-the inhibitor of respiration chain complex-I-recapitulated the protective effects of arg-ii silencing on podocytes under hypoxic conditions. Moreover, the ex vivo experiments with isolated kidney tissues and the in vivo experiments with mice exposed to hypoxic conditions showed increased Arg-II levels in podocytes and decreased podocyte markers regarding synaptopodin in wt mice but not in arg-ii-/- mice. While age-associated albuminuria was reduced in the arg-ii-/- mice, the hypoxia-induced increase in albuminuria was, however, not significantly affected in the arg-ii-/-. Our study demonstrates that Arg-II in podocytes promotes cell injury. Arg-ii ablation seems insufficient to protect mice in vivo against a hypoxia-induced increase in albuminuria, but it does reduce albuminuria in aging.

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Metabolites can regulate stem cell behavior through the STAT3/AKT pathway in a similar trend to that under hypoxic conditions.

Publications

Metabolites can regulate stem cell behavior through the STAT3/AKT pathway in a similar trend to that under hypoxic conditions.

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