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A single-nucleus transcriptomic atlas of primate liver aging uncovers the pro-senescence role of SREBP2 in hepatocytes

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Protein & Cell 2024年第2期15卷 98-120页

作者： Shanshan Yang Chengyu Liu Mengmeng Jiang Xiaoqian Liu Lingling Geng Yiyuan Zhang Shuhui Sun Kang Wang jian Yin Shuai Ma Si Wang Juan Carlos Izpisua Belmonte Weiqi Zhang Jing Qu Guang-Hui Liu Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders Xuanwu Hospital Capital Medical UniversityBeijing 100053China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Aging Translational Medicine Center International Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of Sciences and China National Center for BioinformationBeijing 100101China Xuanwu Hospital Capital Medical University Beijing 100053China University of Chinese Academy of Sciences Beijing 100049China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China Aging Biomarker Consortium Beijing 100101China Altos Labs Inc.San DiegoCA 94022USA

Aging increases the risk ofliver diseases and systemic susceptibility to aging-related diseases.However,cell type-specific changes and the underlying mechanism of liver aging in higher vertebrates remain incompletely characterized.Here,we constructed the first single-nucleus transcriptomic landscape of primate liver aging,in which we resolved cell type-specific gene expression fluctuation in hepatocytes across three liver zonations and detected aberrant cell-cell interactions between hepatocytes and niche cells.Upon in-depth dissection of this rich dataset,we identifed impaired lipid metabolism and upregulation of chronic inflammation-related genes prominently associated with declined liver functions during aging.In particular,hyperactivated sterol regulatory element-binding protein(SREBP)signaling was a hallmark of the aged liver,and consequently,forced activation of SREBP2 in human primary hepatocytes recapitulated in vivo aging phenotypes,manifesting as impaired detoxification and accelerated cellular senescence.This study expands our knowledge of primate liver aging and informs the development of diagnostics and therapeutic interventions for liver aging and associated diseases.

关键词： single-nucleus RNA sequencing liver hepatocytes aging senescence SREBP2

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Long-term functional maintenance of primary hepatocytes in vitro using macroporous hydrogels engineered through liquid-liquid phase separation

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Nano Research 2024年第3期17卷 1725-1736页

作者： Yang Sun Sheng Yin Jian Cui Zhongxia Wang Yueying Han Ding Ma Shuo Wang Junhua Wu Yi Cao Chunping Jiang Xiaosong Gu Jinan Microecological Biomedicine Shandong Laboratory Jinan 250021China Collaborative Innovation Center of Advanced Microstructures National Laboratory of Solid State MicrostructureKey Laboratory of Intelligent Optical Sensing and ManipulationMinistry of EducationDepartment of PhysicsNanjing UniversityNanjing 210093China Department of Hepatobiliary Surgery The Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjing 210093China National Institute of Healthcare Data Science at Nanjing University Nanjing UniversityNanjing 210093China

Preserving the functionality of hepatocytes in vitro poses a significant challenge in liver tissue engineering and bioartificial liver,as these cells rapidly lose their metabolic and functional characteristics after isolation.Inspired by the macroporous structures found in native liver tissues,here we develop synthetic hydrogel scaffolds that closely mimic the liver’s structural organization through the phase separation between polyethylene glycol(PEG)and polysaccharides.Our hydrogels exhibit interconnected macroporous structures and appropriate mechanical properties,providing an optimal microenvironment conducive to hepatocyte adhesion and the formation of sizable aggregates.Compared to two-dimensional hepatocyte cultures,enhanced functionalities of hepatocytes cultured in our macroporous hydrogels were observed for 14 days,as evidenced by quantitative reverse-transcription–polymerase chain reactions(qRT-PCR),immunofluorescence,and enzyme linked immunosorbent assay(ELISA)analyses.Protein sequencing data further confirmed the establishment of cell–cell interactions among hepatocytes when cultured in our hydrogels.Notably,these hepatocytes maintained a protein expression lineage that closely resembled freshly isolated hepatocytes,particularly in the Notch and tumor necrosis factor(TNF)signaling pathways.These results suggest that the macroporous hydrogels are attractive scaffolds for liver tissue engineering.

