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Identification of cytokines involved in hepatic differentiation of mBM-MSCs under liver-injury conditions

World Journal of Gastroenterology 2010年第26期16卷 3267-3278页

作者： Dong, Xue-Jun Zhang, Hui Pan, Ruo-Lang Xiang, Li-Xin Shao, Jian-Zhong Shaoxing Peoples Hosp Mol Med Ctr Shaoxing 312000 Zhejiang Peoples R China Wenzhou Med Coll Sch Lab Med & Life Sci Wenzhou 325035 Zhejiang Peoples R China Zhejiang Univ Coll Life Sci Hangzhou 310058 Zhejiang Peoples R China Key Lab Cell & Gene Engn Zhejiang Prov Hangzhou 310058 Zhejiang Peoples R China

AIM: To identify the key cytokines involved in hepatic differentiation of mouse bone marrow mesenchymal stem cells (mBM-MSCs) under liver-injury conditions. METHODS: Abdominal injection of CCl4 was adopted to duplicate a mouse acute liver injury model. Global gene expression analysis was performed to evaluate the potential genes involved in hepatic commitment under liver-injury conditions. The cytokines involved in hepatic differentiation of mBM-MSCs was function-ally examined by depletion experiment using specifi c antibodies, followed by rescue experiment and direct inducing assay. The hepatic differentiation was characterized by the expression of hepatic lineage genes and proteins, as well as functional features. RESULTS: Cytokines potentially participating in hepatic fate commitment under liver-injury conditions were initially measured by microarray. Among the up-regulated genes determined, 18 cytokines known to closely relate to liver growth, repair and development, were selected for further identif ication. The f ibroblast growth factor-4 (FGF-4), hepatocyte growth factor (HGF) and oncostatin M (OSM) were fi nally found to be involved in hepatic differentiation of mBM-MSCs under liver-injury conditions. hepatic differentiation could be dramatically decreased after removing FGF-4, HGF and OSM from the liver-injury conditioned medium, and could be rescued by supplementing these cytokines. The FGF-4, HGF and OSM play different roles in the hepatic differentiation of mBM-MSCs, in which FGF-4 and HGF are essential for the initiation of hepatic differentiation, while OSM is critical for the maturation of hepatocytes. CONCLUSION: FGF-4, HGF and OSM are the key cytokines involved in the liver-injury conditioned medium for the hepatic differentiation of mBM-MSCs.

关键词： hepatic differentiation Mouse bone marrow mesenchymal stem cells Inducing cytokines Fibroblast growth factor-4 Hepatocyte growth factor Oncostatin M

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Direct hepatic differentiation of mouse embryonic stem cells induced by valproic acid and cytokines

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World Journal of Gastroenterology 2009年第41期15卷 5165-5175页

作者： Xue-Jun Dong Guo-Rong Zhang Qing-Jun Zhou Ruo-Lang Pan Ye Chen Li-Xin Xiang Jian-Zhong Shao Molecular Medicine Center of Shaoxing People's Hospital The First Affiliate Hospital of Shaoxing University Shaoxing 312000 Zhejiang Province China College of Life Sciences Zhejiang UniversityHangzhou 310058 Zhejiang Province China Key Laboratory for Cell and Gene Engineering of Zhejiang Province Hangzhou 310058 Zhejiang Province China

