GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension

Kaela Drzewiecki; Jungmin Choi; Joseph Brancale; Michael A. Leney-Greene; Sinan Sari; Buket Dalgiç; Aysel Ünlüsoy Aksu; Gülseren Evirgen Şahin; Ahmet Ozen; Safa Baris; Elif Karakoc-Aydiner; Dhanpat Jain; David Kleiner; Michael Schmalz; Kadakkal Radhakrishnan; Junhui Zhang; Kasper Hoebe; Helen C. Su; João P. Pereira; Michael J. Lenardo; Richard P. Lifton; Sílvia Vilarinho

doi:10.1084/jem.20201745

GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension

Kaela Drzewiecki, Jungmin Choi, Joseph Brancale, Michael A. Leney-Greene, Sinan Sari, Buket Dalgiç, Aysel Ünlüsoy Aksu, Gülseren Evirgen Şahin, Ahmet Ozen, Safa Baris, Elif Karakoc-Aydiner, Dhanpat Jain, David Kleiner, Michael Schmalz, Kadakkal Radhakrishnan, Junhui Zhang, Kasper Hoebe, Helen C. Su, João P. Pereira, Michael J. LenardoRichard P. Lifton, Sílvia Vilarinho

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30 Citations (Scopus)

Abstract

Portal hypertension is a major contributor to decompensation and death from liver disease, a global health problem. Here, we demonstrate homozygous damaging mutations in GIMAP5, a small organellar GTPase, in four families with unexplained portal hypertension. We show that GIMAP5 is expressed in hepatic endothelial cells and that its loss in both humans and mice results in capillarization of liver sinusoidal endothelial cells (LSECs); this effect is also seen when GIMAP5 is selectively deleted in endothelial cells. Single-cell RNA-sequencing analysis in a GIMAP5-deficient mouse model reveals replacement of LSECs with capillarized endothelial cells, a reduction of macrovascular hepatic endothelial cells, and places GIMAP5 upstream of GATA4, a transcription factor required for LSEC specification. Thus, GIMAP5 is a critical regulator of liver endothelial cell homeostasis and, when absent, produces portal hypertension. These findings provide new insight into the pathogenesis of portal hypertension, a major contributor to morbidity and mortality from liver disease.

Original language	English
Article number	e20201745
Journal	Journal of Experimental Medicine
Volume	218
Issue number	7
DOIs	https://doi.org/10.1084/jem.20201745
Publication status	Published - 2021 May 6

Bibliographical note

Publisher Copyright:
© 2021 Drzewiecki et al.

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1084/jem.20201745

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Drzewiecki, K., Choi, J., Brancale, J., Leney-Greene, M. A., Sari, S., Dalgiç, B., Aksu, A. Ü., Şahin, G. E., Ozen, A., Baris, S., Karakoc-Aydiner, E., Jain, D., Kleiner, D., Schmalz, M., Radhakrishnan, K., Zhang, J., Hoebe, K., Su, H. C., Pereira, J. P., ... Vilarinho, S. (2021). GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension. Journal of Experimental Medicine, 218(7), Article e20201745. https://doi.org/10.1084/jem.20201745

Drzewiecki, K, Choi, J, Brancale, J, Leney-Greene, MA, Sari, S, Dalgiç, B, Aksu, AÜ, Şahin, GE, Ozen, A, Baris, S, Karakoc-Aydiner, E, Jain, D, Kleiner, D, Schmalz, M, Radhakrishnan, K, Zhang, J, Hoebe, K, Su, HC, Pereira, JP, Lenardo, MJ, Lifton, RP & Vilarinho, S 2021, 'GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension', Journal of Experimental Medicine, vol. 218, no. 7, e20201745. https://doi.org/10.1084/jem.20201745

