From Hair to Colon: Hair Follicle-Derived MSCs Alleviate Pyroptosis in DSS-Induced Ulcerative Colitis by Releasing Exosomes in a Paracrine Manner.

Ulcerative colitis (UC) has attracted intense attention due to its high recurrence rate and the difficulty of treatment. Pyroptosis has been suggested to be crucial in the development of UC. Although mesenchymal stem cells (MSCs) are broadly used for UC therapy, they have rarely been studied in the context of UC pyroptosis. Hair follicle-derived MSCs (HFMSCs) are especially understudied with regard to UC and pyroptosis. In this study, we aimed to discover the effects and potential mechanisms of HFMSCs in UC. We administered HFMSCs to dextran sulfate sodium- (DSS-) treated mice and found that the HFMSCs significantly inhibited pyroptosis to alleviate DSS-induced UC. A transwell system and GW4869, an exosome inhibitor, were used to prove the paracrine mechanism of HFMSCs. HFMSC supernatant reduced pyroptosis-related protein expression and promoted cell viability, but these effects were attenuated by GW4869, suggesting a role for HFMSC-released exosomes (Exos) in pyroptosis. Next, Exos were extracted and administered in vitro and in vivo to explore their roles in pyroptosis and UC. In addition, the biodistribution of Exos in mice was tracked using an imaging system and immunofluorescence. The results suggested that Exos not only improved DSS-induced pyroptosis and UC but also were internalized into the injured colon. Furthermore, the therapeutic efficacy of Exos was dose dependent. Among the Exo treatments, administration of 400  μ g of Exos per mouse twice a week exhibited the highest efficacy. The differentially expressed miRNAs (DEmiRNAs) between MSCs and MSC-released Exos suggested that Exos might inhibit pyroptosis through tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) signalling and interferon- (IFN-) gamma pathways. Our study reveals that HFMSCs can alleviate pyroptosis in UC by releasing DEmiRNA-containing Exos in a paracrine manner. This finding may lead to new treatments for UC.