Prof The Chinese University of Hong Kong (CUHK), Hong Kong
Abstract: Mesenchymal stromal cells (MSCs) promote tissue repair via paracrine mechanisms. While past studies mainly identified responsible components within their soluble secretome, MSCs are also excellent producers of extracellular matrix (ECM), their insoluble secretome. ECM assembly allows spatially and stoichiometrically precise organization of signaling factors, thereby harnessing their full bioactivity. We thus hypothesized that MSCs’ therapeutic effects might be mediated through insoluble factors in their ECM. To test this, bone marrow-derived MSCs were stimulated to deposit ECM in the presence of a heparan sulfate mimetic (HSM), facilitating ECM assembly. The resultant decellularized biologic was processed into Microparticles of Solidified Secretome (MIPSOS). Treatment of full-thickness skin wounds with MIPSOS enhanced revascularization and healing, surpassing naïve MSC-derived ECM (cECM), deposited in the absence of HSM. Proteomic analysis showed MIPSOS was enriched in pro-angiogenic factors compared to cECM, with strong protein-protein interactions identified in an IGF signaling cluster, where IGF binding protein 7 (IGFBP7) was most enriched. Prior research showed highly conflicting results on IGFBP7’s pro-angiogenic properties, suggesting its activity may depend on its ECM microenvironment composition. Next, IGFBP7 was knocked down in MSCs synthesizing MIPSOS, creating MIPSOS (IGFBP7-KD). Endothelial cells showed slower adherence, reduced migratory and sprouting ability on MIPSOS (IGFBP7-KD), while their proliferation remained unaffected. MIPSOS enhanced skin wound revascularization and closure, while MIPSOS (IGFBP7-KD) exhibited less therapeutic effects. Application of soluble IGFBP7 or its supplementation to MIPSOS (IGFBP7-KD) had no therapeutic benefit. Our data suggest that MSCs promote tissue repair via their ECM, with IGFBP7 being a key driver of revascularization and wound healing. Proper incorporation of IGFBP7 into MSC-derived ECM appears crucial for this effect, although the exact mechanism by which ECM-incorporated IGFBP7 promotes wound repair remains to be determined. The insoluble format of MSC-derived ECM ensures long-term stability and sustained release of bioactive factors, rendering MIPSOS a suitable off-the-shelf biologic for wound repair.
Funding Source: This work was supported by the general research fund (GRF, 14115723, UGC) and by the research fund to the Center for Neuromusculoskeletal Restorative Medicine from Health@InnoHK program (ITC), Hong Kong SAR
