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Purpose <p>Adipose tissues have long been recognized for their diverse endocrine functions that serve to regulate tissue homeostasis. Although adipose depot-specific secretory profiles can differentially regulate fibroblast fate and fibrotic tissue remodeling, systematic investigation of how adipose depots of varying phenotypes influence fibroblast mechanobiology remains lacking</p> Methods <p>By integrating secretome profiling with functional and mechanobiological assays in a controlled adipose-fibroblast coculture platform, we mechanistically investigate how canonical brown (BAT), white (WAT), and beige adipose tissues (thoracic and abdominal perivascular adipose tissue; T-PVAT and A-PVAT, respectively) govern fibroblast-to-myofibroblast transition (FMT) through depot-specific paracrine signaling.</p> Results <p>Thermogenic depots (BAT and T-PVAT) enhance fibroblast proliferation, collagen deposition, and stiffness (1.9-fold increase in single cell modulus; <i>p</i> &lt; 0.0001) alongside specific adipokines that regulate metabolism (ANGPTL3, FGF1) and inhibit calcification (Fetuin A). In contrast, lipid-storing depots (WAT and A-PVAT) promote fibroblast migration (79% scratch wound closure at 12 h; <i>p</i> &lt; 0.01) and matrix degradation through upregulated pro-inflammatory cytokines (CCL2, IL-6) and fibrogenic mediators (PAI-1, TIMP-1). Mechanistically, BAT and T-PVAT secretomes induce pro-contractile and matrix-producing fibroblast phenotypes, while A-PVAT and WAT promote migratory and matrix-remodeling behaviors. Further, T-PVAT uniquely combines BAT-like genetic identity with elevated RAGE-DPP4 signaling, resulting in excessive fibroblast activation, stiffening, and collagen production that can be attenuated via pharmacological inhibition of DPP4.</p> Conclusions <p>Our findings establish adipose depots as distinct modulators of fibroblast phenotype, wherein depot-specific mediators promote mechanobiological alterations that balance reparative and pathological remodeling processes related to fibrosis. Differential biological responses by fibroblasts exposed to diverse adipose phenotypes underscores the potential for adipose-driven stromal crosstalk to mitigate fibrotic remodeling alongside metabolic and cardiovascular disease comorbidities.</p>

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Paracrine Signaling by Distinct Adipose Tissue Depots Regulate Fibroblast Mechanobiology and Functional Heterogeneity

  • 期刊论文

  • 发表日期：

    2025年10月4日

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  • Yujun Xu,
  • Niyousha Karbasion,
  • Tata A. Toure,
  • Jack A. Esche,
  • Brendan K. Otani,
  • J. Caleb Snider,
  • Matthew R. Bersi

摘要

Purpose

Adipose tissues have long been recognized for their diverse endocrine functions that serve to regulate tissue homeostasis. Although adipose depot-specific secretory profiles can differentially regulate fibroblast fate and fibrotic tissue remodeling, systematic investigation of how adipose depots of varying phenotypes influence fibroblast mechanobiology remains lacking

Methods

By integrating secretome profiling with functional and mechanobiological assays in a controlled adipose-fibroblast coculture platform, we mechanistically investigate how canonical brown (BAT), white (WAT), and beige adipose tissues (thoracic and abdominal perivascular adipose tissue; T-PVAT and A-PVAT, respectively) govern fibroblast-to-myofibroblast transition (FMT) through depot-specific paracrine signaling.

Results

Thermogenic depots (BAT and T-PVAT) enhance fibroblast proliferation, collagen deposition, and stiffness (1.9-fold increase in single cell modulus; p < 0.0001) alongside specific adipokines that regulate metabolism (ANGPTL3, FGF1) and inhibit calcification (Fetuin A). In contrast, lipid-storing depots (WAT and A-PVAT) promote fibroblast migration (79% scratch wound closure at 12 h; p < 0.01) and matrix degradation through upregulated pro-inflammatory cytokines (CCL2, IL-6) and fibrogenic mediators (PAI-1, TIMP-1). Mechanistically, BAT and T-PVAT secretomes induce pro-contractile and matrix-producing fibroblast phenotypes, while A-PVAT and WAT promote migratory and matrix-remodeling behaviors. Further, T-PVAT uniquely combines BAT-like genetic identity with elevated RAGE-DPP4 signaling, resulting in excessive fibroblast activation, stiffening, and collagen production that can be attenuated via pharmacological inhibition of DPP4.

Conclusions

Our findings establish adipose depots as distinct modulators of fibroblast phenotype, wherein depot-specific mediators promote mechanobiological alterations that balance reparative and pathological remodeling processes related to fibrosis. Differential biological responses by fibroblasts exposed to diverse adipose phenotypes underscores the potential for adipose-driven stromal crosstalk to mitigate fibrotic remodeling alongside metabolic and cardiovascular disease comorbidities.