关键词： liver tissue engineering phase separation hepatocytes macroporous hydrogel

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Phosphatidic acid-enabled MKL1 contributes to liver regeneration:Translational implication in liver failure

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Acta Pharmaceutica Sinica B 2024年第1期14卷 256-272页

作者： Jiawen Zhou Xinyue Sun Xuelian Chen Huimin Liu Xiulian Miao Yan Guo Zhiwen Fan Jie Li Yong Xu Zilong Li State Key Laboratory of Natural Medicines Department of PharmacologyChina Pharmaceutical UniversityNanjing 211198China Institute of Biomedical Research Liaocheng UniversityLiaocheng 252200China Department of Pathology Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical SchoolNanjing 210008China Department of Infectious Diseases Nanjing Drum Tower Hospital Affiliated with Nanjing University Medical SchoolNanjing 210008China Institute of Viruses and Infectious Diseases Nanjing UniversityNanjing 210008China

Liver regeneration following injury aids the restoration of liver mass and the recovery of liver function.In the present study we investigated the contribution of megakaryocytic leukemia 1(MKL1),a transcriptional modulator,to liver regeneration.We report that both MKL1 expression and its nuclear translocation correlated with hepatocyte proliferation in cell and animal models of liver regeneration and in liver failure patients.Mice with MKL1 deletion exhibited defective regenerative response in the liver.Transcriptomic analysis revealed that MKL1 interacted with E2F1 to program pro-regenerative transcription.MAPKAPK2 mediated phosphorylation primed MKL1 for its interaction with E2F1.Of interest,phospholipase d2 promoted MKL1 nuclear accumulation and liver regeneration by catalyzing production of phosphatidic acid(PA).PA administration stimulated hepatocyte proliferation and enhanced survival in a MKL1-dependent manner in a pre-clinical model of liver failure.Finally,PA levels was detected to be positively correlated with expression of pro-regenerative genes and inversely correlated with liver injury in liver failure patients.In conclusion,our data reveal a novel mechanism whereby MKL1 contributes to liver regeneration.Screening for small-molecule compounds boosting MKL1 activity may be considered as a reasonable approach to treat acute liver failure.

关键词： Liver failure Liver regeneration Transcription regulation Transcription factor hepatocytes Phosphatidic acid Phospholipase d2 Translational medicine

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Direct reprogramming of fibroblasts into functional hepatocytes via CRISPRa activation of endogenous Gata4 and Foxa3

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中华医学杂志(英文版) 2024年第11期137卷 2024 May 9页

作者： Li Jiacheng Li Ruopu Bai Xue Zhang Wenlong Nie Yu Hu Shengshou State Key Laboratory of Cardiovascular Disease Fuwai Hospital and Cardiovascular Institute National Center for Cardiovascular Diseases Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China Department of Obstetrics and Gynecology Beijing Advanced Innovation Center for Genomics Third Hospital School of Life Sciences Peking University Beijing China

Background: The ability to generate functional hepatocytes without relying on donor liver organs holds significant therapeutic promise in the fields of regenerative medicine and potential liver disease treatments. Clustered regularly interspaced short palindromic repeats (CRISPR) activator (CRISPRa) is a powerful tool that can conveniently and efficiently activate the expression of multiple endogenous genes simultaneously, providing a new strategy for cell fate determination. The main purpose of this study is to explore the feasibility of applying CRISPRa for hepatocyte reprogramming and its application in the treatment of mouse liver fibrosis.Method: The differentiation of mouse embryonic fibroblasts (MEFs) into functional induced hepatocyte-like cells (iHeps) was achieved by utilizing the CRISPRa synergistic activation mediator (SAM) system, which drove the combined expression of three endogenous transcription factors—Gata4,Foxa3, andHnf1a—or alternatively, the expression of two transcription factors,Gata4 andFoxa3.In vivo, we injected adeno-associated virus serotype 6 (AAV6) carrying the CRISPRa SAM system into liver fibroticCol1a1-CreER;Cas9fl/fl mice, effectively activating the expression of endogenousGata4 andFoxa3 in fibroblasts. The endogenous transcriptional activation of genes was confirmed using real-time quantitative polymerase chain reaction (RT-qPCR) and RNA-seq, and the morphology and characteristics of the induced hepatocytes were observed through microscopy. The level of hepatocyte reprogrammingin vivo is detected by immunofluorescence staining, while the improvement of liver fibrosis is evaluated through Sirius red staining, alpha-smooth muscle actin (α-SMA) immunofluorescence staining, and blood alanine aminotransferase (ALT) examination.Results: Activation of only two factors,Gata4 andFoxa3, via CRISPRa was sufficient to successfully induce the transformation of MEFs into iHeps. These iHeps could be expandedin vitro and displayed functional characteristics similar to those of mature hepatocyte

