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Cited by 228Pluripotent Stem Cells ResearchLiver physiology and pathologyDevelopmental Biology and Gene Regulation

A Roadmap for Human Liver Differentiation from Pluripotent Stem Cells

Open access
Ang, Lay Teng, Tan, Antson Kiat Yee, Autio, Matias I., Goh, Su Hua, Choo, Siew Hua, Lee, Kian Leong, Tan, Jianmin, Pan, Bangfen +14 more·2018·Cell Reports
DOI 10.1016/j.celrep.2018.01.087PMC PMC5854481
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Abstract

How are closely related lineages, including liver, pancreas, and intestines, diversified from a common endodermal origin? Here, we apply principles learned from developmental biology to rapidly reconstitute liver progenitors from human pluripotent stem cells (hPSCs). Mapping the formation of multiple endodermal lineages revealed how alternate endodermal fates (e.g., pancreas and intestines) are restricted during liver commitment. Human liver fate was encoded by combinations of inductive and repressive extracellular signals at different doses. However, these signaling combinations were temporally re-interpreted: cellular competence to respond to retinoid, WNT, TGF-β, and other signals sharply changed within 24 hr. Consequently, temporally dynamic manipulation of extracellular signals was imperative to suppress the production of unwanted cell fates across six consecutive developmental junctures. This efficiently generated 94.1% ± 7.35% TBX3 + HNF4A + human liver bud progenitors and 81.5% ± 3.2% FAH + hepatocyte-like cells by days 6 and 18 of hPSC differentiation, respectively; the latter improved short-term survival in the Fah −/− Rag2 −/− Il2rg −/− mouse model of liver failure.

AI snapshot

Written from the paper’s full text.

TL;DR

This paper maps human liver differentiation from pluripotent stem cells as six consecutive lineage choices, showing that extracellular signals are temporally re-interpreted within 24 hr to specify liver while suppressing pancreas, intestine, and biliary fates. The resulting protocol rapidly generates liver bud progenitors and hepatocyte-like cells that engraft and improve short-term survival in FRG mice.

Key findings

  • Temporally dynamic manipulation of RA, WNT, TGF-β, BMP, FGF, and PKA signals across six developmental junctures generated 94.1% ± 7.35% TBX3+ HNF4A+ human liver bud progenitors by day 6 and 81.5% ± 3.2% FAH+ hepatocyte-like cells by day 18 of hPSC differentiation.
  • Day-6 liver bud progenitors were identified by a CD99hiCD10−CD184lo/− surface profile, and an FAH-2A-Clover knockin hESC reporter tracked FAH expression in hepatocyte-like cells.
  • Day-18 hPSC-derived hepatocytes secreted ALBUMIN (5.89 ± 0.71 μg/mL) and FIBRINOGEN (1.38 ± 0.26 μg/mL), had CYP3A4 activity 5.9-fold higher than HepG2 cells but 55-fold lower than primary adult human hepatocytes, and stained positive for periodic acid Schiff and ASGR1.
  • In FRG mice, hPSC-derived hepatocytes engrafted in 7 of 15 neonatal mice; in adult intrasplenic transplants, 72.7% survived longer than negative controls, with human ALBUMIN at 120 ± 36 ng/mL versus 2.06 μg/mL for primary human hepatocytes, and reduced serum bilirubin.

Methods

  • hPSCs (H1, H7, H9, ESI035, and others) were differentiated through anterior primitive streak and definitive endoderm, then posterior foregut, liver bud progenitors, and hepatocyte-like cells using sequential extracellular signal manipulations; purity was assessed by flow cytometry and marker expression.
  • The study screened 242 cell-surface antigens across day-0 hPSCs, day-2 definitive endoderm, and day-6 liver bud progenitors; used CRISPR/Cas9 to generate a FAH-2A-Clover reporter; and performed microarray profiling (GEO: GSE98324).
  • In vivo testing used neonatal intrahepatic and adult intrasplenic transplantation into FRG mice with cyclical NTBC withdrawal, with bioluminescence, human ALBUMIN, and bilirubin measurements.

Limitations

  • The paper states that the bipotent capacity of liver bud progenitors to give rise to hepatic or biliary fates remains to be formally demonstrated in vivo by single-cell lineage tracing.
  • The paper states that hPSC-derived hepatocytes are less metabolically functional than primary human hepatocytes, with CYP3A4 activity 55-fold lower and mouse bloodstream human ALBUMIN ~18-fold lower than adult human hepatocytes; the FRG mouse benefit was short-term survival.
  • Evident from the text: in vivo validation is limited to immunodeficient FRG mouse models and short-term outcomes, so long-term maturation, durability, and safety of the hPSC-derived cells are not established.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.celrep.2018.01.087

Cites

88 of 88 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

7 of 19 cited sources checked · 6 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    HNF4A+ liver progenitors were typically formed on later days (by day 10-14) in other differentiation protocols.

