Distinct gene expression and epigenetic signatures in hepatocyte-like cells produced by different strategies from the same donor
Open accessAbstract
Hepatocyte-like cells (HLCs) can be generated through directed differentiation or transdifferentiation. Employing two strategies, we generated induced pluripotent stem cell (iPSC)-HLCs and hiHeps from the same donor cell line. Both types of HLCs clustered distinctly from each other during gene expression profiling. In particular, differences existed in gene expression for phase II drug metabolism and lipid accumulation, underpinned by H3K27 acetylation status in iPSC-HLCs and hiHeps. While distinct phenotypes were achieved in vitro, both types of HLCs demonstrated similar phenotypes following transplantation into Fah-deficient mice. In conclusion, functional HLCs can be obtained from the same donor using two strategies. Global gene expression defined the differences between those populations in vitro. Importantly, both HLCs displayed partial but markedly improved hepatic function following transplantation in vivo, demonstrating plasticity and the potential for cell-based modeling in the dish and cell-based therapy in the future.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Human HLCs showed limited engraftment capability in mouse livers.
“Nevertheless, human HLCs showed limited engraftment capability in mouse livers (Gao et al., 2017; Ji et al., 2013”
From In Vitro Expansion of Primary Human Hepatocytes with Efficient Liver Repopulation Capacity (2018) · cites this paper as Gao et al., 2017
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Vascularized and functional human liver from an iPSC-derived organ bud transplant
Takebe, T., Sekine, K., Enomura, M., Koike, H., Kimura, M., Ogaeri, T., Zhang, R.-R., Ueno, Y., Zheng, Y.-W., Koike, N., et al. (2013) · Nature · doi:10.1038/nature12271 · Cited by 2,170 · see citing works
Generation of Functional Human Hepatic Endoderm From Human Induced Pluripotent Stem Cells
Sullivan, G. J., Hay, D. C., Park, I.-H., Fletcher, J., Hannoun, Z., Payne, C. M., Dalgetty, D., Black, J. R., Ross, J. A., Samuel, K., et al. (2010) · Hepatology · doi:10.1002/hep.23335 · Cited by 445 · see citing works
Self-citationAssessing the therapeutic potential of lab-made hepatocytes
Rezvani, M., Grimm, A. A., & Willenbring, H. (2016) · Hepatology · doi:10.1002/hep.28569 · Cited by 54 · see citing works
Flagged first, then by citations
Research works printed but not linked: 34
- Azuma H. Paulk N. Ranade A. Dorrell C. Al-Dhalimy M. Ellis E. Strom S. Kay M.A. Finegold M. Grompe M. Robust expansion of human hepatocytes in Fah-/-/Rag2-/-/Il2rg-/- mice Nat. Biotechnol. 25 2007 903 910 17664939 PMC3404624
- Bhatia S.N. Underhill G.H. Zaret K.S. Fox I.J. Cell and tissue engineering for liver disease Sci. Transl. Med. 6 2014 245sr2 25031271 PMC4374645
- Bonn S. Zinzen R.P. Girardot C. Gustafson E.H. Perez-Gonzalez A. Delhomme N. Ghavi-Helm Y. Wilczynski B. Riddell A. Furlong E.E. Tissue-specific analysis of chromatin state identifies temporal signatures of enhancer activity during embryonic development Nat. Genet. 44 2012 148 156 22231485
- Buganim Y. Itskovich E. Hu Y.C. Cheng A.W. Ganz K. Sarkar S. Fu D.D. Welstead G.G. Page D.C. Jaenisch R. Direct reprogramming of fibroblasts into embryonic Sertoli-like cells by defined factors Cell Stem Cell 11 2012 373 386 22958931 PMC3438668
- Cameron K. Tan R. Schmidt-Heck W. Campos G. Lyall M.J. Wang Y. Lucendo-Villarin B. Szkolnicka D. Bates N. Kimber S.J. Recombinant laminins drive the differentiation and self-organization of hESC-derived hepatocytes Stem Cell Reports 5 2015 1250 1262 26626180 PMC4682209
- Carpentier A. Tesfaye A. Chu V. Nimgaonkar I. Zhang F. Lee S.B. Thorgeirsson S.S. Feinstone S.M. Liang T.J. Engrafted human stem cell-derived hepatocytes establish an infectious HCV murine model J. Clin. Invest. 124 2014 4953 4964 25295540 PMC4347235
- Cheng X. Ying L. Lu L. Galvao A.M. Mills J.A. Lin H.C. Kotton D.N. Shen S.S. Nostro M.C. Choi J.K. Self-renewing endodermal progenitor lines generated from human pluripotent stem cells Cell Stem Cell 10 2012 371 384 22482503 PMC3580854