关键词： Liver fibrosis CRISPRa Cell reprogramming Transcriptional activation hepatocytes

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Targeted Mitochondrial Delivery to hepatocytes:A Review

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Journal of Clinical and Translational Hepatology 2022年第2期10卷 321-328页

作者： Brent D.Heineman Xiaocong Liu George Y.Wu Department of Medicine Division of Gastroenterology-HepatologyUniversity of Connecticut Health CenterFarmingtonCTUSA

Defects in mitochondria are responsible for various genetic and acquired diseases.Mitochondrial transplantation,a method that involves introduction of healthy donor mitochondria into cells with dysfunctional mitochondria,could offer a novel approach to treat such diseases.Some studies have demonstrated the therapeutic benefit of mitochondrial transplantation and targeted delivery in vivo and in vitro within hepatocytes and the liver.This review discusses the issues regarding isolation and delivery of mitochondria to hepatocytes and the liver,and examines the existing literature in order to elucidate the utility and practicality of mito-chondrial transplantation in the treatment of liver disease.Studies reviewed demonstrate that mitochondrial uptake could specifically target hepatocytes,address the challenge of non-specific localization of donor mitochondria,and provide evidence of changes in liver function following injection of mitochondria into mouse and rat disease models.While potential benefits and advantages of mitochondrial trans-plantation are evident,more research is needed to determine the practicality of mitochondrial transplantation for the treatment of genetic and acquired liver diseases.

关键词： Mitochondria hepatocytes Transplantation Liver In vitro tech-niques

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Liver cell therapies:cellular sources and grafting strategies

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Frontiers of Medicine 2023年第3期17卷 432-457页

作者： Wencheng Zhang Yangyang Cui Yuan Du Yong Yang Ting Fang Fengfeng Lu Weixia Kong Canjun Xiao Jun Shi Lola M.Reid Zhiying He Institute for Regenerative Medicine Ji’an HospitalShanghai East HospitalSchool of Life Sciences and TechnologyTongji UniversityShanghai 200123China Shanghai Engineering Research Center of Stem Cells Translational Medicine Shanghai 200335China Shanghai Institute of Stem Cell Research and Clinical Translation Shanghai 200120China Postgraduate Training Base of Shanghai East Hospital Jinzhou Medical UniversityJinzhou 121001China The First Affiliated Hospital of Nanchang University Nanchang 330006China Graduate School of Frontier Biosciences Osaka UniversitySuitaOsaka565-0871Japan Department of General Surgery Ji’an HospitalShanghai East HospitalSchool of MedicineTongji UniversityJi’an 343006China Department of Cell Biology and Physiology and Program in Molecular Biology and Biotechnology/UNC School of Medicine Chapel HillNC 27599USA

The liver has a complex cellular composition and a remarkable regenerative capacity.The primary cell types in the liver are two parenchymal cell populations,hepatocytes and cholangiocytes,that perform most of the functions of the liver and that are helped through interactions with non-parenchymal cell types comprising stellate cells,endothelia and various hemopoietic cell populations.The regulation of the cells in the liver is mediated by an insoluble complex of proteins and carbohydrates,the extracellular matrix,working synergistically with soluble paracrine and systemic signals.In recent years,with the rapid development of genetic sequencing technologies,research on the liver’s cellular composition and its regulatory mechanisms during various conditions has been extensively explored.Meanwhile breakthroughs in strategies for cell transplantation are enabling a future in which there can be a rescue of patients with end-stage liver diseases,offering potential solutions to the chronic shortage of livers and alternatives to liver transplantation.This review will focus on the cellular mechanisms of liver homeostasis and how to select ideal sources of cells to be transplanted to achieve liver regeneration and repair.Recent advances are summarized for promoting the treatment of end-stage liver diseases by forms of cell transplantation that now include grafting strategies.

