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GIMAP5 maintains liver sinusoidal endothelial cell identity and prevents portal hypertension

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE158988 | GEO | 2021/03/01

REPOSITORIES: GEO

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Project description:Abstract: Background and aims: Portal hypertension (PH) is the most frequent and severe clinical syndrome associated to chronic liver disease (CLD), defined by a pathological increase in the hepatic venous pressure gradient (HVPG). Considering the known mechanobiological effects of hydrostatic pressure and shear stress on endothelial cells, we hypothesized that PH could not only be a consequence of, but significantly influence the phenotype of liver sinusoidal endothelial cells (LSECs) during disease progression. The aim of this study was to investigate the effects of pathological hydrodynamic pressure on LSECs and to identify endothelial-derived biomarkers of PH. Methods: Primary LSECs were cultured under normal or increased hydrodynamic pressure within a pathophysiological range (1 vs 12 mmHg) using a microfluidic liver-on-a-chip device. RNAseq was used to identify pressure-sensitive genes, which were validated in liver biopsies from two independent cohorts of CLD patients with PH (n=73) vs subjects without PH (n=23). Biomarker discovery was performed in plasma from a third independent cohort of 64 patients (46 with PH vs 18 w/o). Results: Transcriptomic analysis revealed a marked deleterious effect of pathological pressure in LSECs and identified chromobox 7 (CBX7) as a key transcription factor diminished by pressure. Hepatic CBX7 downregulation was validated in patients with PH and significantly correlated with HVPG. MicroRNA 181a-5p was identified as pressure-induced upstream regulator of CBX7. Analysis of two downstream targets of CBX7, ECAD and SPINK1, were found increased in the bloodstream of patients with PH and were highly predictive of PH and clinically significant PH, with a sensitivity of 91.3% and 91.4% respectively. Conclusions: We describe the detrimental effects of increased hydrodynamic pressure on the sinusoidal endothelium, identify CBX7 as a pressure-sensitive transcription factor, and propose that the combination of two of its reported products could be used as plasma biomarkers of PH.

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GIMAP5 maintains liver sinusoidal endothelial cell identity and prevents portal hypertension

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