Mesenchymal stem cells attenuate keloid pathogenesis via TGF-β1/SMAD-driven MMP9 suppression: mechanistic insights into collagen remodeling and extracellular matrix homeostasis

Keloids, characterized by excessive collagen deposition and recurrence, pose significant therapeutic challenges due to limited mechanistic understanding. Mesenchymal stem cells (MSCs) exhibit potential for keloid management, but their precise mechanisms remain unclear. This study investigated how MSCs modulate extracellular matrix (ECM) remodeling in keloid pathogenesis. Using a co-culture system of human umbilical cord MSCs (UC-MSCs) and immortalized keloid fibroblasts (HDIKFs), we demonstrated that UC-MSCs significantly suppressed HDIKF proliferation (via CCK8 assay) and migration (via wound healing assay). Interestingly, UC-MSCs did not alter keloid xenograft growth <i>in vivo</i>. Mechanistically, quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) revealed selective downregulation of matrix metalloproteinases 9 (MMP9) in HDIKFs co-cultured with UC-MSCs, while MMP1, MMP2, and MMP3 remained unaffected. This suppression was linked to inhibition of the transforming growth factor-β1/SMAD (TGF-β1/SMAD) pathway, evidenced by reduced hypoxia-inducible factor-1α (HIF-1α) and SMAD2 expression, alongside upregulated interleukin-10 receptor alpha (IL-10RA). Additionally, UC-MSCs did not alter collagen I/III (COL I/III) ratios or phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling. These findings highlight that MSCs attenuate keloid fibroblast activity through TGF-β1/SMAD-driven MMP9 suppression and IL-10RA enhancement, offering novel insights into MSC-based strategies for ECM homeostasis. This study underscores MMP9 as a therapeutic target and provides a foundation for refining MSC efficacy in keloid treatment.