PTEN regulates adipocyte progenitor growth, differentiation and replicative aging

Abstract

Adipose tissue distribution and insulin sensitivity are altered during aging. The tumor suppressor phosphatase and tensin homolog (PTEN) is known to negatively regulate the insulin signaling pathway and mutations influence adipose tissue redistribution. Germline PTEN pathogenic variants cause PTEN Hamartoma Tumor Syndrome (PHTS), which is associated with lipoma development in children. It remains unclear which mechanisms trigger this aberrant adipose tissue growth. Fat cell (adipocyte) progenitors lose their capacity to differentiate into adipocytes during continuous culture, while adipocyte progenitor cells (APCs) from PHTS patients’ lipomas retain their adipogenic potential over a prolonged period. To investigate the role of PTEN in adipose tissue development we performed functional assays and RNA-sequencing of control and PTEN knockdown APCs. We assessed phenotypical differences as well as genes and pathways regulated in conditions of PTEN insufficiency. Reduction of PTEN levels using siRNA or CRISPR lead to an enhanced proliferation and differentiation of APCs. We observed that PTEN levels were upregulated during long term culture of wild type APCs. PTEN CRISPR cells showed less senescence after continuous culture compared to controls and the senescence marker CDKN1A (p21) was downregulated on protein and RNA level in PTEN knockdown cells. Cellular senescence was the most significantly enriched pathway found in gene set enrichment analysis of RNA from PTEN knockdown vs. control cells. These results provide evidence that PTEN is involved in the regulation of APCs proliferation, differentiation and senescence, thereby contributing to aberrant adipose tissue growth in PHTS patients.

Potential Roles of PTEN on Longevity in Two Closely Related Argopecten Scallops With Distinct Lifespans

“…Overexpression of PTEN significantly inhibited cell migration and cell-cycle progression and promoted apoptosis in PCA cells by decreasing Ccnd1 expression and increasing that of Cdkn1b, which ultimately prolonged the life span of TRAMP mice ( Ai et al, 2020 ). In human, Kirstein et al, (2021) found that cells with knockout PTEN showed less senescence compared with controls, and the senescence marker CDKN1A (p21) was downregulated in cells with knocked-down PTEN. In addition, previous studies implicated PTEN played roles in maintenance of genome integrity for longevity ( Ho et al, 2020 ).…”