Single-cell and bulk transcriptomics of the liver reveals potential targets of NASH with fibrosis

Abstract Fibrosis is characterized by the excessive production of collagen and other extracellular matrix (ECM) components and represents a leading cause of morbidity and mortality worldwide. Previous studies of nonalcoholic steatohepatitis (NASH) with fibrosis were largely restricted to bulk transc...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Zhong-Yi Wang, Adrian Keogh, Annick Waldt, Rachel Cuttat, Marilisa Neri, Shanshan Zhu, Sven Schuierer, Alexandra Ruchti, Christophe Crochemore, Judith Knehr, Julie Bastien, Iwona Ksiazek, Daniel Sánchez-Taltavull, Hui Ge, Jing Wu, Guglielmo Roma, Stephen B. Helliwell, Deborah Stroka, Florian Nigsch
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1e0a2f5a8461417ea4b3375f454caf3c
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:1e0a2f5a8461417ea4b3375f454caf3c
record_format	dspace
spelling	oai:doaj.org-article:1e0a2f5a8461417ea4b3375f454caf3c2021-12-02T17:17:39ZSingle-cell and bulk transcriptomics of the liver reveals potential targets of NASH with fibrosis10.1038/s41598-021-98806-y2045-2322https://doaj.org/article/1e0a2f5a8461417ea4b3375f454caf3c2021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-98806-yhttps://doaj.org/toc/2045-2322Abstract Fibrosis is characterized by the excessive production of collagen and other extracellular matrix (ECM) components and represents a leading cause of morbidity and mortality worldwide. Previous studies of nonalcoholic steatohepatitis (NASH) with fibrosis were largely restricted to bulk transcriptome profiles. Thus, our understanding of this disease is limited by an incomplete characterization of liver cell types in general and hepatic stellate cells (HSCs) in particular, given that activated HSCs are the major hepatic fibrogenic cell population. To help fill this gap, we profiled 17,810 non-parenchymal cells derived from six healthy human livers. In conjunction with public single-cell data of fibrotic/cirrhotic human livers, these profiles enable the identification of potential intercellular signaling axes (e.g., ITGAV–LAMC1, TNFRSF11B–VWF and NOTCH2–DLL4) and master regulators (e.g., RUNX1 and CREB3L1) responsible for the activation of HSCs during fibrogenesis. Bulk RNA-seq data of NASH patient livers and rodent models for liver fibrosis of diverse etiologies allowed us to evaluate the translatability of candidate therapeutic targets for NASH-related fibrosis. We identified 61 liver fibrosis-associated genes (e.g., AEBP1, PRRX1 and LARP6) that may serve as a repertoire of translatable drug target candidates. Consistent with the above regulon results, gene regulatory network analysis allowed the identification of CREB3L1 as a master regulator of many of the 61 genes. Together, this study highlights potential cell–cell interactions and master regulators that underlie HSC activation and reveals genes that may represent prospective hallmark signatures for liver fibrosis.Zhong-Yi WangAdrian KeoghAnnick WaldtRachel CuttatMarilisa NeriShanshan ZhuSven SchuiererAlexandra RuchtiChristophe CrochemoreJudith KnehrJulie BastienIwona KsiazekDaniel Sánchez-TaltavullHui GeJing WuGuglielmo RomaStephen B. HelliwellDeborah StrokaFlorian NigschNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Zhong-Yi Wang Adrian Keogh Annick Waldt Rachel Cuttat Marilisa Neri Shanshan Zhu Sven Schuierer Alexandra Ruchti Christophe Crochemore Judith Knehr Julie Bastien Iwona Ksiazek Daniel Sánchez-Taltavull Hui Ge Jing Wu Guglielmo Roma Stephen B. Helliwell Deborah Stroka Florian Nigsch Single-cell and bulk transcriptomics of the liver reveals potential targets of NASH with fibrosis
description	Abstract Fibrosis is characterized by the excessive production of collagen and other extracellular matrix (ECM) components and represents a leading cause of morbidity and mortality worldwide. Previous studies of nonalcoholic steatohepatitis (NASH) with fibrosis were largely restricted to bulk transcriptome profiles. Thus, our understanding of this disease is limited by an incomplete characterization of liver cell types in general and hepatic stellate cells (HSCs) in particular, given that activated HSCs are the major hepatic fibrogenic cell population. To help fill this gap, we profiled 17,810 non-parenchymal cells derived from six healthy human livers. In conjunction with public single-cell data of