GIMAP5 maintains liver sinusoidal endothelial cell identity and prevents portal hypertension

Chronic liver disease is a major leading cause of portal hypertension that affects approximately 1.5 billion people globally. We show that GIMAP5, a small organellar GTPase, is selectively expressed in liver endothelial cells and human GIMAP5 deficiency causes portal hypertension with capillarization of liver sinusoidal endothelial cells (LSECs). LSEC capillarization is recapitulated in GIMAP5 loss-of-function (LOF) mice, and upon conditional Gimap5 deletion in endothelial cells. Single cell RNA-sequencing analyses reveals replacement of LSECs with capillarized endothelial cells and expansion of liver lymphatic endothelial cells in GIMAP5 LOF mice, and places GIMAP5 upstream of GATA4, a transcription factor required for LSEC-specification. Our studies reveal that GIMAP5 prevents portal hypertension by maintaining LSEC identity and suggest that LSEC is an induced endothelial cell state. Overall design: single cell RNA-sequencing of sorted (CD45-CD31+) liver endothelial cells isolated from Gimap5sph/+ and Gimap5sph/sph mice

慢性肝病是门静脉高压的主要致病诱因，全球约有15亿人群受其影响。本研究证实，GIMAP5作为一种小型细胞器GTP酶，可选择性表达于肝内皮细胞；人类GIMAP5缺乏会引发伴随肝窦内皮细胞（liver sinusoidal endothelial cells, LSECs）毛细血管化的门静脉高压。在GIMAP5功能丧失（loss-of-function, LOF）小鼠以及内皮细胞条件性敲除Gimap5的模型中，均可重现LSEC毛细血管化的表型。单细胞RNA测序分析显示，在GIMAP5功能丧失小鼠体内，LSEC被毛细血管化内皮细胞替代，同时肝淋巴管内皮细胞发生扩增，且GIMAP5位于调控LSEC特化的转录因子GATA4的上游。本研究揭示GIMAP5可通过维持LSEC的细胞身份来预防门静脉高压，并提示LSEC是一种可诱导的内皮细胞状态。实验整体设计：对从Gimap5sph/+与Gimap5sph/sph小鼠中分离分选得到的（CD45-CD31+）肝内皮细胞进行单细胞RNA测序。