# Mindin regulates fibroblast subpopulations through distinct Src family kinases during fibrogenesis

## TL;DR

Mindin influences different skin fibroblast groups through specific proteins, contributing to fibrosis and cancer.

## Contribution

Mindin is identified as a regulator of fibroblast subpopulations via distinct Src family kinases.

## Key findings

- Mindin promotes migration and inflammation in SCA1+ fibroblasts via Fyn kinase.
- Mindin enhances contractility and collagen production in CD26+ fibroblasts through c-Src.
- Mindin's effects extend to generating heterogeneous cancer-associated fibroblasts in tumor stroma.

## Abstract

Fibrosis results from excessive extracellular matrix (ECM) deposition, which causes tissue stiffening and organ dysfunction. Activated fibroblasts, central to fibrosis, exhibit increased migration, proliferation, contraction, and ECM production. However, it remains unclear if the same fibroblast performs all of the processes that fall under the umbrella term of “activation.” Owing to fibroblast heterogeneity in connective tissues, subpopulations with specific functions may operate under distinct regulatory controls. Using a transgenic mouse model of skin fibrosis, we found that Mindin (also known as spondin-2), secreted by Snail-transgenic keratinocytes, differentially regulates fibroblast subpopulations. Mindin promotes migration and inflammatory gene expression in SCA1+ dermal fibroblasts via Fyn kinase. In contrast, it enhances contractility and collagen production in papillary CD26+ fibroblasts through c-Src signaling. Moreover, in the context of the fibrotic microenvironment of the tumor stroma, we found that differential responses of resident fibroblast subpopulations to Mindin extend to the generation of functionally heterogeneous cancer-associated fibroblasts. This study identifies Mindin as a key orchestrator of dermal fibroblast heterogeneity, reshaping cellular dynamics and signaling diversity in the complex landscapes of skin fibrosis and cancer.

The matricellular protein Mindin elicits different responses from specific dermal fibroblasts subpopulations which together drives fibrogenesis