fibrotic/cirrhotic human livers, these profiles enable the identification of potential intercellular signaling axes (e.g., ITGAV–LAMC1, TNFRSF11B–VWF and NOTCH2–DLL4) and master regulators (e.g., RUNX1 and CREB3L1) responsible for the activation of HSCs during fibrogenesis. Bulk RNA-seq data of NASH patient livers and rodent models for liver fibrosis of diverse etiologies allowed us to evaluate the translatability of candidate therapeutic targets for NASH-related fibrosis. We identified 61 liver fibrosis-associated genes (e.g., AEBP1, PRRX1 and LARP6) that may serve as a repertoire of translatable drug target candidates. Consistent with the above regulon results, gene regulatory network analysis allowed the identification of CREB3L1 as a master regulator of many of the 61 genes. Together, this study highlights potential cell–cell interactions and master regulators that underlie HSC activation and reveals genes that may represent prospective hallmark signatures for liver fibrosis.
format	article
author	Zhong-Yi Wang Adrian Keogh Annick Waldt Rachel Cuttat Marilisa Neri Shanshan Zhu Sven Schuierer Alexandra Ruchti Christophe Crochemore Judith Knehr Julie Bastien Iwona Ksiazek Daniel Sánchez-Taltavull Hui Ge Jing Wu Guglielmo Roma Stephen B. Helliwell Deborah Stroka Florian Nigsch
author_facet	Zhong-Yi Wang Adrian Keogh Annick Waldt Rachel Cuttat Marilisa Neri Shanshan Zhu Sven Schuierer Alexandra Ruchti Christophe Crochemore Judith Knehr Julie Bastien Iwona Ksiazek Daniel Sánchez-Taltavull Hui Ge Jing Wu Guglielmo Roma Stephen B. Helliwell Deborah Stroka Florian Nigsch
author_sort	Zhong-Yi Wang
title	Single-cell and bulk transcriptomics of the liver reveals potential targets of NASH with fibrosis
title_short	Single-cell and bulk transcriptomics of the liver reveals potential targets of NASH with fibrosis
title_full	Single-cell and bulk transcriptomics of the liver reveals potential targets of NASH with fibrosis
title_fullStr	Single-cell and bulk transcriptomics of the liver reveals potential targets of NASH with fibrosis
title_full_unstemmed	Single-cell and bulk transcriptomics of the liver reveals potential targets of NASH with fibrosis
title_sort	single-cell and bulk transcriptomics of the liver reveals potential targets of nash with fibrosis
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/1e0a2f5a8461417ea4b3375f454caf3c
work_keys_str_mv	AT zhongyiwang singlecellandbulktranscriptomicsoftheliverrevealspotentialtargetsofnashwithfibrosis AT adriankeogh singlecellandbulktranscriptomicsoftheliverrevealspotentialtargetsofnashwithfibrosis AT annickwaldt singlecellandbulktranscriptomicsoftheliverrevealspotentialtargetsofnashwithfibrosis AT rachelcuttat singlecellandbulktranscriptomicsoftheliverrevealspotentialtargetsofnashwithfibrosis AT marilisaneri singlecellandbulktranscriptomicsoftheliverrevealspotentialtargetsofnashwithfibrosis AT shanshanzhu singlecellandbulktranscriptomicsoftheliverrevealspotentialtargetsofnashwithfibrosis AT svenschuierer singlecellandbulktranscriptomicsoftheliverrevealspotentialtargetsofnashwithfibrosis AT alexandraruchti singlecellandbulktranscriptomicsoftheliverrevealspotentialtargetsofnashwithfibrosis AT christophecrochemore singlecellandbulktranscriptomicsoftheliverrevealspotentialtargetsofnashwithfibrosis AT judithknehr singlecellandbulktranscriptomicsoftheliverrevealspotentialtargetsofnashwithfibrosis AT juliebastien singlecellandbulktranscriptomicsoftheliverrevealspotentialtargetsofnashwithfibrosis AT iwonaksiazek singlecellandbulktranscriptomicsoftheliverrevealspotentialtargetsofnashwithfibrosis AT danielsancheztaltavull singlecellandbulktranscriptomicsoftheliverrevealspotentialtargetsofnashwithfibrosis AT huige singlecellandbulktranscriptomicsoftheliverrevealspotentialtargetsofnashwithfibrosis AT jingwu singlecellandbulktranscriptomicsoftheliverrevealspotentialtargetsofnashwithfibrosis AT guglielmoroma singlecellandbulktranscriptomicsoftheliverrevealspotentialtargetsofnashwithfibrosis AT stephenbhelliwell singlecellandbulktranscriptomicsoftheliverrevealspotentialtargetsofnashwithfibrosis AT deborahstroka singlecellandbulktranscriptomicsoftheliverrevealspotentialtargetsofnashwithfibrosis AT floriannigsch singlecellandbulktranscriptomicsoftheliverrevealspotentialtargetsofnashwithfibrosis
_version_	1718381131719507968

Single-cell and bulk transcriptomics of the liver reveals potential targets of NASH with fibrosis

Ejemplares similares