- Creyghton M.P. Cheng A.W. Welstead G.G. Kooistra T. Carey B.W. Steine E.J. Hanna J. Lodato M.A. Frampton G.M. Sharp P.A. Histone H3K27ac separates active from poised enhancers and predicts developmental state Proc. Natl. Acad. Sci. USA 107 2010 21931 21936 21106759 PMC3003124
- Du Y. Wang J. Jia J. Song N. Xiang C. Xu J. Hou Z. Su X. Liu B. Jiang T. Human hepatocytes with drug metabolic function induced from fibroblasts by lineage reprogramming Cell Stem Cell 14 2014 394 403 24582926
- Fisher R.A. Strom S.C. Human hepatocyte transplantation: worldwide results Transplantation 82 2006 441 449 16926585
- Forbes S.J. Gupta S. Dhawan A. Cell therapy for liver disease: from liver transplantation to cell factory J. Hepatol. 62 2015 S157 S169 25920085
- Forster R. Chiba K. Schaeffer L. Regalado S.G. Lai C.S. Gao Q. Kiani S. Farin H.F. Clevers H. Cost G.J. Human intestinal tissue with adult stem cell properties derived from pluripotent stem cells Stem Cell Reports 2 2014 838 852 24936470 PMC4050346
- Fox I.J. Daley G.Q. Goldman S.A. Huard J. Kamp T.J. Trucco M. Stem cell therapy. Use of differentiated pluripotent stem cells as replacement therapy for treating disease Science 345 2014 1247391 25146295 PMC4329726
- Gerbal-Chaloin S. Funakoshi N. Caillaud A. Gondeau C. Champon B. Si-Tayeb K. Human induced pluripotent stem cells in hepatology: beyond the proof of concept Am. J. Pathol. 184 2014 332 347 24269594
- Godoy P. Schmidt-Heck W. Natarajan K. Lucendo-Villarin B. Szkolnicka D. Asplund A. Bjorquist P. Widera A. Stober R. Campos G. Gene networks and transcription factor motifs defining the differentiation of stem cells into hepatocyte-like cells J. Hepatol. 63 2015 934 942 26022688 PMC4580233
- Grompe M. Strom S. Mice with human livers Gastroenterology 145 2013 1209 1214 24042096
- Hay D.C. Fletcher J. Payne C. Terrace J.D. Gallagher R.C. Snoeys J. Black J.R. Wojtacha D. Samuel K. Hannoun Z. Highly efficient differentiation of hESCs to functional hepatic endoderm requires ActivinA and Wnt3a signaling Proc. Natl. Acad. Sci. USA 105 2008 12301 12306 18719101 PMC2518825
- Holmberg J. Perlmann T. Maintaining differentiated cellular identity Nat. Rev. Genet. 13 2012 429 439 22596319
- Huang P. Zhang L. Gao Y. He Z. Yao D. Wu Z. Cen J. Chen X. Liu C. Hu Y. Direct reprogramming of human fibroblasts to functional and expandable hepatocytes Cell Stem Cell 14 2014 370 384 24582927
- Kajiwara M. Aoi T. Okita K. Takahashi R. Inoue H. Takayama N. Endo H. Eto K. Toguchida J. Uemoto S. Donor-dependent variations in hepatic differentiation from human-induced pluripotent stem cells Proc. Natl. Acad. Sci. USA 109 2012 12538 12543 22802639 PMC3411998
- Lim K.T. Lee S.C. Gao Y. Kim K.P. Song G. An S.Y. Adachi K. Jang Y.J. Kim J. Oh K.J. Small molecules facilitate single factor-mediated hepatic reprogramming Cell Rep. 15 2016 814 829 27149847
- Loh K.M. Ang L.T. Zhang J. Kumar V. Ang J. Auyeong J.Q. Lee K.L. Choo S.H. Lim C.Y. Nichane M. Efficient endoderm induction from human pluripotent stem cells by logically directing signals controlling lineage bifurcations Cell Stem Cell 14 2014 237 252 24412311 PMC4045507
- Ma H. Morey R. O'Neil R.C. He Y. Daughtry B. Schultz M.D. Hariharan M. Nery J.R. Castanon R. Sabatini K. Abnormalities in human pluripotent cells due to reprogramming mechanisms Nature 511 2014 177 183 25008523 PMC4898064
- Morris S.A. Cahan P. Li H. Zhao A.M. San Roman A.K. Shivdasani R.A. Collins J.J. Daley G.Q. Dissecting engineered cell types and enhancing cell fate conversion via CellNet Cell 158 2014 889 902 25126792 PMC4291075
- Nicolas C.T. Hickey R.D. Chen H.S. Mao S.A. Lopera Higuita M. Wang Y. Nyberg S.L. Concise review: liver regenerative medicine: from hepatocyte transplantation to bioartificial livers and bioengineered grafts Stem Cells 35 2017 42 50 27641427 PMC5529050
- Rashidi H. Alhaque S. Szkolnicka D. Flint O. Hay D.C. Fluid shear stress modulation of hepatocyte-like cell function Arch. Toxicol. 90 2016 1757 1761 26979076 PMC4894932
- Shi X.L. Gao Y. Yan Y. Ma H. Sun L. Huang P. Ni X. Zhang L. Zhao X. Ren H. Improved survival of porcine acute liver failure by a bioartificial liver device implanted with induced human functional hepatocytes Cell Res. 26 2016 206 216 26768767 PMC4746613