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title = "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension",

abstract = "Portal hypertension is a major contributor to decompensation and death from liver disease, a global health problem. Here, we demonstrate homozygous damaging mutations in GIMAP5, a small organellar GTPase, in four families with unexplained portal hypertension. We show that GIMAP5 is expressed in hepatic endothelial cells and that its loss in both humans and mice results in capillarization of liver sinusoidal endothelial cells (LSECs); this effect is also seen when GIMAP5 is selectively deleted in endothelial cells. Single-cell RNA-sequencing analysis in a GIMAP5-deficient mouse model reveals replacement of LSECs with capillarized endothelial cells, a reduction of macrovascular hepatic endothelial cells, and places GIMAP5 upstream of GATA4, a transcription factor required for LSEC specification. Thus, GIMAP5 is a critical regulator of liver endothelial cell homeostasis and, when absent, produces portal hypertension. These findings provide new insight into the pathogenesis of portal hypertension, a major contributor to morbidity and mortality from liver disease.",

author = "Kaela Drzewiecki and Jungmin Choi and Joseph Brancale and Leney-Greene, {Michael A.} and Sinan Sari and Buket Dalgi{\c c} and Aksu, {Aysel {\"U}nl{\"u}soy} and {\c S}ahin, {G{\"u}lseren Evirgen} and Ahmet Ozen and Safa Baris and Elif Karakoc-Aydiner and Dhanpat Jain and David Kleiner and Michael Schmalz and Kadakkal Radhakrishnan and Junhui Zhang and Kasper Hoebe and Su, {Helen C.} and Pereira, {Jo{\~a}o P.} and Lenardo, {Michael J.} and Lifton, {Richard P.} and S{\'i}lvia Vilarinho",

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AU - Drzewiecki, Kaela

AU - Choi, Jungmin

AU - Brancale, Joseph

AU - Leney-Greene, Michael A.

AU - Sari, Sinan

AU - Dalgiç, Buket

AU - Aksu, Aysel Ünlüsoy

AU - Şahin, Gülseren Evirgen

AU - Ozen, Ahmet

AU - Baris, Safa

AU - Karakoc-Aydiner, Elif

AU - Jain, Dhanpat

AU - Kleiner, David

AU - Schmalz, Michael

AU - Radhakrishnan, Kadakkal

AU - Zhang, Junhui

AU - Hoebe, Kasper

AU - Su, Helen C.

AU - Pereira, João P.

AU - Lenardo, Michael J.

AU - Lifton, Richard P.

AU - Vilarinho, Sílvia

PY - 2021/5/6

Y1 - 2021/5/6

N2 - Portal hypertension is a major contributor to decompensation and death from liver disease, a global health problem. Here, we demonstrate homozygous damaging mutations in GIMAP5, a small organellar GTPase, in four families with unexplained portal hypertension. We show that GIMAP5 is expressed in hepatic endothelial cells and that its loss in both humans and mice results in capillarization of liver sinusoidal endothelial cells (LSECs); this effect is also seen when GIMAP5 is selectively deleted in endothelial cells. Single-cell RNA-sequencing analysis in a GIMAP5-deficient mouse model reveals replacement of LSECs with capillarized endothelial cells, a reduction of macrovascular hepatic endothelial cells, and places GIMAP5 upstream of GATA4, a transcription factor required for LSEC specification. Thus, GIMAP5 is a critical regulator of liver endothelial cell homeostasis and, when absent, produces portal hypertension. These findings provide new insight into the pathogenesis of portal hypertension, a major contributor to morbidity and mortality from liver disease.

AB - Portal hypertension is a major contributor to decompensation and death from liver disease, a global health problem. Here, we demonstrate homozygous damaging mutations in GIMAP5, a small organellar GTPase, in four families with unexplained portal hypertension. We show that GIMAP5 is expressed in hepatic endothelial cells and that its loss in both humans and mice results in capillarization of liver sinusoidal endothelial cells (LSECs); this effect is also seen when GIMAP5 is selectively deleted in endothelial cells. Single-cell RNA-sequencing analysis in a GIMAP5-deficient mouse model reveals replacement of LSECs with capillarized endothelial cells, a reduction of macrovascular hepatic endothelial cells, and places GIMAP5 upstream of GATA4, a transcription factor required for LSEC specification. Thus, GIMAP5 is a critical regulator of liver endothelial cell homeostasis and, when absent, produces portal hypertension. These findings provide new insight into the pathogenesis of portal hypertension, a major contributor to morbidity and mortality from liver disease.

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GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension

Abstract

Bibliographical note

ASJC Scopus subject areas

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