Journal
NPJ REGENERATIVE MEDICINE
Volume 7, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41536-022-00244-5
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Funding
- National Institute of Diabetes, Digestive and Kidney Diseases award [R01DK109508]
- American Heart Association [17POST33670196]
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Adipogenic differentiation of visceral adipose tissue-resident multipotent mesenchymal stromal cells is suppressed under chronic inflammatory stress by IFN gamma and TGF beta, with the central regulator being the IFN gamma/JAK2-activated STAT5 transcription factor. Adipogenesis can be rescued by disrupting the synergy between IFN gamma and TGF beta signaling pathways.
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 IFN gamma and TGF beta 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 IFN gamma/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, IFN gamma-activated STAT5 and TGF beta-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 CEBP delta, CEBP alpha, and PPAR gamma. Genetic or pharmacological disruption of IFN gamma-TGF beta 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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