Pregnane X receptor activation promotes hematopoiesis during liver regeneration by inducing proliferation of hematopoietic stem and progenitor cells in mice

Liver regeneration is a complex process that involves the recruitment of bone marrow (BM)-derived hematopoietic stem and progenitor cells (HSPCs). Pregnane X receptor (PXR), also known as NR1I2, is an important regulator for liver enlargement and regeneration. However, the role of PXR activation in hematopoiesis during liver regeneration remains unclear. This study investigates the effects of PXR activation on HSPCs and hematopoiesis during liver regeneration, as well as the underlying mechanisms involved. Using a 70 % partial hepatectomy (PHx) on C57BL/6 wild-type (WT) and Pxr-null mice, we observed a significant correlation between the changes in HSPCs numbers in BM and the process of liver regeneration. PXR activation significantly increased the population of Lineage^- Sca-1⁺ c-Kit⁺ (LSK) cells in the BM, which are key HSPCs involved in hematopoiesis. Additionally, PXR activation increased serum levels of thrombopoietin (TPO) and erythropoietin (EPO), factors known to support HSPCs proliferation and hematopoiesis in the process of liver regeneration. PXR activation does not affect the hematopoietic function of normal mice. Furthermore, mice subjected to irradiation or busulfan-induced hematopoietic dysfunction exhibited impaired liver regeneration, which was alleviated by PXR activation. Importantly, in Pxr-null mice, the promotive effects of PXR activation on liver regeneration and increase of HSPCs were markedly diminished. Moreover, liver-specific Pxr silencing using AAV-Pxr shRNA attenuated the PXR activation-mediated liver regeneration and increase in BM LSK cells, confirming the critical role of hepatic PXR in hematopoiesis during liver regeneration. Collectively, these findings reveal that PXR activation promotes HSPCs proliferation and hematopoiesis during liver regeneration, providing new insights into the molecular mechanisms underlying the role of PXR in liver regeneration and hematopoiesis.