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

Area of Science:

• Adipose tissue biology
• Cellular mechanobiology
• Fibrosis research

Background:

• Adipose tissues regulate homeostasis through endocrine functions.
• Adipose depot-specific secretomes influence fibroblast fate and fibrotic remodeling.
• Limited understanding exists on how adipose depot phenotypes affect fibroblast mechanobiology.

Purpose of the Study:

• Investigate how brown (BAT), white (WAT), and beige adipose tissues (T-PVAT, A-PVAT) govern fibroblast-to-myofibroblast transition (FMT).
• Elucidate the role of depot-specific paracrine signaling in modulating fibroblast mechanobiology.
• Determine how adipose secretomes influence fibroblast proliferation, migration, and matrix remodeling.

Main Methods:

• Integrated secretome profiling with functional and mechanobiological assays.
• Utilized a controlled adipose-fibroblast coculture platform.
• Compared canonical BAT, WAT, and beige adipose tissues (T-PVAT, A-PVAT).

Main Results:

• Thermogenic depots (BAT, T-PVAT) enhanced fibroblast proliferation, collagen deposition, and stiffness.
• Lipid-storing depots (WAT, A-PVAT) promoted fibroblast migration and matrix degradation.
• T-PVAT exhibited unique RAGE-DPP4 signaling, leading to excessive fibroblast activation and stiffening, which was attenuated by DPP4 inhibition.

Conclusions:

• Adipose depots are distinct modulators of fibroblast phenotype, influencing fibrotic remodeling.
• Adipose-driven stromal crosstalk can mitigate fibrotic remodeling and associated comorbidities.
• Findings highlight the potential of targeting adipose-fibroblast interactions for therapeutic benefit.