Mindin regulates fibroblast subpopulations through distinct Src family kinases during fibrogenesis
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.
Authors
- Krithika Badarinath (ORCID: https://orcid.org/0000-0003-0941-5504)
- Isha Rana (ORCID: https://orcid.org/0000-0002-1512-0000)
- Binita Dam (ORCID: https://orcid.org/0000-0003-1684-4614)
- Abrar Rizvi (ORCID: https://orcid.org/0000-0003-2867-5758)
- Rania Faouzi Zaarour (ORCID: https://orcid.org/0000-0001-9132-5940)
- Akash Gulyani (ORCID: https://orcid.org/0000-0003-4130-4257)
- A. K. Dutta (ORCID: https://orcid.org/0009-0001-7032-1921)
- Colin Jamora (ORCID: https://orcid.org/0000-0003-2127-2972)
- Ravindra K. Zirmire (ORCID: https://orcid.org/0000-0002-6003-2771)
- Edries Yousaf Hajam (ORCID: https://orcid.org/0000-0002-3589-5823)
- Gaurav Kansagara (ORCID: https://orcid.org/0000-0003-0779-3165)
- Sunny Kataria (ORCID: https://orcid.org/0000-0002-0690-6300)
- Dyuti Saha (ORCID: https://orcid.org/0000-0002-5468-4853)
- Pankaj Kumar (ORCID: https://orcid.org/0000-0002-8411-1634)
- Sultan Ahmed (ORCID: https://orcid.org/0009-0000-0347-8198)
Institutions
- Manipal Academy of Higher Education (IN)
- National Centre for Biological Sciences (IN)
- Shiv Nadar University (IN)
- Institute for Stem Cell Biology and Regenerative Medicine (IN)
- Integrative Medicine Institute (US)
- SASTRA University (IN)
Publication Details
- Journal
- JCI Insight
- Published
- 2024-12-31
- DOI
- https://doi.org/10.1172/jci.insight.173071
- Primary Topic
- Hippo pathway signaling and YAP/TAZ
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- American Cancer Society
- Department of Biotechnology, Ministry of Science and Technology, India
- Indian Council of Medical Research
- National Institutes of Health
- Directorate for Biological Sciences
- National Institute of Arthritis and Musculoskeletal and Skin Diseases