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

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: GSE131802 | 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 [Fig4]

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

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

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

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]

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

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