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Age-associated adipose-derived stem cell activity is dictated by IGF2BP3-dependent regulation of glutamine and BCAA catabolism

ABSTRACT: Cultured human adipose-derived stem cells(hASCs) are considered as a homogeneous population in vitro. We used single cell RNA sequencing (scRNA-seq) to reveal the cellular heterogeneity of hASCs and identify aging-related cell clusters in hASCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE267783 | GEO | 2025/05/20

REPOSITORIES: GEO

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Age-associated adipose-derived stem cell activity is dictated by IGF2BP3-dependent regulation of glutamine and BCAA catabolism

Project description:Aging-related diseases were commonly considered being attribute to age-dependent loss in numbers or differentiation potential, whereas aging effects on stem cell characteristics were poorly concerned. In the present study, we investigated age-related alterations of human adipose-derived stem cells (hASCs) from infant (I-hASCs) and elderly (E-hASCs) donors. Based on the integration of multi-omics analyses including scRNA-seq, proteomic, and metabolomic profiles, we unveiled the ACTA2+TAGLN+ cluster primarily confers hASC stemness and tissue repair function. In particular, E-hASCs exhibited attenuated BCAA and glutamine catabolism, potentially due to the decreased BCAT1 and GLS expression in ACTA2+TAGLN+ cluster, which subsequently reduced the energy production and ROS elimination ability of hASCs. Mechanistic studies revealed that BCAT1 and GLS were positively regulated by IGF2BP3 which was diminished in the ACTA2+TAGLN+ cluster of E-hASCs. Suppression of IGF2BP3 decreased I-hASCs self-renewal and multidirectional differentiation potential through the negative regulation of redox homeostasis and energy production, whereas BCAT1 or GLS expression can partly reverse the negative effect of IGF2BP3 knockdown. Furthermore, m6A modification of BCAT1 or GLS mRNAs is required for IGF2BP3-mediated mRNA stability, as demonstrated by the use of METTL3 shRNA or m6A inhibitors. Glutamine and BCAA supplementation effectively restored E-hASC self-renewal and multidirectional differentiation potential both in vitro and in vivo, suggesting the clinical application value to E-hASCs therapy in the treatment of aging-related diseases or in the wound healing for elder.

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Heme biosynthesis regulates BCAA catabolism and thermogenesis in brown adipose tissue

Project description:The distinctive color of brown adipose tissue (BAT) is attributed to its high content of heme-rich mitochondria. Despite this, the mechanisms by which BAT regulates intracellular heme levels remain largely unexplored. Here, we demonstrate that heme biosynthesis is the primary source of heme in brown adipocytes. Inhibiting heme biosynthesis results in an accumulation of the branched-chain amino acids (BCAAs) valine and isoleucine, due to a heme-associated metabolon that channels BCAA-derived carbons into heme biosynthesis. Heme synthesis-deficient brown adipocytes display reduced mitochondrial respiration and lower UCP1 levels compared to wild-type cells. While exogenous heme supplementation can restore intracellular heme levels and mitochondrial function, downregulation persists. This sustained UCP1 suppression is linked to epigenetic regulation induced by the accumulation of propionyl-CoA, a byproduct of disrupted heme synthesis. Finally, disruption of heme biosynthesis in BAT impairs thermogenic response and, in female, but not male, mice, hinders the cold- induced clearance of circulating BCAAs in a sex-hormone-dependent manner. These findings establish adipose heme biosynthesis as a key regulator of thermogenesis and sex-dependent BCAA homeostasis.

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Heme Biosynthesis Regulates BCAA Catabolism and Thermogenesis in Brown Adipose Tissue

Project description:The distinctive color of brown adipose tissue (BAT) is attributed to its high content of heme-rich mitochondria. Despite this, the mechanisms by which BAT regulates intracellular heme levels remain largely unexplored. Here, we demonstrate that heme biosynthesis is the primary source of heme in brown adipocytes. Inhibiting heme biosynthesis results in an accumulation of the branched-chain amino acids (BCAAs) valine and isoleucine, due to a heme-associated metabolon that channels BCAA-derived carbons into heme biosynthesis. Heme synthesis-deficient brown adipocytes display reduced mitochondrial respiration and lower UCP1 levels compared to wild-type cells. While exogenous heme supplementation can restore intracellular heme levels and mitochondrial function, UCP1 downregulation persists. This sustained UCP1 suppression is linked to epigenetic regulation induced by the accumulation of propionyl-CoA, a byproduct of disrupted heme synthesis. Finally, disruption of heme biosynthesis in BAT impairs thermogenic response and, in female, but not male, mice, hinders the cold- induced clearance of circulating BCAAs in a sex-hormone-dependent manner. These findings establish adipose heme biosynthesis as a key regulator of thermogenesis and sex-dependent BCAA homeostasis.

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Expression profiling of human adipose stromal cell (hASC) adipogenesis

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Genome-wide gene expression during osteogenic and myogenic differentiation from adipose- derived stem cells.

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MicroRNA expression profiling of human adipose stromal cell (hASC) adipogenesis

Project description:Human abdominal adipose tissue was obtained with informed consent from a 33-year old Caucasian female (BMI = 32.96 Kg/m2) undergoing lipoaspiration. Adipose stromal cells (hASCs) were isolated and differentiated into adipocytes in vitro. Two technical replicates from 9 time points relative to induction of adipogenesis (day 0). Also, one sample from pre-adipocytes (day -2) grown without FGF.

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Genome-wide gene expression during osteogenic and myogenic differentiation from adipose- derived stem cells.

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Heme Biosynthesis Regulates BCAA Catabolism and Thermogenesis in Brown Adipose Tissue

Project description:Heme Biosynthesis Regulates BCAA Catabolism and Thermogenesis in Brown Adipose Tissue

| PRJNA1222362 | ENA