A STAT5-Smad3 Dyad Regulates Adipogenic Plasticity of Visceral Adipose Mesenchymal Stromal Cells During Chronic Inflammation

Overview

Journal NPJ Regen Med

Date 2022 Aug 31

PMID 36045134

Authors

Rahul Das

Jayeeta Giri

Pradyut K Paul

Nicole Froelich

Raghavan Chinnadurai

Sara McCoy

Wade Bushman

Jacques Galipeau

Affiliations

Soon will be listed here.

Abstract

Adipogenic differentiation of visceral adipose tissue-resident multipotent mesenchymal stromal cells (VA-MSC) into adipocytes is metabolically protective. Under chronic inflammatory stress, this neoadipogenesis process is suppressed by various pro-inflammatory cytokines and growth factors. However, the underlying mechanism(s) regulating VA-MSC plasticity remains largely unexplored. Using an adipogenic differentiation screen, we identified IFNγ and TGFβ as key inhibitors of primary human VA-MSC differentiation. Further studies using human and mouse VA-MSCs and a chronic high-fat diet-fed murine model revealed that IFNγ/JAK2-activated STAT5 transcription factor is a central regulator of VA-MSC differentiation under chronic inflammatory conditions. Furthermore, our results indicate that under such conditions, IFNγ-activated STAT5 and TGFβ-activated Smad3 physically interact via Smad4. This STAT5-Smad4-Smad3 complex plays a crucial role in preventing the early adipogenic commitment of VA-MSCs by suppressing key pro-adipogenic transcription factors, including CEBPδ, CEBPα, and PPARγ. Genetic or pharmacological disruption of IFNγ-TGFβ synergy by inhibiting either STAT5 or Smad3 rescued adipogenesis under chronic inflammatory stress. Overall, our study delineates a central mechanism of MSC plasticity regulation by the convergence of multiple inflammatory signaling pathways.

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