Splenectomy reduces shear stress and inflammation in liver endothelial cells during regeneration after partial hepatectomy in mice

TL;DR

Splenectomy in mice reduces liver endothelial cell stress and inflammation during liver regeneration after partial hepatectomy.

Contribution

This study reveals that splenectomy mitigates pro-inflammatory activation and shear stress in liver endothelial cells during regeneration.

Findings

Splenectomized mice showed fewer VCAM-1 and CD144 + endothelial cells post-liver resection.

Splenectomy increased Ki67 + endothelial cell proliferation and reduced apoptotic cells on day 1 post-resection.

Gene profiling showed enrichment of PI3K-Akt-mTOR and chemokine pathways in splenectomized animals.

Abstract

Clinical and experimental findings indicate that splenectomy stimulates liver regeneration. The mechanisms of this effect are uncertain. This study aimed to assess the effect of splenectomy on the state of sinusoidal endothelial cells during liver regeneration after 70% resection in mouse model. Two series of experiments were performed. In the first series, splenectomy was performed on sexually mature male C57BL/6 mice, followed by 70% liver resection 7 days later. In the second series, only 70% liver resection was performed. The animals were withdrawn from the experiment 1, 3, or 7 days post-resection. The measurements encompassed the liver mass recovery dynamics; the AST, ALT, and albumin levels; and the proliferation activity of hepatocytes, as well as gene expression profiles, apoptosis rates, and proliferation activity of liver sinusoidal endothelial cells. Animals that underwent splenectomy before liver resection showed a decrease in the number of endothelial cells positive for VCAM-1 on days 1 and 7 post-resection and VE-cadherin-positive (CD144 +) cells on day 7. Liver resection caused an increase in the relative counts of dying (Annexin-PI +) and Ki67 + endothelial cells in the remnant. The apoptotic endothelial cell counts were significantly higher in the group with preserved spleen on day 1 post-resection, while the number of Ki67 + endotheliocytes was higher in splenectomized animals on day 1 and day 3 post-resection. Splenectomy exerts significant effect on the state of endothelial cells of the sinusoidal capillaries of the regenerating liver. The gene expression profiling studied by microarray technology using Clariom™ S Assay (mouse) revealed specific enrichment of the following signaling pathways in the endothelial cells of regenerating liver in splenectomized animals: PI3K-Akt-mTOR signaling pathway, Focal adhesion pathway, Chemokine signaling pathway. In this case, most of the differentially expressed genes were repressed. The decreased proinflammatory activation of sinusoidal endothelium results in decreased immigration of lymphocytes, notably CD3 + и NK1.1 lymphocytes known to inhibit the regeneration. The results indicate that prior splenectomy mitigates the manifestation of shear stress in endothelial cells of the liver and reduces their pro-inflammatory activation, resulting in lower rates of migration of regeneration-inhibiting lymphocytes to the regenerating liver.

The online version contains supplementary material available at 10.1038/s41598-025-32446-4.

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