    “whereas HNF4A+ liver progenitors were typically formed on later days (by day 10–14) in other differentiation protocols (Carpentier et al., 2016; Hay et al., 2008; Si-Tayeb et al., 2010; Zhao et al., 2013).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Carpentier et al., 2016 source
    • cites Hay et al., 2008 source
    • cites Si-Tayeb et al., 2010 source
  • Interpretationown data

    RA is crucial for human posterior foregut specification.

    “Thus, RA is crucial for human posterior foregut specification, consistent with the role for RA in generating foregut derivatives such as stomach endoderm in vitro (McCracken et al., 2014) and how inhibiting RA synthesis abrogates both liver and pancreas formation in zebrafish embryos (Stafford and Prince, 2002).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites McCracken et al., 2014 source
    • cites Stafford and Prince, 2002 source
  • Interpretationcitation

    These lineage segregations could be efficiently negotiated by providing the relevant inductive signal(s) to drive differentiation toward the desired lineage while repressing the signal(s) that otherwise promoted the alternate fate.

    “With this knowledge, these lineage segregations could be efficiently negotiated by providing the relevant inductive signal(s) to drive differentiation toward the desired lineage while repressing the signal(s) that otherwise promoted the alternate fate (Loh et al., 2014).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Loh et al., 2014 source
  • Interpretationcitation

    The amounts of ALBUMIN and FIBRINOGEN secreted by day-18 hPSC-derived hepatocytes were in the same order of magnitude as the amount secreted by hepatocytes in vivo in human beings.

    “Second, day-18 hPSC-derived hepatocytes secreted ALBUMIN and FIBRINOGEN proteins into the medium (5.89 ± 0.71 μg/mL and 1.38 ± 0.26 μg/mL, respectively [Figures 4G and S4L]) in the same order of magnitude as the amount secreted by hepatocytes in vivo in human beings (Bernardi et al., 2012; Tennent et al., 2007).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Bernardi et al., 2012 source

      The Introduction (page not specified) gives an in-vivo human albumin production rate of 9–12 g per day and says liver cells release albumin into the bloodstream. It gives no fibrinogen secretion rate and does not establish that either in-vivo rate is in the same order of magnitude as the reported day-18 culture-medium concentrations. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Tennent et al., 2007 source
  • Findingown data

    PKA agonists (e.g., 8-bromo-cAMP) potently specified liver bud from foregut.

    “Second, we found that PKA agonists (e.g., 8-bromo-cAMP) also potently specified liver bud from foregut (Figure 2F), supporting the notion that prostaglandin E2 specifies zebrafish liver progenitors by activating the PKA cascade (Nissim et al., 2014).”
    Quote in the paperSubstantial claim
  • May combine two claims. 28
  • Classified as probably not a substantial claim. 1

  • May combine two claims.

    Findingown data

    The PSC-to-liver bud differentiation system was significantly more rapid and yielded higher expression of liver bud markers compared to four extant liver differentiation methods.

    “Finally, this PSC-to-liver bud differentiation system was significantly more rapid and yielded higher expression of liver bud markers, compared to four extant liver differentiation methods (Avior et al., 2015; Carpentier et al., 2016; Chen et al., 2012; Si-Tayeb et al., 2010; Zhao et al., 2013) (Figures 3A–3C and S3C).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Avior et al., 2015 source
    • cites Carpentier et al., 2016 source
    • cites Chen et al., 2012 source

  • May combine two claims.

    Findingown data

    Simultaneous activation of TGF-β, BMP, and PKA-but transient suppression of WNT-drove day-3 posterior foregut into day-6 liver bud progenitors while simultaneously blocking pancreatic and midgut/hindgut differentiation.

    “In summary, we showed that simultaneous activation of TGF-β, BMP, and PKA—but transient suppression of WNT—drove day-3 posterior foregut into day-6 liver bud progenitors while simultaneously blocking pancreatic and midgut/hindgut differentiation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Foregut specification by day 3 was promoted by TGF-β inhibition and activation of the BMP and FGF pathways.

