Das Rahul, Giri Jayeeta, K Paul Pradyut, Froelich Nicole, Chinnadurai Raghavan, McCoy Sara, Bushman Wade, Galipeau Jacques
Department of Medicine, University of Wisconsin-Madison, Madison, WI, 53705, USA.
School of Medicine, Mercer University, Savannah, GA, 31404, USA.
NPJ Regen Med. 2022 Aug 31;7(1):41. doi: 10.1038/s41536-022-00244-5.
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.
内脏脂肪组织驻留的多能间充质基质细胞（VA-MSC）向脂肪细胞的成脂分化具有代谢保护作用。在慢性炎症应激下，这种新脂肪生成过程受到多种促炎细胞因子和生长因子的抑制。然而，调节VA-MSC可塑性的潜在机制在很大程度上仍未被探索。通过成脂分化筛选，我们确定IFNγ和TGFβ是原代人VA-MSC分化的关键抑制剂。使用人和小鼠VA-MSC以及慢性高脂饮食喂养的小鼠模型进行的进一步研究表明，IFNγ/JAK2激活的STAT5转录因子是慢性炎症条件下VA-MSC分化的核心调节因子。此外，我们的结果表明，在这种条件下，IFNγ激活的STAT5和TGFβ激活的Smad3通过Smad4发生物理相互作用。这种STAT5-Smad4-Smad3复合物通过抑制关键的促脂肪生成转录因子，包括CEBPδ、CEBPα和PPARγ，在防止VA-MSC早期脂肪生成承诺方面发挥关键作用。通过抑制STAT5或Smad3对IFNγ-TGFβ协同作用进行基因或药理学破坏，可在慢性炎症应激下挽救脂肪生成。总体而言，我们的研究描绘了多种炎症信号通路汇聚调节MSC可塑性的核心机制。
