The effect of acidosis on adipose-derived stem cell
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE130288 | GEO | 2024/04/30
REPOSITORIES: GEO
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Project description:The accumulation of acidic metabolic waste products within the tumor microenvironment profoundly inhibits effector functions of tumor-infiltrating lymphocytes (TILs). However, it is unclear whether extracellular-acidosis impacts T cell metabolic fitness and differentiation status. Here, we surprisingly found that prolonged acid exposure reprogrammed T cell intracellular metabolism and mitochondrial fitness, and preserved T cell stemness. Elevated extracellular-acidosis impaired methionine uptake and metabolism via downregulating SLC7A5, therefore altering H3K27me3 deposition at the promoters of crucial T cell stemness genes. These changes promoted the maintenance of a “stem-like memory” state and improved long-term in vivo persistence and anti-tumor efficacy. Our findings not only reveal the unexpected roles of extracellular-acidosis in the maintenance of stem-like properties of T cells, but also advance our understanding of the direct involvement of methionine metabolism in T cell stemness.
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Project description:Acidic tissue microenvironment is commonly found in a variety of pathophysiological conditions. GPR4 is a proton-sensing G protein-coupled receptor that is fully activated by acidic extracellular pH but has lesser activity at the physiological pH 7.4 and minimal activity at more alkaline pH. To determine the effects of GPR4 activation by acidosis on vascular endothelial cells, we examined the global gene expression of the acidosis response in primary human umbilical vein endothelial cells (HUVEC) with varying level of GPR4. HUVEC with endogenous or overexpressed GPR4 level (designated as HUVEC/Vector & HUVEC/GPR4 cells). Two treatment conditions: pH 6.4 vs. pH 8.4 for 5 h. Biological replicates: 4 HUVEC/Vector replicates (pH6.4 vs pH 8.4), and 4 HUVEC/GPR4 replicates (pH6.4 vs pH 8.4).
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Project description:Purpose: The aim of the study was to analyze the impact of acidic pHe on gene expression in two experimental tumor lines of the rat in vitro and in vivo. The results of short-term incubation (24 h) were compared to chronically acidosis-adapted cells (5 weeks). Methods: Gene expression was analyzed in AT1 prostate and Walker-256 mammary carcinoma of the rat. Cells were exposed to pH 7.4 and 6.6 for 24 h or 5 weeks. Experimental tumors were implanted in rats and control tumors were compared to tumors in which the glycolytic metabolism was intensified. Results: The analyses revealed that 147 genes were uniformly regulated in both cell lines (in vitro) and 79 genes in both experimental tumors after 24 h at low pH. 265 genes were uniformly regulated during long- and short-term exposure to low pH.
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Project description:The accumulation of acidic metabolic waste products within the tumor microenvironment profoundly inhibits effector functions of tumor-infiltrating lymphocytes (TILs). However, it is unclear whether extracellular-acidosis impacts T cell metabolic fitness and differentiation status. Here, we surprisingly found that prolonged acid exposure reprogrammed T cell intracellular metabolism and mitochondrial fitness, and preserved T cell stemness. Elevated extracellular-acidosis impaired methionine uptake and metabolism via downregulating SLC7A5, therefore altering H3K27me3 deposition at the promoters of crucial T cell stemness genes. These changes promoted the maintenance of a “stem-like memory” state and improved long-term in vivo persistence and anti-tumor efficacy. Our findings not only reveal the unexpected roles of extracellular-acidosis in the maintenance of stem-like properties of T cells, but also advance our understanding of the direct involvement of methionine metabolism in T cell stemness.
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