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Inhibitory effects of HNF4α on migration/maltransformation of hepatic progenitors: HNF4α-overexpressing hepatic progenitors for liver repopulation
BACKGROUND: Although they are expandable in vitro, hepatic progenitors are immature cells and share many immunomarkers with hepatocellular carcinoma, raising potential concerns regarding maltransformation after transplantation. This study investigated the effects of hepatic nuclear factor (HNF) 4α o...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557474/ https://www.ncbi.nlm.nih.gov/pubmed/28807057 http://dx.doi.org/10.1186/s13287-017-0629-8 |
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author | Wang, Ping Cong, Min Liu, Tianhui Xu, Hufeng Wang, Lin Sun, Guangyong Yang, Aiting Zhang, Dong Huang, Jian Sun, Yameng Zhao, Wenshan Ma, Hong Jia, Jidong You, Hong |
author_facet | Wang, Ping Cong, Min Liu, Tianhui Xu, Hufeng Wang, Lin Sun, Guangyong Yang, Aiting Zhang, Dong Huang, Jian Sun, Yameng Zhao, Wenshan Ma, Hong Jia, Jidong You, Hong |
author_sort | Wang, Ping |
collection | PubMed |
description | BACKGROUND: Although they are expandable in vitro, hepatic progenitors are immature cells and share many immunomarkers with hepatocellular carcinoma, raising potential concerns regarding maltransformation after transplantation. This study investigated the effects of hepatic nuclear factor (HNF) 4α on the proliferation, migration, and maltransformation of hepatic progenitors and determined the feasibility of using these manipulated cells for transplantation. METHODS: The effects of HNF4α on rat hepatic progenitors (i.e. hepatic oval cells) were analyzed by HNF4α overexpression and HNF4α shRNA. Nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice injured by carbon chloride (CCl(4)) were then transplanted with control, HNF4α-overexpressing or HNF4α-suppressing hepatic oval cells. Finally, the engraftment of these cells in the recipient liver was analyzed. RESULTS: Rat hepatic progenitors (i.e. hepatic oval cells) expressed HNF4α, although less than that in hepatocytes. When HNF4α was overexpressed in these cells, the proliferation and migration of hepatic oval cells were reduced; but when HNF4α was suppressed by shRNA, the proliferation and migration, and even anchorage-independent growth, of these cells were accelerated. RNA microarray and gene functional analysis revealed that suppressing HNF4α not only impaired many biosynthesis and metabolism pathways of hepatocytes but also increased pathways for cancer. When transplanted into CCl(4)-injured NOD/SCID mice, few HNF4α-suppressing hepatic oval cells localized into the liver, while control cells and HNF4α-overexpressing cells engrafted into the liver and differentiated into albumin-positive hepatocytes. Interestingly, the hepatocytes derived from HNF4α-overexpressing cells were less migrative and expressed less c-Myc than the cells derived from control cells. CONCLUSION: HNF4α constrains proliferation, migration, and maltransformation of hepatic progenitors, and HNF4α-overexpressing hepatic progenitors serve as an optimal candidate for cell transplantation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13287-017-0629-8) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5557474 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-55574742017-08-16 Inhibitory effects of HNF4α on migration/maltransformation of hepatic progenitors: HNF4α-overexpressing hepatic progenitors for liver repopulation Wang, Ping Cong, Min Liu, Tianhui Xu, Hufeng Wang, Lin Sun, Guangyong Yang, Aiting Zhang, Dong Huang, Jian Sun, Yameng Zhao, Wenshan Ma, Hong Jia, Jidong You, Hong Stem Cell Res Ther Research BACKGROUND: Although they are expandable in vitro, hepatic progenitors are immature cells and share many immunomarkers with hepatocellular carcinoma, raising potential concerns regarding maltransformation after transplantation. This study investigated the effects of hepatic nuclear factor (HNF) 4α on the proliferation, migration, and maltransformation of hepatic progenitors and determined the feasibility of using these manipulated cells for transplantation. METHODS: The effects of HNF4α on rat hepatic progenitors (i.e. hepatic oval cells) were analyzed by HNF4α overexpression and HNF4α shRNA. Nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice injured by carbon chloride (CCl(4)) were then transplanted with control, HNF4α-overexpressing or HNF4α-suppressing hepatic oval cells. Finally, the engraftment of these cells in the recipient liver was analyzed. RESULTS: Rat hepatic progenitors (i.e. hepatic oval cells) expressed HNF4α, although less than that in hepatocytes. When HNF4α was overexpressed in these cells, the proliferation and migration of hepatic oval cells were reduced; but when HNF4α was suppressed by shRNA, the proliferation and migration, and even anchorage-independent growth, of these cells were accelerated. RNA microarray and gene functional analysis revealed that suppressing HNF4α not only impaired many biosynthesis and metabolism pathways of hepatocytes but also increased pathways for cancer. When transplanted into CCl(4)-injured NOD/SCID mice, few HNF4α-suppressing hepatic oval cells localized into the liver, while control cells and HNF4α-overexpressing cells engrafted into the liver and differentiated into albumin-positive hepatocytes. Interestingly, the hepatocytes derived from HNF4α-overexpressing cells were less migrative and expressed less c-Myc than the cells derived from control cells. CONCLUSION: HNF4α constrains proliferation, migration, and maltransformation of hepatic progenitors, and HNF4α-overexpressing hepatic progenitors serve as an optimal candidate for cell transplantation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13287-017-0629-8) contains supplementary material, which is available to authorized users. BioMed Central 2017-08-14 /pmc/articles/PMC5557474/ /pubmed/28807057 http://dx.doi.org/10.1186/s13287-017-0629-8 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Wang, Ping Cong, Min Liu, Tianhui Xu, Hufeng Wang, Lin Sun, Guangyong Yang, Aiting Zhang, Dong Huang, Jian Sun, Yameng Zhao, Wenshan Ma, Hong Jia, Jidong You, Hong Inhibitory effects of HNF4α on migration/maltransformation of hepatic progenitors: HNF4α-overexpressing hepatic progenitors for liver repopulation |
title | Inhibitory effects of HNF4α on migration/maltransformation of hepatic progenitors: HNF4α-overexpressing hepatic progenitors for liver repopulation |
title_full | Inhibitory effects of HNF4α on migration/maltransformation of hepatic progenitors: HNF4α-overexpressing hepatic progenitors for liver repopulation |
title_fullStr | Inhibitory effects of HNF4α on migration/maltransformation of hepatic progenitors: HNF4α-overexpressing hepatic progenitors for liver repopulation |
title_full_unstemmed | Inhibitory effects of HNF4α on migration/maltransformation of hepatic progenitors: HNF4α-overexpressing hepatic progenitors for liver repopulation |
title_short | Inhibitory effects of HNF4α on migration/maltransformation of hepatic progenitors: HNF4α-overexpressing hepatic progenitors for liver repopulation |
title_sort | inhibitory effects of hnf4α on migration/maltransformation of hepatic progenitors: hnf4α-overexpressing hepatic progenitors for liver repopulation |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557474/ https://www.ncbi.nlm.nih.gov/pubmed/28807057 http://dx.doi.org/10.1186/s13287-017-0629-8 |
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