PhD Student State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science; Shanghai, China, China (People's Republic)
Abstract: Hepatocyte transplantation (HTx) holds promise as a therapeutic approach for liver diseases, yet its clinical application has been hindered by the absence of effective conditioning regimens and approved drugs to enhance hepatocyte engraftment and repopulation. In this study, we identified estradiol as the key factor underlying the sex-dependent differences in hepatocyte repopulation observed in Fah-deficient mice. Administration of estradiol post-HTx significantly enhanced the repopulation efficiency of transplanted hepatocytes in both male and female recipients. Mechanistically, estradiol exerts its effects through estrogen receptor alpha (ESR1), which modulates the sterol regulatory element-binding protein 2 (SREBP2)-mediated cholesterol biosynthesis pathway, thereby promoting the proliferation of transplanted hepatocytes. Additionally, we comprehensively evaluated the safety profile of estradiol in the context of HTx, demonstrating that a one-month estradiol treatment had no adverse effects on the liver or estrogen-responsive tissues, including the uterus and mammary glands, in normal mice. These findings establish estradiol as a clinically feasible and safe pharmacological strategy to enhance hepatocyte repopulation, providing a significant step forward in advancing HTx towards clinical implementation.