    “Foregut specification by day 3 was also promoted by TGF-β inhibition (Figure 1I) and activation of the BMP (Figure 1J) and FGF pathways (Figures S1D and S1E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    WNT inhibition (using C59) from days 4 to 5 suppressed midgut/hindgut formation and transiently promoted the formation of liver bud progenitors that had the ability to subsequently form hepatocytes.

    “Finally, WNT inhibition (using C59) from days 4 to 5 suppressed midgut/hindgut (MHG; posterior endoderm) formation (Figures S1F and S1G) and, instead, transiently promoted the formation of liver bud progenitors that had the ability to subsequently form hepatocytes (Figures S2B and S2C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    BMP or FGF activation differentiated foregut into liver bud while blocking pancreas formation; BMP or FGF inhibition suppressed liver formation.

    “first, we found that BMP or FGF activation differentiated foregut into liver bud while blocking pancreas formation (Figures 2E, S2D, and S2E); by contrast, BMP or FGF inhibition suppressed liver formation (Figures 2E, S2D, and S2E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TGF-β activation promoted liver bud specification on days 4-6, leading to enhanced liver bud marker expression by day 6.

    “Akin to RA signaling, the role for TGF-β in liver specification was also temporally dynamic: TGF-β inhibition initially promoted foregut formation by day 3 (Figure 1I), but 24 hr later, TGF-β activation promoted liver bud specification on days 4–6, leading to enhanced liver bud marker expression by day 6 (Figure 2D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    RA repressed subsequent progression into liver bud progenitors and promoted formation of ODD1+ stomach endoderm on days 4-6.

    “While RA initially differentiated endoderm into day-3 posterior foregut (discussed earlier), 24 hr later, it repressed subsequent progression into liver bud progenitors and promoted formation of ODD1+ stomach endoderm on days 4–6 (Figure 2C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    At the pancreas-liver branchpoint, application of BMP (among other signals) specified liver bud precursors while inhibiting pancreatic fate, generating 94.1 ± 7.35% TBX3+HNF4A+ human liver bud progenitors by day 6 of hPSC differentiation.

    “For example, at the pancreas-liver branchpoint, application of BMP (among other signals) specified liver bud precursors while inhibiting pancreatic fate, thus generating 94.1 ± 7.35% TBX3+HNF4A+ human liver bud progenitors by day 6 of hPSC differentiation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CD10 was expressed in 92.6 ± 5.6% of undifferentiated hPSCs but was abruptly down-regulated upon differentiation, being expressed in <2% of cells in day-2 definitive endoderm or day-6 liver bud populations.

    “First, CD10 was expressed in 92.6 ± 5.6% of undifferentiated hPSCs but was abruptly down-regulated upon differentiation, being expressed in <2% of cells in day-2 definitive endoderm or day-6 liver bud populations (Figures 3E and S3B; Table S1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    One month post-transplantation of hPSC-derived hepatocyte-like cells, human ALBUMIN+ liver cells were detected in the mouse liver, some of which were localized near the vasculature.

    “1 month post-transplantation of hPSC-derived hepatocyte-like cells, human ALBUMIN+ liver cells were detected in the mouse liver, some of which were localized near the vasculature (Figure 6D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    hPSC-derived hepatocyte-like cells stained positive for periodic acid Schiff (implying glycogen storage) and the liver-specific surface marker ASGR1.

    “Fourth, they stained positive for periodic acid Schiff (implying glycogen storage; Figure S4M) as well as the liver-specific surface marker ASGR1 (Figure S4J).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    Over a brief 24-hr interval, RA activation and TGF-β blockade were necessary to drive definitive endoderm into posterior foregut progenitors, but 24 hr later, they limited further progression of posterior foregut toward a liver bud fate.

    “For instance, over a brief 24-hr interval, RA activation and TGF-β blockade were necessary to drive definitive endoderm into posterior foregut progenitors, but 24 hr later, they limited further progression of posterior foregut toward a liver bud fate.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    hPSC-derived hepatocyte-like cells possessed CYP3A4 enzymatic activity at levels 5.9-fold higher than those of HepG2 cells, although they were still 55-fold lower than in primary adult human hepatocytes.

    “Third, hPSC-derived hepatocyte-like cells possessed CYP3A4 enzymatic activity at levels 5.9-fold higher than those of HepG2 cells, although they were still 55-fold lower than in primary adult human hepatocytes (Figure 4H).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Combining hepatocyte-specifying signals efficiently generated ALBUMIN+ hepatocyte-like cells by day 18 of differentiation, which displayed various hepatocyte functions in vitro.

