RUNX2 enhances vascular remodeling to promote endothelial proliferation in acute liver injury

Abstract

Background and Aims: The liver has a unique capacity for self-renewal, maintaining a proper liver-to-bodyweight ratio, which is essential for sustaining homeostasis. Regenerative process in the liver involves intricate communication between various cell types such as hepatocytes, hepatic stellate cells, endothelial cells, and inflammatory cells. Although the role of endothelial cells in liver regeneration has been extensively studied, detailed knowledge regarding specific endothelial cell-derived factors that promote the regeneration of liver endothelial cells (LECs) remains limited. This study aimed to identify the regenerative capacity of endothelial progenitor cells (EPCs) after acute liver injury. Methods: Thioacetamide (TAA) was used to induce acute liver injury. Bulk and single-cell RNA sequencing were analyzed to investigate changes in endothelial cells after TAA injection. Runx2 heterozygous mice were analyzed to investigate the role of RUNX2 in endothelial regeneration. Results: TAA resulted in the delamination of LECs, which exhibited the highest regenerative capacity after three days of TAA injection. TAA increased the number of EPCs and RUNX2 was significantly enriched in the EPC population. Endothelial RUNX2 promotes regeneration by regulating its target genes such as Lrp1, Gadd45b, Ptprj, Hmox1, and Junb. In addition, Runx2 haplodeficient mice exhibited diminished liver regenerative capacity compared with wild-type mice. RUNX2 is also expressed in the endothelial cells of patients with chronic liver diseases. Conclusion: These findings provide novel insights into the intricate mechanisms regulating LEC regeneration and highlight the pivotal role played by RUNX2 in vascular remodeling.