PPAR gamma-dependent hepatic macrophage switching acts as a central hub for hUCMSC-mediated alleviation of decompensated liver cirrhosis in rats

Background Decompensated liver cirrhosis (DLC), a terminal-stage complication of liver disease, is a major cause of morbidity and mortality in patients with hepatopathies. Human umbilical cord mesenchymal stem cell (hUCMSC) therapy has emerged as a novel treatment alternative for the treatment of DLC. However, optimized therapy protocols and the associated mechanisms are not entirely understood. Methods We constructed a DLC rat model consistent with the typical clinical characteristics combined use of PB and-CCL4. Performing dynamic detection of liver morphology and function in rats for 11 weeks, various disease characteristics of DLC and the therapeutic effect of hUCMSCs on DLC in experimental rats were thoroughly investigated, according to ascites examination, histopathological, and related blood biochemical analyses. Flow cytometry analysis of rat liver, immunofluorescence, and RT-qPCR was performed to examine the changes in the liver immune microenvironment after hucMSCs treatment. We performed RNA-seq analysis of liver and primary macrophages and hUCMSCs co-culture system in vitro to explore possible signaling pathways. PPAR gamma antagonist, GW9662, and clodronate liposomes were used to inhibit PPAR activation and pre- exhaustion of macrophages in DLC rats' livers, respectively. Results We found that changing the two key issues, the frequency and initial phase of hUCMSCs infusion, can affect the efficacy of hUCMSCs, and the optimal hUCMSCs treatment schedule is once every week for three weeks at the early stage of DLC progression, providing the best therapeutic effect in reducing mortality and ascites, and improving liver function in DLC rats. hUCMSCs treatment skewed the macrophage phenotype from M1-type to M2-type by activating the PPAR gamma signaling pathway in the liver, which was approved by primary macrophages and hUCMSCs co-culture system in vitro. Both inhibition of PPAR gamma activation with GW9662 and pre- exhaustion of macrophages in DLC rats' liver abolished the regulation of hUCMSCs on macrophage polarization, thus attenuating the beneficial effect of hUCMSCs treatment in DLC rats. Conclusions These data demonstrated that the optimal hUCMSCs treatment effectively inhibits the ascites formation, prolongs survival and significantly improves liver structure and function in DLC rats through the activation

Automated summary

The optimal treatment for decompensated liver cirrhosis (DLC) using human umbilical cord mesenchymal stem cells (hUCMSCs) is once every week for three weeks at the early stage of DLC progression. This treatment reduces mortality, ascites formation, and improves liver function. hUCMSCs treatment activates the PPAR gamma signaling pathway, leading to a shift in macrophage phenotype from M1-type to M2-type, which is crucial for the therapeutic effect. However, inhibition of PPAR gamma activation and macrophage depletion attenuate the beneficial effect of hUCMSCs treatment.