Accelerated differentiation of photothermal effect-induced mesenchymal stem cells regulated by activating HSP90-autophagy boosts wound repair

Mesenchymal Stem Cells (MSC) have the potential for pluripotent differentiation, transformation into stromal cells, and release of various cytokines to accelerate tissue healing as well as fight against inflammatory response. However, the differentiation and maturation of MSC require considerable time, which limits their clinical application. To tackle this difficulty, we herein propose a strategy of "selective accelerated activation of MSC by photothermal effect (PTE)" based on our previous work of "laser-controlled platelet activation". In vitro experiments presented that a photothermal agent (Indocyanine green, ICG) could be loaded by bone marrow-derived MSC (BMSC), which facilitated temperature increase under laser irradiation, leading to the speed differentiation and maturity of BMSC. Further findings revealed that PTE prevented BMSC from oxidative stress, thereby reducing inflammation and apoptosis. The ICG-loaded BMSC, which mixed with hydrogel, was further covered on the acute wounds in rats, promoting wound healing and blood vessel regeneration under laser irradiation. In-depth RNA-sequencing results indicated that PTE treatment led to the differentially expressed genes (DEGs) enriched in autophagy and PI3K signaling pathways, as confirmed by the increased expression of autophagy-associated biomarkers and observed autophagosome in BMSC. Furthermore, the HSP90 was activated in response to the PTE, which inhibited PI3K signaling. Finally, the silence of HSP90 abolished PTE-driven PI3K blockage, autophagy, and differentiation of BMSC. To summarize, PTE could facilitate the differentiation of MSC by triggering HSP90-mediated autophagy, which provides a novel approach for controlled MSC differentiation and the potential application of MSC cytopharmaceutics in wound repair.