MM： To develop a protocol for direct hepatic lineage differentiation from early developmental progenitors to a population of mature hepatocytes, METHODS： hepatic progenitor cells and then mature hepatocytes from mouse embryonic stem （ES） cells were obtained in a sequential manner, induced by valproic acid （VPA） and cytokines （hepatocyte growth factor, epidermal growth factor and insulin）, Morphological changes of the differentiated cells were examined by phase-contrast microscopy and electron microscopy, Reverse transcription polymerase chain reaction and immunocytochemical analyses were used to evaluate the gene expression profiles of the VPA-induced hepatic progenitors and the hepatic progenitor-derived hepa- tocytes, Glycogen storage, cytochrome P450 activity, transplantation assay, differentiation of bile duct-like structures and tumorigenic analyses were performed for the functional identification of the differentiated cells, Furthermore, FACS and electron microscopy were used for the analyses of cell cycle profile and apoptosis in VPA-induced hepatic differentiated ***： Based on the combination of VPA and cytokines, mouse ES cells differentiated into a uniform and homogeneous cell population of hepatic progenitor cells and then matured into functional hepatocytes. The progenitor population shared several characteristics with ES cells and hepatic stem/progenitor cells, and represented a novel progenitor cell between ES and hepatic oval cells in embryonic development. The dif- ferentiated hepatocytes from progenitor cells shared typical characteristics with mature hepatocytes, including the patterns of gene expression, immunological markers,in vitro hepatocyte functions and in vivo capacity to restore acute-damaged liver function. In addition, the differentiation of hepatic progenitor cells from ES cells was accompanied by significant cell cycle arrest and selective survival of differentiating cells to-wards hepatic lineages. CONCLUSION： hepatic cells

关键词： hepatic differentiation Embryonic stem cells Histone deacetylase inhibitor Progenitor cell Cell cycle arrest

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Genetic Correction and hepatic differentiation of Hemophilia B-specific Human Induced Pluripotent Stem Cells

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Chinese Medical Sciences Journal 2017年第3期32卷 135-144页

作者：何琼王惠荟程涛袁卫平马钰波蒋永平任志华中国医学科学院北京协和医学院方舟生物医药研发中心苏州215126 苏州方舟基因药业有限公司苏州215126 中国医学科学院北京协和医学院干细胞医学中心血液病医院实验血液学国家重点实验室天津300020 长岛高科技孵化器iCell基因治疗有限责任公司研究开发部石溪大学医学院病理部澳门科技大学澳门药物及健康应用研究院

Objective To genetically correct a disease-causing point mutation in human induced pluripotent stem cells （iPSCs） derived from a hemophilia B patient. Methods First, the disease-causing mutation was detected by sequencing the encoding area of human coagulation factor IX （F IX） gene. Genomic DNA was extracted from the iPSCs, and the primers were designed to amplify the eight exons of F IX. Next, the point mutation in those iPSCs was genetically corrected using CRISPR/Cas9 technology in the presence of a 129-nucleotide homologous repair template that contained two synonymous mutations. Then, top 8 potential off-target sites were subsequently analyzed using Sanger sequencing. Finally, the corrected clones were differentiated into hepatocyte-like cells, and the secretion of F IX was validated by immunocytochemistry and ELISA *** The cell line bore a missense mutation in the 6th coding exon （c.676 C〉T） of F IX gene. Correction of the point mutation was achieved via CRISPR/Cas9 technology in situ with a high efficacy at about 22% （10/45） and no off-target effects detected in the corrected iPSC clones. F IX secretion, which was further visualized by immunocytochemistry and quantified by ELISA in vitro, reached about 6 ng/ml on day 21 of differentiation procedure. Conclusions Mutations in human disease-specific iPSCs could be precisely corrected by CRISPR/Cas9 technology, and corrected cells still maintained hepatic differentiation capability. Our findings might throw a light on iPSC-based personalized therapies in the clinical application, especially for hemophilia B.

关键词： hemophilia B human induced pluripotent stem cells CRISPR/Cas9 genetic correction hepatic differentiation

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Role of Hepatocyte Nuclear Factor 4α in Regulating hepatic differentiation and the Inflammatory Response in HCC

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Journal of Nutritional Oncology 2019年第3期4卷 115-120页

作者： Wen Li Zhou Zhan Wang Ming Yong Miao Yuan Sheng Zang Department of Medical Oncology Changzheng HospitalNavy Medical UniversityShanghai 200070China Department of Biochemistry and Molecular Biology Navy Medical UniversityShanghai 200433China

