1. PTEN regulates adipose progenitor cell growth, differentiation, and replicative aging
- Author
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Kirstein, A., Kehr, S., Nebe, M., Hanschkow, M., Barth, L., Lorenz, J., Penke, M., Breitfeld, J., Le Duc, D., https://orcid.org/0000-0001-7289-2552, Landgraf, K., Körner, A., Kovacs, P., Stadler, P., Kiess, W., and Garten, A.
- Subjects
pS6, ribosomal protein S6 phosphorylation ,lipoma ,mTOR, mammalian target of rapamycin ,adipocyte ,FOXO1, forkhead box protein O1 ,KEGG, Kyoto Encyclopedia of Genes and Genomes ,adipogenesis ,cellular senescence ,Humans ,SVF, stromal vascular fraction ,PTEN CR, PTEN CRISPR cells ,Cells, Cultured ,Cell Proliferation ,mesenchymal stem cells ,Forkhead Box Protein O1 ,SREBP1, sterol regulatory element-binding protein 1 ,PTEN Phosphohydrolase ,RNPs, ribonucleoproteins ,Cell Differentiation ,PHTS, PTEN hamartoma tumor syndrome ,pAKT, phosphorylated AKT ,NAMPT, nicotinamide phosphoribosyltransferase ,PTEN, phosphatase and tensin homolog ,PTEN KD, knockdown of PTEN ,Adipose Tissue ,SA-β-gal, senescence-associated β-galactosidase ,PTEN hamartoma tumor syndrome ,PI3K, phosphoinositide 3-kinase ,Research Article ,Signal Transduction - Abstract
The tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates the insulin signaling pathway. Germline PTEN pathogenic variants cause PTEN hamartoma tumor syndrome (PHTS), associated with lipoma development in children. Adipose progenitor cells (APCs) lose their capacity to differentiate into adipocytes during continuous culture, whereas APCs from lipomas of patients with PHTS retain their adipogenic potential over a prolonged period. It remains unclear which mechanisms trigger this aberrant adipose tissue growth. To investigate the role of PTEN in adipose tissue development, we performed functional assays and RNA-Seq of control and PTEN knockdown APCs. Reduction of PTEN levels using siRNA or CRISPR led to enhanced proliferation and differentiation of APCs. Forkhead box protein O1 (FOXO1) transcriptional activity is known to be regulated by insulin signaling, and FOXO1 was downregulated at the mRNA level while its inactivation through phosphorylation increased. FOXO1 phosphorylation initiates the expression of the lipogenesis-activating transcription factor sterol regulatory element-binding protein 1 (SREBP1). SREBP1 levels were higher after PTEN knockdown and may account for the observed enhanced adipogenesis. To validate this, we overexpressed constitutively active FOXO1 in PTEN CRISPR cells and found reduced adipogenesis, accompanied by SREBP1 downregulation. We observed that PTEN CRISPR cells showed less senescence compared with controls and the senescence marker CDKN1A (p21) was downregulated in PTEN knockdown cells. Cellular senescence was the most significantly enriched pathway found in RNA-Seq of PTEN knockdown versus control cells. These results provide evidence that PTEN is involved in the regulation of APC proliferation, differentiation, and senescence, thereby contributing to aberrant adipose tissue growth in patients with PHTS.
- Published
- 2021