LRRC15 + Myofibroblasts as a Stromal State Linking Repair, Fibrosis, and Scarring

Abstract

Fibroblasts are essential for tissue repair, but persistent activation of matrix-remodelling myofibroblasts can promote fibrosis, tissue stiffening and immune dysfunction. LRRC15 is a leucine-rich repeat-containing cell-surface protein enriched in selected activated mesenchymal compartments, with the strongest functional evidence arising from cancer-associated stroma. State-level evidence also links LRRC15 to a TGF-β-regulated extracellular matrix-remodelling myofibroblast state in idiopathic pulmonary fibrosis and to disease-specific myofibroblast programs in human skin, including inflamed hidradenitis suppurativa associated with scarring risk. However, LRRC15-specific causal evidence in physiological wound repair and pathological scarring remains limited. This review therefore considers LRRC15 positivity a context-dependent stromal state rather than a universal fibroblast lineage or intrinsically pathological identity. Focusing on pulmonary fibrosis and tumour stroma, with skin repair as a comparative framework, we integrate single-cell transcriptomics, spatial mapping, matrix biology and cancer immunology. Current evidence supports LRRC15 as a marker of activated stromal programs and, in selected tumour models, as a contributor to immunoregulatory stromal function, but does not establish universal control of fibroblast contractility, matrix persistence, or scar formation. We propose that temporal persistence and anatomical context may distinguish adaptive from maladaptive LRRC15-associated remodelling. Across tissues, these observations suggest related or convergent programs rather than a demonstrated conserved molecular identity. The proposed repair-to-pathology spectrum is therefore hypothesis-generating and requires validation through temporal lineage tracing, tissue-relevant LRRC15 perturbation, spatial protein analysis, and stage-specific therapeutic studies. LRRC15 is best viewed as a biological readout and potential targeting handle whose significance must be defined in each tissue context.