Limited treatment options are available for hepatocellular carcinoma(HCC),especially in the advanced stage,which is associated with a poor *** studies have demonstrated that hepatocyte nuclear factor 4α(HNF 4α)plays an important role in hepatic differentiation and the carcinogenesis of *** 4αcritically regulates hepatic differentiation by controlling a large number of genes involved in hepatic functions including metabolism,xenobiotic detoxification,bile acid synthesis,and serum protein *** has also been confirmed to play an important role in the inflammatory environment in ***,HNF 4αis considered to be a promising target for the treatment of *** studies have demonstrated that regulating HNF 4αexpression in HCC had beneficial effects in in vivo and in vitro *** herein review the role of HNF 4αin regulating hepatic metabolism and the inflammatory response,aiming to provide some ideas on induced hepatic differentiation therapy and regulating the inflammatory microenvironment for the treatment of advanced HCC.

关键词： Hepatocyte nuclear factor 4α(HNF 4α) Metabolism Inflammation hepatic differentiation Hepatocellular carcinoma(HCC)

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Embryonic stem cells develop into hepatocytes after intrasplenic transplantation in CCl_4-treated mice

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World Journal of Gastroenterology 2007年第6期13卷 866-873页

作者： Kei Moriya Masahide Yoshikawa Ko Saito Yukiteru Ouji Mariko Nishiofuku Noriko Hayashi Shigeaki Ishizaka Hiroshi Fukui Division of Hepatology Third Department of Internal Medicine Nara Medical University 840 Shijo-cho Kashihara Nara 634-8521 Japan Division of Developmental Biology Department of Parasitology Nara Medical University 840 Shijo-cho Kashihara Nara 634-8521 Japan

AIM： To transplant undifferentiated embryonic stem （ES） cells into the spleens of carbon tetrachloride （CCl4）-treated mice to determine their ability to differentiate into hepatocytes in the liver. METHODS： CCh, 0.5 mL/kg body weight, was injected into the peritoneum of C57BL/6 mice twice a week for 5 wk. In group 1 （n = 12）, 1 × 10^5 undifferentiated ES cells （0.1 mL of 1 × 10^6/mL solution）, genetically labeled with GFP, were transplanted into the spleens 1 d after the second injection. Group 2 mice （n = 12） were injected with 0.2 mL of saline twice a week, instead of CCh, and the same amount of ES cells was transplanted into the spleens. Group 3 mice （n = 6） were treated with CCh and injected with 0.1 mL of saline into the spleen, instead of ES cells. Histochemical analyses of the livers were performed on post-transplantation d （PD） 10, 20, and 30. RESULTS： Considerable numbers of GFP-immunopositive cells were found in the periportal regions in group 1 mice （CCh-treated） on PD 10, however, not in those untreated with CCh （group 2）. The GFP-positive cells were also immunopositive for albumin （ALB）, alpha-1 antitrypsin, cytokeratin 18, and hepatocyte nuclear factor 4 alpha on PD 20. Interestingly, most of the GFP-positive cells were immunopositive for DLK, a hepatoblast marker, on PD 10. Although very few ES-derived cells were demonstrated immunohistologically in the livers of group 1 mice on PD 30, improvements in liver fibrosis were observed. Unexpectedly, liver tumor formation was not observed in any of the mice that received ES cell transplantation during the experimental period CONCLUSION： Undifferentiated ES cells developed into hepatocyte-like cells with appropriate integration into tissue, without uncontrolled cell growth.