    “Combining these signals efficiently generated ALBUMIN+ hepatocyte-like cells by day 18 of differentiation, which displayed various hepatocyte functions in vitro.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Activation of NOTCH and TGF-β, together with insulin, upregulated SOX9, differentiating day-6 liver bud progenitors into CK7+/CK19+ biliary progenitors by day 12 of hPSC differentiation while reducing formation of ALBUMIN+ hepatocyte-like cells.

    “Activation of NOTCH and TGF-β, together with insulin, upregulated SOX9, thus differentiating day-6 liver bud progenitors into CK7+/CK19+ biliary progenitors by day 12 of hPSC differentiation (Figures 4B and S4H) (Ogawa et al., 2015; Sampaziotis et al., 2015) while reducing formation of ALBUMIN+ hepatocyte-like cells (Figures 4C and 4D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Treatment with NOTCH inhibitor, AAP, forskolin, or insulin upregulated genes associated with gene ontology classifications pertaining to metabolic processes, indicating these individual manipulations each promote the metabolic competence of hPSC-derived hepatocytes.

    “Microarray profiling showed that treatment with NOTCH inhibitor, AAP, forskolin, or insulin upregulated genes associated with gene ontology classifications pertaining to metabolic processes (Figures 4F and S4I; Table S5), asserting that these individual manipulations each promote the metabolic competence of hPSC-derived hepatocytes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    hPSC-derived hepatocytes engrafted in 7 out of 15 mice and continued to expand in vivo, as shown by an increase in bioluminescence intensity over time.

    “Strikingly, hPSC-derived hepatocytes engrafted in 7 out of 15 mice (Figure 6B) and continued to expand in vivo as shown by an increase in bioluminescence intensity over time (Figures 6B, S6B, and S6E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After ∼10 weeks of liver injury, all surviving mice had detectable bioluminescence, and mice that initially had little/no bioluminescence had died by this time point.

    “After ∼10 weeks of liver injury, all surviving mice had detectable bioluminescence (indicating the presence of transplanted cells); mice that initially had little/no bioluminescence had died by this time point (Figure 6B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Liver bud and midgut/hindgut (intestinal) progenitors are transcriptionally distinct lineages and can be produced in mutually exclusive signaling conditions in vitro from hPSCs.

    “Taken together, though liver bud and midgut/hindgut (intestinal) progenitors are spatially adjacent in vivo, they are transcriptionally distinct lineages and can be produced in mutually exclusive signaling conditions in vitro from hPSCs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    While there is a common requirement for BMP and FGF in liver and midgut/hindgut specification, signals uniquely specify liver, clarifying how these lineages become segregated from one another.

    “Importantly, while there is a common requirement for BMP and FGF in liver and midgut/hindgut specification, we revealed signals that uniquely specify liver, thus clarifying how these lineages become segregated from one another.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Temporally dynamic manipulation of extracellular signals enables the efficient generation of human liver bud progenitors by day 6 of PSC differentiation, which is ∼2 times faster than extant methods.

    “Hence the temporally dynamic manipulation of extracellular signals enables the efficient generation of human liver bud progenitors by day 6 of PSC differentiation, which is ∼2 times faster than extant methods.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The provisional early liver developmental roadmap provides a framework to understand liver commitment at the expense of non-liver fates and may avail the as-yet-unrealized goal of generating fully functional hepatocytes.

    “Taken together, the provisional early liver developmental roadmap (Figure 7) provides a framework to understand liver commitment at the expense of non-liver fates and may avail the as-yet-unrealized goal of generating fully functional hepatocytes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    It is possible to rapidly and efficiently generate hPSC-derived liver bud progenitors and hepatocyte-like cells, the latter of which can engraft in vivo and improve the survival of injured FRG mice.

    “Consequently, it is possible to rapidly and efficiently generate hPSC-derived liver bud progenitors and hepatocyte-like cells, the latter of which can engraft in vivo and improve the survival of injured FRG mice.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    These liver progenitors provide a fertile venue for subsequent liver maturation efforts and, perhaps, the assembly of enhanced 3D liver "organoids".

    “Thus, these liver progenitors provide a fertile venue for subsequent liver maturation efforts and, perhaps, the assembly of enhanced 3D liver “organoids” (Camp et al., 2017; Ogawa et al., 2013; Takebe et al., 2013).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Camp et al., 2017 source
    • cites Ogawa et al., 2013 source
    • cites Takebe et al., 2013 source

  • May combine two claims.

