Generation of human hepatic progenitor cells with regenerative and metabolic capacities from primary hepatocytes
- National Cancer Center Research Institute, Japan
- Nihon Pharmaceutical University, Japan
- Kobe Pharmaceutical University, Japan
- Keio University, Japan
Abstract
Hepatocytes are regarded as the only effective cell source for cell transplantation to treat liver diseases; however, their availability is limited due to a donor shortage. Thus, a novel cell source must be developed. We recently reported that mature rodent hepatocytes can be reprogrammed into progenitor-like cells with a repopulative capacity using small molecule inhibitors. Here, we demonstrate that hepatic progenitor cells can be obtained from human infant hepatocytes using the same strategy. These cells, named human chemically induced liver progenitors (hCLiPs), had a significant repopulative capacity in injured mouse livers following transplantation. hCLiPs redifferentiated into mature hepatocytes in vitro upon treatment with hepatic maturation-inducing factors. These redifferentiated cells exhibited cytochrome P450 (CYP) enzymatic activities in response to CYP-inducing molecules and these activities were comparable with those in primary human hepatocytes. These findings will facilitate liver cell transplantation therapy and drug discovery studies.
Data availability
Microarray transcriptome data are available with accession numbers GSE133776 (Reprogramming of primary human hepatocytes (PHHs) into hCLiPs); GSE133777 (Hepatic induction of hCLiPs); GSE133778(Characterization of long term-cultured of hCLiPs); GSE133779 (Transcriptomic analysis of PHHs isolated from hCLiP-transplanted mouse chimeric liver). GSE133776-GSE133779 are included in Superseries GSE133797. Comparative analysis of IPHH and APHH transcriptome is available with an accession number GSE134672.
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Reprogramming of primary human hepatocytes (PHHs) into hCLiPsNCBI Gene Expression Omnibus, GSE133776.
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Hepatic induction of hCLiPsNCBI Gene Expression Omnibus, GSE133777.
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Characterization of long term-cultured of hCLiPsNCBI Gene Expression Omnibus, GSE133778.
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Transcriptomic analysis of PHHs isolated from hCLiP-transplanted mouse chimeric liverNCBI Gene Expression Omnibus, GSE133779.
Article and author information
Author details
Funding
Japan Agency for Medical Research and Development (16fk0310512h0005)
- Takahiro Ochiya
Japan Agency for Medical Research and Development (17fk0310101h0001)
- Takahiro Ochiya
Japan Society for the Promotion of Science London (16K16643)
- Takeshi Katsuda
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Hao Zhu, University of Texas Southwestern Medical Center, United States
Ethics
Animal experimentation: Animal experiments in this study were performed in compliance with the guidelines of the Institute for Laboratory Animal Research, National Cancer Center Research Institute. The protocol was approved by the Committee on the Ethics of Animal Experiments of National Cancer Center Research Institute (Permit Number: T14-015-E). All surgery was performed under isoflurane anesthesia, and every effort was made to minimize suffering.
Version history
- Received: April 1, 2019
- Accepted: August 8, 2019
- Accepted Manuscript published: August 8, 2019 (version 1)
- Version of Record published: September 6, 2019 (version 2)
- Version of Record updated: August 1, 2022 (version 3)
Copyright
© 2019, Katsuda et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Generation of human hepatic progenitor cells with regenerative and metabolic capacities from primary hepatocytes
eLife 8:e47313.
https://doi.org/10.7554/eLife.47313
Further reading
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Alternative RNA splicing is an essential and dynamic process in neuronal differentiation and synapse maturation, and dysregulation of this process has been associated with neurodegenerative diseases. Recent studies have revealed the importance of RNA-binding proteins in the regulation of neuronal splicing programs. However, the molecular mechanisms involved in the control of these splicing regulators are still unclear. Here, we show that KIS, a kinase upregulated in the developmental brain, imposes a genome-wide alteration in exon usage during neuronal differentiation in mice. KIS contains a protein-recognition domain common to spliceosomal components and phosphorylates PTBP2, counteracting the role of this splicing factor in exon exclusion. At the molecular level, phosphorylation of unstructured domains within PTBP2 causes its dissociation from two co-regulators, Matrin3 and hnRNPM, and hinders the RNA-binding capability of the complex. Furthermore, KIS and PTBP2 display strong and opposing functional interactions in synaptic spine emergence and maturation. Taken together, our data uncover a post-translational control of splicing regulators that link transcriptional and alternative exon usage programs in neuronal development.