关键词： liver regeneration hepatocytes cholangiocytes stem cells organoids regulatory mechanisms transplantation/grafting strategies

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Mechanism of reduction of albumin expression induced by lipopolysaccharide in rat hepatocytes

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Chinese Medical Journal 2005年第20期118卷 1695-1702页

作者： WANG Xin-ying LI Wei-qin LU Jun LI Ning LI Jie-shou Research Institute of General Surgery Jinling Hospital Nanjing210002 China Department of Orthopaedics Zhongda Hospital Nanjing 210009China

Background The severity of hypoalbuminemia has been shown to be related to morbidity and mortality in some critical illnesses, illustrating the need for better understanding of molecular mechanism of hypoalbuminemia. Lipopolysaccharide （LPS） is a key mediator inducing hypoalbuminemia in sepsis and septic shock. The present study was designed to identify if the reduction of albumin expression is directly induced by LPS and modulated by activated extracellular signal-regulated protein kinase （ERK） and p38 mitogen-activated protein kinase （MAPK） in rat hepatocytes.Methods Primary rat hepatocytes were divided into five groups. In two of them, hepatocytes were treated with normal saline or 1 μg/ml LPS, then albumin mRNA expression was observed at 0, 2, 8, 12 and 24 hours after treatment. In another group, hepatocytes were pretreated with 100, 40 or 20 μmol/L of cycloheximide （CHX, an inhibitor of protein synthesis） for 30 minutes followed by 1 μg/ml LPS for 24 hours. Then the RNA was extracted from the cells for RT-PCR to detect the expression of albumin. The other two groups were administered 1μmol/L, 10 μmol/L and 50 μmol/L of SB203580 （p38 MAPK inhibitor） or PD98059 （ERK inhibitor） 30 minutes prior to 1μg/ml LPS treatment. After 24 hours of LPS treatment, the supernatant was collected and assayed for albumin concentrations. Data were analyzed by one-way analysis of variance, followed by the Newman-Keul test; a P〈0.05 was considered significant.Results There was no marked change in albumin mRNA expression in the control group during 2d-hours treatment with normal saline. The reduction did not occur until 24 hours after LPS treatment, and albumin mRNA decreased by 30% approximately compared to the control group at 24 hours （0.587 vs 0. 832, P = 0. 007 ）. CHX could inhibit the decline of albumin mRNA induced by LPS and the effect was correlated with the dose of CHX. The ERK inhibitor PD98059 caused a significant increase in LPS-induced albumin production at the three concentrations （ 119. 7, 111.4 and 80.0 ng/ml v

关键词： lipopolysaccharide hepatocytes albumin hypoalbuminemia signal transduction

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Effects of Hypoxia on the Growth and Development of the Fetal Ovine hepatocytes in Primary Culture

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Biomedical and Environmental Sciences 2019年第8期32卷 592-601页

作者： CAO Li WANG Juan BO Le LI Da Wei YIN Na ZHOU An Wen MAO Cai Ping Reproductive Medicine Center First Affiliated Hospital of Soochow UniversitySuzhou 215006JiangsuChina College of Pharmaceutical Sciences Soochow UniversitySuzhou 215006JiangsuChina

Objective To investigate the development and characterizations of the hepatocytes isolated from fetal ovine and to determine the effect of hypoxia on their growth and metabolism.Methods Fresh hepatocytes were isolated from the liver of fetal ovine at late gestation, cultured in specific media, and exposed to normoxia(21% O2) or hypoxia(2% O2).The cellular characteristics and population purity were identified by immunocytochemistry and flow cytometry(FCM).The effects of hypoxia on cell cycle and apoptosis of the hepatocytes were evaluated by FCM, whereas the cellular ultrastructure changes were examined with a transmission electron microscope.Results The cell purity of hepatocytes was over 95%.Under hypoxia exposure, the hepatocytes showed a gradual increase in proportion at the S phase and in proliferative index, followed with a compatible increase in apoptosis and progressively decreased cell viability.Additionally, the organelles of the hepatocytes demonstrated dramatic changes, including swelling of mitochondria, disorder in cristae arrangement, expansion of endoplasmic reticulum, and a large number of circular lipid droplets emerging in the cytoplasm.Conclusion Fetal ovine hepatocytes could be primarily cultured in a short-term culture system with a high purity of over 95% and with their preserved original characteristics.Hypoxia could induce changes in ultrastructural and inhibit the proliferation of cultured fetal ovine hepatocytes through apoptotic mechanisms.

