Inhibition of nuclear factor (erythroid-derived 2)-like 2 promotes hepatic progenitor cell activation and differentiation

Abstract The stem cell ability to self-renew and lead regeneration relies on the balance of complex signals in their microenvironment. The identification of modulators of hepatic progenitor cell (HPC) activation is determinant for liver regeneration and may improve cell transplantation for end-stage...

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Autores principales:	Francesco Bellanti, Giorgia di Bello, Giuseppina Iannelli, Giuseppe Pannone, Maria Carmela Pedicillo, Luke Boulter, Wei-Yu Lu, Rosanna Tamborra, Rosanna Villani, Gianluigi Vendemiale, Stuart J. Forbes, Gaetano Serviddio
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R
Acceso en línea:	https://doaj.org/article/d61f8bccbb224beb9600090ce80a0056
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spelling	oai:doaj.org-article:d61f8bccbb224beb9600090ce80a00562021-12-02T15:00:39ZInhibition of nuclear factor (erythroid-derived 2)-like 2 promotes hepatic progenitor cell activation and differentiation10.1038/s41536-021-00137-z2057-3995https://doaj.org/article/d61f8bccbb224beb9600090ce80a00562021-05-01T00:00:00Zhttps://doi.org/10.1038/s41536-021-00137-zhttps://doaj.org/toc/2057-3995Abstract The stem cell ability to self-renew and lead regeneration relies on the balance of complex signals in their microenvironment. The identification of modulators of hepatic progenitor cell (HPC) activation is determinant for liver regeneration and may improve cell transplantation for end-stage liver disease. This investigation used different models to point out the Nuclear factor (erythroid-derived 2)-like 2 (NRF2) as a key regulator of the HPC fate. We initially proved that in vivo models of biliary epithelial cells (BECs)/HPC activation show hepatic oxidative stress, which activates primary BECs/HPCs in vitro. NRF2 downregulation and silencing were associated with morphological, phenotypic, and functional modifications distinctive of differentiated cells. Furthermore, NRF2 activation in the biliary tract repressed the ductular reaction in injured liver. To definitely assess the importance of NRF2 in HPC biology, we applied a xenograft model by inhibiting NRF2 in the human derived HepaRG cell line and transplanting into SCID/beige mice administered with anti-Fas antibody to induce hepatocellular apoptosis; this resulted in effective human hepatocyte repopulation with reduced liver injury. To conclude, NRF2 inhibition leads to the activation and differentiation of liver progenitors. This redox-dependent transcription factor represents a potential target to regulate the commitment of undifferentiated hepatic progenitors into specific lineages.Francesco BellantiGiorgia di BelloGiuseppina IannelliGiuseppe PannoneMaria Carmela PedicilloLuke BoulterWei-Yu LuRosanna TamborraRosanna VillaniGianluigi VendemialeStuart J. ForbesGaetano ServiddioNature PortfolioarticleMedicineRENnpj Regenerative Medicine, Vol 6, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R
spellingShingle	Medicine R Francesco Bellanti Giorgia di Bello Giuseppina Iannelli Giuseppe Pannone Maria Carmela Pedicillo Luke Boulter Wei-Yu Lu Rosanna Tamborra Rosanna Villani Gianluigi Vendemiale Stuart J. Forbes Gaetano Serviddio Inhibition of nuclear factor (erythroid-derived 2)-like 2 promotes hepatic progenitor cell activation and differentiation
description	Abstract The stem cell ability to self-renew and lead regeneration relies on the balance of complex signals in their microenvironment. The identification of modulators of hepatic progenitor cell (HPC) activation is determinant for liver regeneration and may improve cell transplantation for end-stage liver disease. This investigation used different models to point out the Nuclear factor (erythroid-derived 2)-like 2 (NRF2) as a key regulator of the HPC fate. We initially proved that in vivo models of biliary epithelial cells (BECs)/HPC activation show hepatic oxidative stress, which activates primary BECs/HPCs in vitro. NRF2 downregulation and silencing were associated with morphological, phenotypic, and functional modifications distinctive of differentiated cells. Furthermore, NRF2 activation in the biliary tract repressed the ductular reaction in injured liver. To definitely assess the importance of NRF2 in HPC biology, we applied a xenograft model by inhibiting NRF2 in the human derived HepaRG cell line and transplanting into SCID/beige mice administered with anti-Fas antibody to induce hepatocellular apoptosis; this resulted in effective human hepatocyte repopulation with reduced liver injury. To conclude, NRF2 inhibition leads to the activation and differentiation of liver progenitors. This redox-dependent transcription factor represents a potential target to regulate the commitment of undifferentiated hepatic progenitors into specific lineages.
format	article
author	Francesco Bellanti Giorgia di Bello Giuseppina Iannelli Giuseppe Pannone Maria Carmela Pedicillo Luke Boulter Wei-Yu Lu Rosanna Tamborra Rosanna Villani Gianluigi Vendemiale Stuart J. Forbes Gaetano Serviddio
author_facet	Francesco Bellanti Giorgia di Bello Giuseppina Iannelli Giuseppe Pannone Maria Carmela Pedicillo Luke Boulter Wei-Yu Lu Rosanna Tamborra Rosanna Villani Gianluigi Vendemiale Stuart J. Forbes Gaetano Serviddio
author_sort	Francesco Bellanti
title	Inhibition of nuclear factor (erythroid-derived 2)-like 2 promotes hepatic progenitor cell activation and differentiation
title_short	Inhibition of nuclear factor (erythroid-derived 2)-like 2 promotes hepatic progenitor cell activation and differentiation
title_full	Inhibition of nuclear factor (erythroid-derived 2)-like 2 promotes hepatic progenitor cell activation and differentiation
title_fullStr	Inhibition of nuclear factor (erythroid-derived 2)-like 2 promotes hepatic progenitor cell activation and differentiation
title_full_unstemmed	Inhibition of nuclear factor (erythroid-derived 2)-like 2 promotes hepatic progenitor cell activation and differentiation
title_sort	inhibition of nuclear factor (erythroid-derived 2)-like 2 promotes hepatic progenitor cell activation and differentiation
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/d61f8bccbb224beb9600090ce80a0056
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Inhibition of nuclear factor (erythroid-derived 2)-like 2 promotes hepatic progenitor cell activation and differentiation

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