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Chemical–induced generation of adult-like human hepatocytes from pluripotent stem cells

ABSTRACT: Hepatocytes differentiated from human pluripotent stem cells (hPSCs) may provide a truly unlimited cell source to model and treat liver diseases. However, immaturity of hPSC-derived hepatocytes significantly limited their applications. Here we devised a step-wise pharmacological approach to induce adult-like hPSC-differentiated hepatocytes (a-Hep), which closely resemble primary human hepatocytes (PHHs) in terms of morphology, polarity, transcriptome, epigenome, and capacity to execute hepatic specific-functions. Importantly, a-Heps upon transplantation enabled unprecedented engraftment efficiency in liver parenchyma with comparably rapid dynamics as PHHs. Mechanically, inhibition of ERK pathway was indispensable for the generation of middle-stage hPSC-differentiated hepatocyte (mid-Hep), an essential step to obtain further mature a-Heps, by upregulating metabolic functions and repressing cell growth. In summary, our studies paved a promising avenue for clinical application of hPSC-derived hepatocytes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE221769 | GEO | 2025/12/31

REPOSITORIES: GEO

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			Action	DRS
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	GSE221769_6Cminus1C_counts.txt.gz	Txt
	GSE221769_fma_AND_timecourse_counts.txt.gz	Txt
	GSE221769_fma_AND_timecourse_samp_annot.txt.gz	Txt

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Small molecule-induced adult-like human hepatocytes from pluripotent stem cells (ATAC-Seq)

Project description:Hepatocytes differentiated from human pluripotent stem cells (hPSCs) may provide a truly unlimited cell source to model and treat liver diseases. However, immaturity of hPSC-derived hepatocytes significantly limited their applications. Here we devised a step-wise pharmacological approach to induce adult-like hepatocytes (a-Heps) from hPSCs, which closely resemble primary human hepatocytes (PHHs) in terms of morphology, polarity, transcriptome, epigenome, and capacity to execute hepatic specific-functions. Importantly, a-Heps upon transplantation generated unprecedented engraftment in liver parenchyma with comparably high efficiency and rapid dynamics as PHHs. Mechanically, inhibition of ERK pathway was indispensable for the generation of middle-stage hepatocytes (mid-Heps), an essential step to obtain further mature a-Heps, by upregulating metabolic functions and repressing cell growth. In summary, our studies paved a promising avenue for the clinical applications of hPSC-derived hepatocytes.

2025-12-31 | GSE221768 | GEO

Gene expression profiles in human liver organoid-derived hepatocytes

Project description:Human liver organoids are expected to be a hepatocyte source for preclinical in vitro studies. Although these organoids show long-term proliferation, their hepatic functions remain low. Here, we propose a novel method for two dimensional (2D)-cultured hepatic differentiation from human liver organoids. When cultured under a 2D condition, the single cells from human liver organoids were seeded on collagen type I-coated plates. Then, optimal conditions for hepatic differentiation were screened using several reagents. We determined the 2D-cultured hepatocyte differentiation method from human liver organoids. Hepatic gene expressions in human liver organoids-derived hepatocytes (Org-HEPs) were greatly increased, compared to those in human liver organoids. The metabolic activities of cytochrome P450 (CYP) 1A2, CYP2C8, CYP2E1 and CYP3A4 were at levels comparable to those in primary human hepatocytes (PHHs). These results suggested that human liver organoids could be differentiated into highly functional hepatocytes in 2D culture. We also treated Org-HEPs and PHHs with hepatotoxic drugs. The cell viability of Org-HEPs was almost the same as that of PHHs, suggesting that Org-HEPs could be used for hepatotoxicity tests. Thus, Org-HEPs will be useful for pharmaceutical research.

2024-08-29 | GSE234459 | GEO

Generation of functional hepatocytes from extended pluripotent stem cells

Project description:We established efficiently differentiation protocol of human extented pluripotent stem (EPS) cells to functional hepatocytes (EPS-Heps) by simply adding a pre-treatment step before applying the directed differentiation protocol for conventional human pluripotent stem cells. Importantly, compared to hepatocytes derived from conventional human pluripotent stem cells, EPS-Heps transcriptionally more resemble primary human hepatocytes.