- Si-Tayeb K. Noto F.K. Nagaoka M. Li J. Battle M.A. Duris C. North P.E. Dalton S. Duncan S.A. Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells Hepatology 51 2010 297 305 19998274 PMC2946078
- Szkolnicka D. Farnworth S.L. Lucendo-Villarin B. Hay D.C. Deriving functional hepatocytes from pluripotent stem cells Curr. Protoc. Stem Cell Biol. 30 2014 1G.5.1–1G.5.12 25081564
- Szkolnicka D. Hay D.C. Concise review: advances in generating hepatocytes from pluripotent stem cells for translational medicine Stem Cells 34 2016 1421 1426 27015786 PMC4982058
- Takahashi K. Tanabe K. Ohnuki M. Narita M. Ichisaka T. Tomoda K. Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors Cell 131 2007 861 872 18035408
- Touboul T. Hannan N.R. Corbineau S. Martinez A. Martinet C. Branchereau S. Mainot S. Strick-Marchand H. Pedersen R. Di Santo J. Generation of functional hepatocytes from human embryonic stem cells under chemically defined conditions that recapitulate liver development Hepatology 51 2010 1754 1765 20301097
- Yang J. Wang Y. Zhou T. Wong L.Y. Tian X.Y. Hong X. Lai W.H. Au K.W. Wei R. Liu Y. Generation of human liver chimeric mice with hepatocytes from familial hypercholesterolemia induced pluripotent stem cells Stem Cell Reports 8 2017 605 618 28262545 PMC5355732
- Yu B. He Z.Y. You P. Han Q.W. Xiang D. Chen F. Wang M.J. Liu C.C. Lin X.W. Borjigin U. Reprogramming fibroblasts into bipotential hepatic stem cells by defined factors Cell Stem Cell 13 2013 328 340 23871605
Cited by
Sorted by citations
In Vitro Expansion of Primary Human Hepatocytes with Efficient Liver Repopulation Capacity
Zhang, K., Zhang, L., Liu, W., Ma, X., Cen, J., Sun, Z., Wang, C., Feng, S., Zhang, Z., Yue, L., et al. (2018) · Cell Stem Cell · doi:10.1016/j.stem.2018.10.018 · Cited by 252 · see citing works
Self-citationWang, Y., Zheng, Q., Sun, Z., Wang, C., Cen, J., Zhang, X., Jin, Y., Wu, B., Yan, T., Wang, Z., et al. (2023) · Cell Stem Cell · doi:10.1016/j.stem.2023.03.013 · Cited by 55 · see citing works
Self-citation
- Authors
- Gao, Y., Zhang, X., Zhang, L., Cen, J., Ni, X., Liao, X., Yang, C., Li, Y., Chen, X., Zhang, Z., Shu, Y., Cheng, X., Hay, D. C., Lai, D., Pan, G., Wei, G., & Hui, L.
- Affiliations
- Chinese Academy of Sciences (CN)
- Shanghai Institutes for Biological Sciences (CN)
- East China University of Science and Technology (CN)
- MRC Centre for Regenerative Medicine (GB)
- Shanghai Jiao Tong University (CN)
- Corresponding author
- Wei, Gang
- Hui, Lijian
- ORCID
- Venue
- Stem Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-12
- Volume
- 9
- Issue
- 6
- Pages
- 1813-1824
- ISSN
- 2213-6711 (ISSN-L)
- PMC
- PMC5785700
- OpenAlex
- W2769935541
- Cited by
- 50
- References
- 3
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 7 · 2023: 5 · 2022: 8 · 2021: 4 · 2020: 5 · 2019: 9 · 2018: 5
- FWCI
- 2.12
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Stem Cell Reports (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by-nc-nd)
- Funders
- CAS- CSIRO (153D31KYSB20160247)
- CAS-NWO Programme (153D31KYSB20150085)
- National Natural Science Foundation of China (31630044, 31601186, 81471948, 31771431, 31271354, 31401263)
- Ministry of Science and Technology of China (2013CB967103)
- Science and Technology Commission of Shanghai Municipality (16JC1400202, 15JC1400200)
- Shanghai Zhangjiang National Independent Innovation Demonstration (ZJ2014-ZD-002)
- UK Regenerative Medicine (MR/L022974/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- hepatocyte-like cells, iPSC-derived hepatocytes, directed differentiation, transdifferentiation, gene expression profiling, epigenetic signatures, H3K27 acetylation, phase II metabolism, lipid accumulation, cell transplantation, liver function, cell therapy
- MeSH terms
- Animals, Cell Differentiation, Cell Line, Humans, Tissue Donors, Gene Expression Regulation, Developmental, Hepatocytes, Epigenesis, Genetic, Mice, Induced Pluripotent Stem Cells, Cell- and Tissue-Based Therapy
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
