Secretive derived from hypoxia preconditioned mesenchymal stem cells promote cartilage regeneration and mitigate joint inflammation via extracellular vesicles

Secretome derived from mesenchymal stem cells (MSCs) have profound effects on tissue regeneration, which could become the basis of future MSCs therapies. Hypoxia, as the physiologic environment of MSCs, has great potential to enhance MSCs paracrine therapeutic effect. In our study, the paracrine effects of secretome derived from MSCs preconditioned in normoxia and hypoxia was compared through both in vitro functional assays and an in vivo rat osteochondral defect model. Specifically, the paracrine effect of total EVs were compared to that of soluble factors to characterize the predominant active components in the hypoxic secretome. We demonstrated that hypoxia conditioned medium, as well as the corresponding EVs, at a relatively low dosage, were efficient in promoting the repair of critical-sized osteochondral defects and mitigated the joint inflammation in a rat osteochondral defect model, relative to their normoxia counterpart. In vitro functional test shows enhancement through chondrocyte proliferation, migration, and matrix deposition, while inhibit IL-1β-induced chondrocytes senescence, inflammation, matrix degradation, and pro-inflammatory macrophage activity. Multiple functional proteins, as well as a change in EVs’ size profile, with enrichment of specific EV-miRNAs were detected with hypoxia preconditioning, implicating complex molecular pathways involved in hypoxia pre-conditioned MSCs secretome generated cartilage regeneration.

Se-sensitized NIR hot band absorption photosensitizer for anti-Stokes excitation deep photodynamic therapy

Conventional anti-Stokes materials-involved deep photodynamic therapy(dPDT)requires much high-intensity irradiance due to low photosensitization efficiency.Herein,we proposed a"booster effector"approach to construct highly efficient hot band absorption phototherapeutics for low/biosafety power anti-Stokes light-triggered d PDT.Se,as"booster effector",was introduced into hot band absorption luminophores(HBAs),which not only significantly facilitated intersystem crossing,but also simultaneously enhanced hot band excitation efficiency atν808,as a result successfully enabling excellent photogenerated singlet oxygen capability of HBAs under ultra-low power anti-Stokes excitation(10 mW cm^(-2)in vitro).As far as we know,such low laser power-initiated photosensitization activity has never been reported in the existing anti-Stokes material systems.Importantly,FUC-Se ME can self-assemble into uniform nanospheres in water,greatly boosting cellular uptake(>25-fold larger than FUC-Se),and achieve superior cancer-killing effect(808 nm,10 mW cm^(-2),5 min,the half-maximal inhibitory concentration IC50=1.36μM).After further PEGylation with folate-attached polymer,the resultant FUC-Se ME@FA can effectively enrich at the tumor(signal-to-background ratio,10).Under safety irradiation(330 mW cm^(-2)),FUC-Se ME@FA effectively inhibits deep-seated tumor progression(the tumor growth inhibition rate,84%).This work provides a successful paradigm,possibly being more clinically beneficial than conventional anti-Stokes materials.

Development of annulus fibrosus tissue construct with hydrogel coils containing pre-conditioned mesenchymal stem cell

Low back pain associated with degenerative disc diseases has been a major health concern that brings suffering to the patients physically and economically.Many existing therapeutic strategies provide shortterm relief of symptoms rather than treatment of the underlying cause.Development of an engineered tissue for disc regeneration is still in its infancy due to the limited autologous healthy disc cell source from the patients.It is also challenging to mimic the complexity of micro-architecture in the native disc tissue that determine their unique structural properties.To date,simple tissue models that mimic the annulus fibrosus(AF)micro-environment for understanding the potential of mesenchymal stem cells(MSCs)in AF tissue engineering are still lacking.In this study,the assembly of a coiled hydrogel microfiber has shown its capability to encapsulate MSCs and create an engineered tissue model that mimics the multiple lamellae of native AF.Using this model,we investigated the potential of MSCs that were previously induced by ascorbic acid(AA).Compared to non-induced MSCs,AA-induced MSCs exhibited significant increase in AF-associated biomarkers during later development in the engineered AF tissue model and also encouraged collagen accumulation through the down-regulated catabolic gene MMP1 and upregulated anti-catabolic gene TIMP1.Furthermore,AA-induced MSCs exhibited a Col2/Col1 ratio closer to that of a native AF tissue.These results suggested that AA-induced MSCs could be a potential cell source for AF tissue engineering and this established tissue model may provide a simple tool for successful AF tissue engineering strategies in the future.