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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE131803 | GEO | 2022/03/04

REPOSITORIES: GEO

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

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 | GSE131805 | GEO

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

2022-03-04 | GSE131802 | GEO

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

Gene expression patterns define the hepatocyte-like cells derived by different strategies [RNA-seq]

Project description:We performed genome-wide gene profiling in hiPSC-Hep and hiHep and compared gene expression patterns in these two types of hepatocyte-like cells.Genes involving in fat digestion and absorption and metabolism enzymes were induced in both hiHeps and hiPSC-Heps. There were also hepatic genes not expressed in either hiPSC-Heps or hiHeps, including cytochrome P450-based metabolism genes and coagulation complements. Interestingly, when genes were clustered based on their hepatic functions, we found that for each hepatic function there were always a few genes not fully induced in either hiPSC-Heps or hiHeps.

2017-11-23 | GSE103075 | GEO

ATP7B Gene Therapy of Autologous Reprogrammed Hepatocytes Alleviates Copper Accumulation in a Murine Model of Wilson’s Disease

Project description:Purpose：Wilson's disease (WD) is a rare hereditary disorder due to ATP7B gene mutation, causing pathologic copper storage mainly in the liver and neurological systems. Hepatocyte transplantation showed therapeutic potential, however, this strategy is often hindered by a shortage of quality donor cells and by allogeneic immune rejection. Here we evaluate the function and efficacy of autologous reprogrammed, ATP7B gene-restored hepatocytes using a murine model of WD Mathods and Results: By reprogramming hepatocytes from ATP7B-/- mice with small molecules, sufficient liver progenitor cells (LPCs) are harvested. After lentivirus-mediated miniATP7B gene transfection and re-differentiation, functional LPC-ATP7B-Heps are developed. RNA-seq data show that compared with LPC-GFP-Heps with enrichment of genes mainly in pathways of oxidative stress and cell apoptosis, in LPC-ATP7B-Heps under high copper stress pathways for copper ion binding and cell proliferation are enriched. LPC-ATP7B-Heps transplantation into ATP7B-/- mice alleviates deposition of excess liver copper with its associated inflammation and fibrosis, comparable to those observed using normal primary hepatocytes at four months after transplantation. Conclusion: We establish the autologous reprogrammed, ATP7B gene restored LPC-ATP7B-Heps and further transplantation demonstrate alleviated copper accumulation in WD mice.

2022-03-05 | GSE197948 | GEO

In vivo hepatic reprogramming of myofibroblasts with AAV vectors as a therapeutic strategy for liver fibrosis

Project description:We developed in vivo reprogramming of myofibroblasts (MFs) into induced hepatocytes (MF-iHeps) using adeno-associated virus serotype 6 (AAV6) vectors expressing hepatic transcription factors in MF fate tracing (Lrat-Cre;R26R-ZsGreen) mice with carbon tetrachloride (CCl4)-induced liver fibrosis. To determine whether MF-iHeps acquire full hepatocyte differentiation, we used microarrays to profile their global gene expression. We isolated MF-iHeps and primary hepatocytes (Heps) from the same mice by laser-capture microdissection (5 and 3 biological replicates, respectively) and hepatic MFs from CCl4-treated littermates isolated by fluorescence-activated cell sorting (3 biological replicates). Total RNA was extracted, transcribed, amplified and biotin labeled. Labeled cDNA targets were hybridized to GeneChip Mouse Gene 1.0 ST arrays (Affymetrix).

2016-05-17 | E-GEOD-81491 | biostudies-arrayexpress

Genome-wide analysis of DNA methylation and gene expression patterns in purified, uncultured human liver cells and activated hepatic stellate cells

Project description:The human liver contains multiple cell types whose epigenetic patterns are undetermined. We examined the promoter methylome of purified and uncultured hepatic stellate cells (HSCs), hepatocytes (HEPs) and liver sinusoidal endothelial cells (LSECs), by methylated DNA immunoprecipitation (MeDIP) and array hybridization. Uncultured HSCs, LSECs and Heps show ~7000-8000 methylated promoters, with 60-70% similarity between all cell types. GO analysis for commonly methylated genes reveals involvement in germ cell development, segregating germ-line from somatic lineage methylation. HSCs, LSECs and HEPs also contain ~500-1000 uniquely methylated promoters; these are implicated in signaling and biosynthetic processes (HSCs), lipid transport and metabolism (LSECs), and chromatin assembly (HEPs). The promoter methylome of culture-activated HSCs deviates from that of their uncultured (quiescent) counterparts. HSC culture-induced activation also enhances methylation differences between individual donors; however this does not necessarily relate to changes in gene expression. HSc activation results in a net gain of promoter DNA methylation, despite the demethylation and de novo methylation of thousands of promoters. Our data provide to our knowledge the first genome-wide maps of promoter DNA methylation in human purified and uncultured liver cell types. Although methylation profiles are largely similar between HSCs, LSECs and hepatocytes, the detection of cell type-specific methylation patterns suggests a differential epigenetic programming of these cell types in the liver. Determine the promoter DNA methylation pattern of 3 uncultured, reshly isolated, human healthy liver cell types (hepatocytes (HEPs), liver sinusoidal endothelial cells (LSECs) and haptic stellate cells (HSCs), and of HSCs after a 24-h culture-induced activation.

2015-12-21 | E-GEOD-66796 | biostudies-arrayexpress

Single-cell RNA sequencing of human liver development and hiPSC models

Project description:scRNA-seq of primary human adult liver, primary human fetal liver (5 post conceptional weeks), EPCAM+ MACS sorted primary human intrahepatic duct cholangiocytes, sequential timepoints of hiPSC-derived hepatocyte-like cells (HLC), sequential timepoints of hiPSC-derived cholangiocyte-like cells (CLC), sequential timepoints of hiPSC-derived hepatic stellate-like cells (HSLC), sequential timepoints of hiPSC-derived endothelial-like cells (ELC), sequential timepoints of hiPSC-derived macrophage-like cells (MLC) and lentiviral transduced hiPSC-derived hepatocyte-like cells.

2022-05-04 | E-MTAB-8210 | biostudies-arrayexpress

Direct reprogramming of human fibroblasts to functional hepatocyte-like cells

Project description:Plasticity of differentiated cells has been proved by nuclear transfer, induced pluripotent cells and transdifferentiation. Here we show that by transduction of 3 factors (FOXA3, HNF1A and HNF4A), human fetal fibroblasts can be converted to hepatocyte-like cells (hiHep cells), expressing hepatic marker genes, and acquiring many mature hepatocyte functions in vitro and in vivo. Human fetal fibroblasts (HFF) were tranfected with 3 liver enriched transcription factors (FOXA3, HNF1A, HNF4A), and converted to hepatocyte-like cells (hiHep cells). HFF and primary human hepatocytes (PHH) serve as control.

2014-03-06 | E-GEOD-42643 | biostudies-arrayexpress

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