关键词： Cell cycle Fetal ovine hepatocytes hepatocytes structure Hypoxia Primary culture

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5-Hydroxymethylfurfural protects against ER stress-induced apoptosis in GalN/TNF-α-injured L02 hepatocytes through regulating the PERK-eIF2α signaling pathway

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Chinese Journal of Natural Medicines 2015年第12期13卷 896-905页

作者： JIANG Ze-Qun MA Yan-Xia LI Mu-Han ZHAN Xiu-Qin ZHANG Xu WANG Ming-Yan Nanjing University of Chinese Medicine Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine(TCM) Prevention and Treatment of Tumor

5-Hydroxymethylfurfural(5-HMF), a water-soluble compound extracted from wine-processed Fructus corni, is a novel hepatic protectant for treating acute liver injury. The present study was designed to investigate the protective effect of 5-HMF in human L02 hepatocytes injured by D-galactosamine(Gal N) and tumor necrosis factor-α(TNF-α) in vitro and to explore the underlying mechanisms of action. Our results showed that 5-HMF caused significant increase in the viability of L02 cells injured by Gal N/TNF-α, in accordance with a dose-dependent decrease in apoptotic cell death confirmed by morphological and flow cytometric analyses. Based on immunofluorescence and Western blot assays, we found that Gal N/TNF-α induced ER stress in the cells, as indicated by the disturbance of intracellular Ca2+ concentration, the activation of protein kinase RNA(PKR)-like ER kinase(PERK), phosphorylation of eukaryotic initiation factor 2 alpha(e IF2α), and expression of ATF4 and CHOP proteins, which was reversed by 5-HMF pre-treatment in a dose-dependent manner. The anti-apoptotic effect of 5-HMF was further evidenced by balancing the expression of Bcl-2 family members. In addition, the knockdown of PERK suppressed the expression of phospho-PERK, phospho-e IF2α, ATF4, and CHOP, resulting in a significant decrease in cell apoptosis after the treatment with Gal N/TNF-α. 5-HMF could enhance the effects of PERK knockdown, protecting the cells against the Gal N/TNF-α insult. In conclusion, these findings demonstrate that 5-HMF can effectively protect Gal N/TNF-α-injured L02 hepatocytes against ER stress-induced apoptosis through the regulation of the PERKe IF2α signaling pathway, suggesting that it is a possible candidate for liver disease therapy.

关键词： 5-Hydroxymethylfurfural GalN/TNF-α L02 hepatocytes Apoptosis PERK-elF2α

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Differentiation of embryoid-body cells derived from embryonic stem cells into hepatocytes in alginate microbeads in vitro

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Acta Pharmacologica Sinica 2007年第12期28卷 1924-1930页

作者： Sheng FANG,Yu-dong QIU,Liang MAO,Xiao-lei SHI,De-cai YU,Yi-tao DING~2Department of Hepatobiliary Surgery,Affiliated Drum Tower Hospital,Medical College of Nanjing University,Nanjing 210008,China Department of Hepatobiliary Surgery Affiliated Drum Tower Hospital Medical College of Nanjing University Nanjing China

Aim:Embryonic stem (ES) cells are being widely investigated as a promisingsource of hepatocytes with their proliferative,renewable,and pluripotentcapacities.However,controlled and scalable ES cell differentiation culture intofunctional hepatocytes is challenging.In this study,we examined the differentiat-ing potential of embryoid-body cells derived from ES cells into hepatocytes inalginate microbeads containing exogenous growth factors in vitro.Methods:.Embryoid bodies were formed from ES cells by suspension methods.Embryoidbodies cultured for 5 d were treated with trypsin-EDTA.The disaggregated cellswere encapsulated in alginate microbeads and stimulated with exogenous growthfactors to induce hepatic differentiation.In the course of cell differentiation,cellmorphology and viability were observed,and the expression patterns of somegenes of the hepatocyte were confirmed by RT-PCR.An immunofluorescenceanalysis revealed the expression of albumin (ALB) and cytokeratin-18 (CK18).Hepatocyte functional assays were confirmed by the secretion of ALB and urea.Results:We showed that embryoid-body cells could maintain cell viability inalginate microbeads in vitro.We also found that directed differentiated cellsexpressed several hepatocyte genes including α-fetoprotein (AFP),ALB,Cyp7a1,CK18,transthyretin (TTR) and tyrosine aminotransferase (TAT) and producedALB and urea in alginate microbeads.The directed differentiated cells expressedALB and CK18 proteins on d 14.However,embryoid-body cells could not formhepatocytes without exogenous growth factors in alginate microbeads.Conclusion:The differentiation of embryoid-body cells into hepatocytes con-taining exogenous growth factors in alginate microbeads gives rise to functionalhepatocytes and may develop scalable stem cell differentiation strategies forbioartificial livers and hepatocyte transplantation.

关键词： alginate cell culture encapsulation hepatocytes stem cell differentiation

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