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Gene expression data of hepatocytes derived from human fibroblasts, human iPSCs, and human adult hepatocytes

Project description:Generation of human fibroblast-derived hepatocytes capable of extensive proliferation, as evidenced by significant liver repopulation of mice. Unlike current protocols for deriving hepatocytes from human fibroblasts, ours did not generate iPSCs, but shortcut reprogramming to pluripotency to generate an induced multipotent progenitor cell (iMPC) stage from which endoderm progenitor cells (iMPC-EPCs) and subsequently hepatocytes (iMPC-Heps) could be efficiently differentiated. After transplantation into an immune-deficient mouse model of human liver failure, iMPC-Heps were able to engraft and proliferate, and acquired levels of hepatocyte function similar to adult hepatocytes. Microarray analysis has been used to show: 1. post-transplant maturation in vivo of iMPC-Heps compared to aHeps, 2. differences between iMPC-Heps and freshly isolated aHeps in vitro, 3. similar profile of freshly isolated aHeps to aHeps and iMPC-Heps in vivo, and 4. similarities of expression levels of most, but not all, genes between iMPC-Heps and iPSC-Heps in vitro. We isolated repopulating nodules of iMPC-Heps and aHeps by laser-capture microscopy (LCM) around 9 months after transplantation and analyzed their gene expression on the microarray, together with RNA from in vitro samples.

2014-01-22 | E-GEOD-52309 | biostudies-arrayexpress

Gene expression data of hepatocytes derived from human fibroblasts, human iPSCs, and human adult hepatocytes

2014-01-22 | GSE52309 | GEO

Histone Hypoacetylation Impairs the Plasticity of Human Hepatocytes with Aging [Fig1, FigS1 and Fig3]

Project description:Although aging associated decline of liver regeneration was discovered half a century ago, how aging contributes to the decline of liver regenerative capacity and how to improve this capacity in the elderly is still unknown. Hepatocyte plasticity is known to play a central role in the maintenance of liver regeneration; hence, we describe a strategy to explore the mechanisms underlying the relation between aging and hepatocyte plasticity: experiments with human induced-pluripotent-stem-cell–derived hepatocytes (hiPSC-Heps). Here, we established a simple and convenient method for generation of hiPSC-Heps that can maintain hepatic function for a long time with gradual accumulation of aging related markers and characteristics. We found that in contrast to rodent hepatocytes, FGF2 is essential for the plasticity of human hepatocytes, and the FGF2-activated MAPK–EZH2 axis can help to reprogram hiPSC-Heps into proliferative hepatic cells with a bipotential differentiation ability. Notably, our results showed the plasticity of hiPSC-Heps decreases with aging and this phenomenon strongly correlates with histone acetylation. Moreover, we found that selective inhibition of histone deacetylases can markedly improve the plasticity of old hiPSC-Heps and primary human hepatocytes and surprisingly increases the repopulation capacity of old PHHs in a liver injury model. Therefore, we can conclude that aging-associated histone hypoacetylation impairs hepatocyte plasticity.

2022-03-04 | GSE131802 | GEO

Histone Hypoacetylation Impairs the Plasticity of Human Hepatocytes with Aging [FigS3]

2022-03-04 | GSE131805 | GEO

Histone Hypoacetylation Impairs the Plasticity of Human Hepatocytes with Aging [Fig4]

2022-03-04 | GSE131803 | GEO

Transplantation-induced reprogramming determines successful hepatocyte engraftment

Project description:While demonstrated safety and efficacy in treating liver diseases, hepatocyte-based therapy faces the challenge of limited engraftment of transplanted hepatocytes (Tx-Heps) in clinical settings, akin to issues encountered in cell therapy for other solid organs. Here, we identified a conserved reprogramming state of Tx-Heps during engraftment, marked by the activation of liver progenitor genes and bipotential differentiation capacity. Transplantation reprogramming of Tx-Heps is crucial for successful engraftment, as proven by transplantation failure upon hepatocyte-specific ablation of Arid1a, which is required for Tx-Hep reprogramming. To validate translational potential, we artificially induced Tx-Hep reprogramming by in vivo treatment of either IL6 or IC7, a chimeric IL6 family protein, both of which significantly enhance hepatocyte engraftment. Our findings unveil early-stage cell fate reprogramming during transplantation and also propose a promising strategy to augment hepatocyte engraftment, which is an interesting framework to be studied in cell transplantation for other solid organs.

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Project description:Cell fate can be directly converted between differentiated cells by lineage reprogramming, thus generating multiple cell types across developmental lineages. However, lineage reprogramming is hindered by incomplete cell-fate conversion with residual initial cell identity and partial functions compared with the native counterparts. Here, we develop a high-fidelity reprogramming strategy, by mimicking the natural cell-fate changing route, thus permitting the production of functionally competent human hepatocytes from another cell type. We first converted fibroblasts into plastic hepatic progenitor-like cells (hHPLCs) and chemically induced them into mature hepatocytes. The molecular identity of human induced hepatocytes (hiHeps) are suggested a terminally differentiated state, resembling primary human hepatocytes (PHHs). Functionally, hiHeps were competent to replace PHHs for equivalent drug-metabolizing activities, toxicity prediction and hepatitis B virus infection. Remarkably, the stably robust expansion of hHPLCs allowed large-scale generation of mature hepatocytes. Our results demonstrate the necessity of taking a reprogramming step for plastic progenitors for efficient cell-fate conversion. This strategy is promising for the generation of other mature human cell types.

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