AhR-STAT3-Hmox1/Ptgs2 signaling pathway may restrict ferroptosis and improve hMSC accumulation and efficacy in mice liver

Background The insufficient efficacy of mesenchymal stem cells (MSCs) restricted its application in liver diseases. Emerging evidence suggested that ferroptosis may provoke hepatocyte dysfunction and exacerbate liver microenvironment damages. Purpose In this study, the contribution of liver ferroptosis to hMSCs elimination and efficacy were investigated. Furthermore, the potential link between liver ferroptosis and AhR was explored. Experimental Approach Two independent mice models, iron supplement-induced hepatic ferroptosis and hepatic ischemia/reperfusion (I/R) injury were employed to identify ferroptosis impacts on hMSC PK/PD in mice. Key Results The results indicated that AhR inhibition could attenuate ferroptosis in liver and improve hMSC cell fate. The viability of hMSCs could be significantly decreased by iron supplement or serum from I/R mice. Aryl hydrocarbon receptor (AhR) antagonist CH223191 could reverse iron overload and oxidative stress induced by ferroptosis, and increase hMSCs concentration and efficacy in liver disease animal models. Its effects were much stronger than deferoxamine, a conventional ferroptosis inhibitor. Transcriptomics results suggested the AhR-STAT3-Hmox1/Ptgs2 signaling pathway is critical to this process. The phenomenon was confirmed in the I/R liver injury model. In AhR pre-inhibited mice, hMSC exhibited more potent protective effects which was linked to less ferroptosis in liver. Conclusion and Implications Overall, these findings revealed that ferroptosis was critical to hMSC cell fate; the inhibition of AhR may reduce liver ferroptosis which enhanced MSCs' exposure and therapeutic effects.

文章引用产品列表