Abstract:

Transplantation of bone marrow mesenchymal stem cells (BM-MSCs) has been considered as an alternative therapy, replacing liver transplantation in clinical trials, to treat liver cirrhosis, an irreversible disease that may eventually lead to liver cancer development. However, low survival rate of the BM-MSCs leading to un-satisfactory efficacy remains a major concern. Gender differences have been suggested in BM-MSCs therapeutic application, but the effect of the androgen receptor (AR), a key factor in male sexual phenotype, in this application is not clear. Using two liver cirrhosis mouse models induced by CCl4 or TAA, we show targeting AR in the BM-MSCs improves their self-renewal and migration potentials and increases paracrine effects to exert anti-inflammatory and anti-fibrotic actions to enhance liver repair. Mechanism dissection studies suggested that knocking out AR in BM-MSCs led to improved self-renewal and migration via alteration of the signaling of EGFR and MMP9, and resulted in suppression of infiltrating macrophages and hepatic stellate cells (HSC) activation through the modulation of IL1R/IL1Ra signaling. Therapeutic approaches using either AR-siRNA or the AR degradation enhancer, ASC-J9, to target AR in BM-MSCs, all led to increased efficacy for repair liver, which may provide us a new way to battle liver cirrhosis.

Conclusion: In summary, we provide this field a new process by which targeting AR, a key factor in male sexual phenotype, in BM-MSCs to improve the transplantation therapeutic efficacy for treating liver fibrosis may help us to better battle this irreversible disease in the future.

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