    Interpretationown data

    Mapping the parallel formation of multiple endodermal lineages provides insight into liver commitment and enables the rational suppression of unwanted, non-liver lineages during hPSC differentiation.

    “Here, we demonstrate that mapping the parallel formation of multiple endodermal lineages provides insight into liver commitment and powerfully enables the rational suppression of unwanted, non-liver lineages during hPSC differentiation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The provisional roadmap for human liver development from PSCs delineates a signaling code for liver development significantly extending beyond the use of prolonged BMP and FGF and illuminates several key features.

    “Our provisional roadmap for human liver development from PSCs (Figure 7) delineates a signaling code for liver development significantly extending beyond the use of prolonged BMP and FGF and illuminates several key features.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    We determined the signals that specify liver fate and suppress unwanted, non-liver lineage(s) at each lineage branchpoint, revealing how alternate fate choices are suppressed in stepwise fashion at successive stages of hepatocyte commitment.

    “First, we determined the signals that specify liver fate and suppress unwanted, non-liver lineage(s) at each lineage branchpoint, thus revealing how alternate fate choices are suppressed in stepwise fashion at successive stages of hepatocyte commitment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The CD99hiCD10−CD184lo/− surface marker profile may be used to track the early specification of, and enrich for, hPSC-derived liver bud progenitors.

    “Thus, a CD99hiCD10−CD184lo/− surface marker profile may be used to track the early specification of, and enrich for, hPSC-derived liver bud progenitors (Figure 3F).”
    Quote in the paperSubstantial claim
28 of 28

  • The paper relies on this without support.

    Liver development from pluripotent cells in vivo entails more than three steps.

    “However, current three-step differentiation approaches may not precisely mirror liver development, as liver development from pluripotent cells in vivo likely entails more than three steps.”

  • The paper relies on this without support.

    The FRG mouse model of hereditary tyrosinemia is a valid model for human liver failure and for assessing the therapeutic potential of human hepatocytes.

    “We further tested the ability of day-18 hPSC-derived hepatocytes to ameliorate liver failure in a second mouse model by intrasplenically transplanting them into 4- to 6-week-old adult FRG mice”
    “improved short-term survival in the FRG mouse model of hereditary tyrosinemia”
2 of 2

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • FRG mouse genotype is spelled two different ways

    Minor

    The same FRG mouse model is identified with Ilr2g in the introduction but Il2rg in the abstract.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Ledouarin, 1964, Induction of prehepatic endoderm by mesoderm of the cardiac region in the chick embryo, J. Embryol. Exp. Morphol., 12, 651

Cited by

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Related

Authors
Ang, L. T., Tan, A. K. Y., Autio, M. I., Goh, S. H., Choo, S. H., Lee, K. L., Tan, J., Pan, B., Lee, J. J. H., Lum, J. J., Lim, C. Y. Y., Yeo, I. K. X., Wong, C. J. Y., Liu, M., Oh, J. L. L., Chia, C. P. L., Loh, C. H., Chen, A., Chen, Q., Weissman, I. L., Loh, K. M., & Lim, B.
Affiliations
  • Agency for Science, Technology and Research (SG)
  • Duke-NUS Medical School (SG)
  • Stanford Medicine (US)
Corresponding author
  • Ang, Lay Teng
  • Lim, Bing
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2018-02
Volume
22
Issue
8
Pages
2190-2205
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2018.01.087
PMC
PMC5854481
OpenAlex
W2788541418
Cited by
220
References
88
Citations by year
2026: 15 · 2025: 27 · 2024: 34 · 2023: 19 · 2022: 39 · 2021: 35 · 2020: 30 · 2019: 19 · 2018: 1 · 2017: 1
FWCI
6.67
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion, cc-by-nc-nd)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • National University of Singapore (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DR-NTU (Nanyang Technological University) (submittedVersion, cc-by-nc-nd)
Funders
NIH Office of the Director (DP5OD024558)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
human pluripotent stem cells, liver differentiation, hepatocyte-like cells, extracellular signaling, retinoid signaling, Wnt signaling, TGF-beta signaling, TBX3, HNF4α
MeSH terms
Animals, Animals, Newborn, Biliary Tract, Cell Differentiation, Endoderm, Fibroblast Growth Factors, Humans, Liver, Tretinoin, Signal Transduction, Biomarkers, Cyclic AMP-Dependent Protein Kinases, Bone Morphogenetic Proteins, Hepatocytes, Pluripotent Stem Cells, Gastrointestinal Tract, Mice, High-Throughput Screening Assays, Wnt Signaling Pathway

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