Notch activation shifts the fate decision of senescent progenitors toward myofibrogenesis in human adipose tissue

Senescence is a key event in the impairment of adipose tissue (AT) function with obesity and aging but the underlying molecular and cellular players remain to be fully defined, particularly with respect to the human AT progenitors. We have found distinct profiles of senescent progenitors based on AT location between stroma from visceral versus subcutaneous AT. In addition to flow cytometry, we characterized the location differences with transcriptomic and proteomic approaches, uncovering the genes and developmental pathways that are underlying replicative senescence. We identified key components to include INBHA as well as SFRP4 and GREM1, antagonists for the WNT and BMP pathways, in the senescence-associated secretory phenotype and NOTCH3 in the senescence-associated intrinsic phenotype. Notch activation in AT progenitors inhibits adipogenesis and promotes myofibrogenesis independently of TGF beta. In addition, we demonstrate that NOTCH3 is enriched in the premyofibroblast progenitor subset, which preferentially accumulates in the visceral AT of patients with an early obesity trajectory. Herein, we reveal that NOTCH3 plays a role in the balance of progenitor fate determination preferring myofibrogenesis at the expense of adipogenesis. Progenitor NOTCH3 may constitute a tool to monitor replicative senescence and to limit AT dysfunction in obesity and aging.

Automated summary

Senescence is a critical event in the dysfunction of adipose tissue (AT) due to obesity and aging, but the molecular and cellular factors underlying this process in human AT progenitors are not yet fully understood. Researchers have identified distinct profiles of senescent progenitors based on their location within AT, specifically visceral and subcutaneous AT. In addition to flow cytometry, the study used transcriptomic and proteomic approaches to uncover the genes and developmental pathways involved in replicative senescence, including INBHA, SFRP4, GREM1, and NOTCH3. Activation of NOTCH3 in AT progenitors inhibits adipogenesis and promotes myofibrogenesis, contributing to AT dysfunction in obesity and aging.