关键词： Embryonic stem cells hepatic differentiation Intrasplenic transplantation Carbon tetrachloride

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Promoted differentiation of cynomolgus monkey ES cells into hepatocyte-like cells by co-culture with mouse fetal liver-derived cells

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World Journal of Gastroenterology 2006年第42期12卷 6818-6827页

作者： Ko Saito Masahide Yoshikawa Yukiteru Ouji Kei Moriya Mariko Nishiofuku Shigehiko Ueda Noriko Hayashi Shigeaki Ishizaka Hiroshi Fukui Department of Gastroenterology and Hepatology Nara Medical University Kashihara Nara Japan Division of Developmental Biology Department of Parasitology Nara Medical University Kashihara Nara Japan

AIM: To explore whether a co-culture of cynomolgus monkey embryonic stem (cES) cells with embryonic liver cells could promote their differentiation into hepatocytes. METHODS: Mouse fetal liver-derived cells (MFLCs) were prepared as adherent cells from mouse embryos on embryonic d (ED) 14, after which undifferentiated cES cells were co-cultured with MFLCs. The induction of cES cells along a hepatic lineage was examined in MFLC- assisted differentiation, spontaneous differentiation, and growth factors (GF) and chemicals-induced differentiations (GF-induced differentiation) using retinoic acid, leukemia inhibitory factor (LIF), FGF2, FGF4, hepatocyte growth factor (HGF), oncostatin M (OSM), and dexamethasone. RESULTS: The mRNA expression of α-fetoprotein, albumin (ALB), α-1-antitrypsin, and hepatocyte nuclear factor 4α was observed earlier in the differentiating cES cells co-cultured with MFLCs, as compared to cES cells undergoing spontaneous differentiation and those subjected to GF-induced differentiation. The expression of cytochrome P450 7a1, a possible marker for embryonic endoderm-derived mature hepatocytes, was only observed in cES cells that had differentiated in a co-culture with MFLCs. Further, the disappearance of Oct3/4, a representative marker of an undifferentiated state, was noted in cells co-cultured with MFLCs, but not in those undergoing spontaneous or GF-induced differentiation. Immunocytochemical analysis revealed an increased ratio of ALB-immunopositive cells among cES cells co-cultured with MFLCs, while glycogen storageand urea synthesis were also demonstrated. CONCLUSION: MFLCs showed an ability to induce cES cells to differentiate toward hepatocytes. The co-culture system with MFLCs is a useful method for induction of hepatocyte-like cells from undifferentiated cES cells.

关键词： Primate embryonic stem cells Fetal liver hepatic differentiation Co-culture

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Hepatoblast-Like Progenitor Cells Derived From Embryonic Stem Cells Can Repopulate Livers of Mice

Hepatoblast-Like Progenitor Cells Derived From Embryonic Ste...

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“细胞活动生命活力”——中国细胞生物学学会全体会员代表大会暨第十二次学术大会

作者： Kirk Wangensteen Department of Genetics Cell Biology and Development

BACKGROUND & AIMS:Hepatocyte-like cells can be derived from pluripotent stem cells such as embryonic stem(ES) cells,but ES cell-derived hepatic cells with extensive capacity to repopulate liver have not been identified. We aimed to identify and purify ES cell-derived hepatoblast-like progenitor cells and to explore their capacity for liver repopulation in mice after in vitro ***:Unmanipulated mouse ES cells were cultured under defined conditions and allowed to undergo stepwise hepatic *** derived hepatic cells were examined by morphologic,fluorescence-activated cell sorting,gene expression,and clonal expansion *** capacities of ES cell-derived hepatic progenitor cells to repopulate liver were investigated in mice that were deficient in fumarylacetoacetate hydrolase(Fah)(a model of liver injury).RESULTS:Mouse ES cells were induced to differentiate into a population that contained hepatic progenitor cells;this population included cells that expressed epithelial cell adhesion molecule(EpCAM) but did not express *** hepatic progenitors that arose from single c-KitEpCAM cells could undergo long-term expansion and maintain hepatoblast-like *** c-KitEpCAM cells and clonally expanded hepatic progenitor cells repopulated the livers of Fah-deficient mice without inducing ***:ES cell-derived c-KitEpCAM cells contain a population of hepatoblast-like progenitor cells that can repopulate livers of mice.

关键词： hepatic differentiation Bipotency Cell Transplantation Liver Injury

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