Aortic carboxypeptidase-like protein potentiates β1 integrin signaling in mesenchymal progenitors (Primary stromal cells)

Aortic carboxypeptidase-like protein (ACLP), an ECM-associated protein that binds fibrillar collagen, is upregulated in fibrotic tissues and promotes fibroblast differentiation through canonical TGFβ receptor I signaling. We hypothesized that when presented within the collagen matrix, ACLP engages mechanically driven signaling pathway that contribute to fibroblast activation.

Here, we identified a previously unrecognized mechanism through which collagen-bound ACLP activates primary stromal cells towards a myofibroblast phenotype via β1 integrin-mediated signaling. Collagen-bound ACLP induced rapid fibroblast spreading, increased β1 integrin activation, and promoted focal adhesion maturation. These early adhesion events were followed by elevated activation of the GTPases RhoA and Rac1, with enhanced F-actin assembly and nuclear accumulation of myocardin-related transcription factor A (MRTFA), a key regulator of activated fibroblast gene expression.