Rxiv mechanobiohttps://doi.org/doi:10.26508/lsa.202503600
https://pubmed.ncbi.nlm.nih.gov/41951338/
#Mechanical #Ecm
Aortic carboxypeptidase-like protein potentiates β1 integrin signaling in mesenchymal progenitors
Fibrosis is a pathological process characterized by persistent fibroblast activation and excessive ECM accumulation. Aortic carboxypeptidase-like protein (ACLP), a secreted ECM protein that binds fibrillar collagen, is up-regulated in fibrotic tissues and promotes fibroblast differentiation through canonical TGFβ receptor signaling. We hypothesized that when presented within the collagen matrix, ACLP would engage integrin-dependent mechanical signaling pathways that contribute to fibrogenic activation. Using 10T1/2 mouse mesenchymal progenitor cells, we identify a previously unrecognized mechanism through which collagen-bound ACLP induces fibrogenic activation via β1 integrin–mediated signaling. Collagen-bound ACLP induced rapid cell spreading, increased β1 integrin activation, and promoted focal adhesion maturation. These adhesion events triggered activation of the GTPases RhoA and Rac1, accompanied by enhanced F-actin assembly and nuclear accumulation of myocardin-related transcription factor A, a key regulator of fibrogenic gene expression. Transcriptomic profiling revealed enrichment of focal adhesion, ECM–receptor interaction, and actin cytoskeletal pathways downstream of collagen-bound ACLP, which was conserved in primary adipose-derived stromal cells. Together, these findings establish collagen-bound ACLP as a matrix-derived cue that links ECM composition to integrin-dependent fibrogenic activation. The RNA-sequencing data that support the findings of this study are publicly available on Sequencing Read Archive (SRA) under BioProject [PRJNA1368594][1] and processed data in the Gene Expression Omnibus (GEO) repository under accession numbers [GSE312027][2] (10T1/2 cells) and [GSE324887][3] (primary stromal cells). [1]: https://www.ncbi.nlm.nih.gov/bioproject/?term=PRJNA1368594 [2]: /lookup/external-ref?link_type=NCBIGEO&access_num=GSE312027&atom=%2Flsa%2F9%2F6%2Fe202503600.atom [3]: /lookup/external-ref?link_type=NCBIGEO&access_num=GSE324887&atom=%2Flsa%2F9%2F6%2Fe202503600.atom
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