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RLSC and MMH-D3 cell lines

ABSTRACT: Increasing evidence provide support that the mammalian liver contains stem/progenitor cells, but their molecular phenotype, embryological derivation, cell biology as well as of their role in the liver cell turnover and regeneration remain to be further clarified. We report the isolation, characterization and reproducible establishment in line of a resident liver stem cell (RLSC) with immunophenotype and differentiative potential distinct from other previously reported liver precursor/stem cells. RLSCs, derived from foetal and neonatal murine livers as well as from immortalized hepatocytic MMH lines and established in lines, are Sca+, CD34-, CD45-, alfa-fetoprotein+, albumin-. This immunophenotype suggests a non-haematopoietic origin. RLSCs transcriptional profile, defined by microArray technology, highlighted the expression of a broad spectrum of “plasticity-related genes” and “developmental genes” suggesting a multi-differentiative potential. RLSCs, indeed, spontaneously differentiate into hepatocytes and cholangiocytes and, when cultured in appropriate conditions, into mesenchymal and neuro-ectodermal cell lineages, such as osteoblasts/osteocytes, chondrocytes, astrocytes and neuronal cells. RLSCs capability to spontaneously differentiate into hepatocytes, the lack of albumin expression and the broad differentiative potentiality locate them in a pre-hepatoblast/liver precursor cells hierarchical position. In conclusion, RLSCs may provide an useful tool to improve liver stem cell knowledge and to assess new therapeutic approaches for liver diseases. Keywords: cell type comparison

ORGANISM(S): Mus musculus

PROVIDER: GSE7038 | GEO | 2008/06/03

SECONDARY ACCESSION(S): PRJNA98349

REPOSITORIES: GEO

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Transcription profiling of mouse RLSC and MMH-D3 cell lines

Project description:Increasing evidence provide support that the mammalian liver contains stem/progenitor cells, but their molecular phenotype, embryological derivation, cell biology as well as of their role in the liver cell turnover and regeneration remain to be further clarified. We report the isolation, characterization and reproducible establishment in line of a resident liver stem cell (RLSC) with immunophenotype and differentiative potential distinct from other previously reported liver precursor/stem cells. RLSCs, derived from foetal and neonatal murine livers as well as from immortalized hepatocytic MMH lines and established in lines, are Sca+, CD34-, CD45-, alfa-fetoprotein+, albumin-. This immunophenotype suggests a non-haematopoietic origin. RLSCs transcriptional profile, defined by microArray technology, highlighted the expression of a broad spectrum of âplasticity-related genesâ and âdevelopmental genesâ suggesting a multi-differentiative potential. RLSCs, indeed, spontaneously differentiate into hepatocytes and cholangiocytes and, when cultured in appropriate conditions, into mesenchymal and neuro-ectodermal cell lineages, such as osteoblasts/osteocytes, chondrocytes, astrocytes and neuronal cells. RLSCs capability to spontaneously differentiate into hepatocytes, the lack of albumin expression and the broad differentiative potentiality locate them in a pre-hepatoblast/liver precursor cells hierarchical position. In conclusion, RLSCs may provide an useful tool to improve liver stem cell knowledge and to assess new therapeutic approaches for liver diseases. Experiment Overall Design: We compared the gene expression profile of a RLSC line to that of the previously characterised hepatocytic differentiated cell line MMH-D3 (ref Amicone), using Affymetrix Mouse430_2 GeneChip array.

2008-06-18 | E-GEOD-7038 | biostudies-arrayexpress

Human pluripotent stem cell-derived mesenchymal stem cells regenerate injured GUNN rat liver

Project description:Gunn rats bear a mutation within the uridine diphosphate glucuronosyltransferase-1A1 (Ugt1A1) gene resulting in high serum bilirubin levels as seen in Crigler-Najjar syndrome. In the present study, the Gunn rat was used as an animal model for heritable liver dysfunction. Human pluripotent stem cell-derived mesenchymal stem cells (iMSCs) were transplanted into Gunn rats after partial hepatectomy. The iMSCs engrafted and survived in the liver for up to 2 months without the need for immunosuppression. The transplanted iMSCs differentiated into functional hepatocytes and partially suppressed hyperbilirubinemia. Furthermore, human Albumin as well as the human immunomodulatory factors, RANTES and SERPINE1, were detected in the rat serum upon iMSC transplantation. The differentiation of iMSCs into hepatocytes was confirmed by qPCR and/or immunohistochemistry, detecting expression of human hepatocyte nuclear factor 4α, UGT1A1, cytokeratin 18, α-fetoprotein and Albumin. These findings indicate transplanted iMSCs differentiated into hepatocytes and thus contributed to tissue repair in an injury model of hepatocyte-based liver regeneration.

2019-04-30 | GSE97692 | GEO

A hierarchical regulatory network ensures stable albumin transcription under various pathophysiological conditions

Project description:Physiologically, albumin is produced by hepatocytes. It remains largely unknown how patients are capable of maintaining essential albumin levels even in the condition of liver failure. Here, we delineate a hierarchical regulatory network that controls albumin transcription under different pathophysiological conditions. The ALB core promoter possesses a TATA box and nucleosome-free area, which allows constitutive binding of RNA Pol II and thus initiation of transcription. In normal conditions, HNF4α and C/EBPα facilitate albumin transcription through binding to its promoter. In severely damaged livers, hepatocellular HNF4α and C/EBPα expression is often inhibited. The absence of HNF4 and C/EBPα increases hedgehog ligand biosynthesis. Hedgehog upregulates FOXA2 expression through transcription factor GLI2 binding to the FOXA2 promoter. Subsequently, FOXA2 maintains albumin expression in the hepatocytes lacking HNF4α and C/EBPα. In patients with massive hepatocyte loss, the expression of albumin is activated in liver progenitor cells. Albumin transcription in these cells is regulated by HNF4α or FOXA2. Taken together, HNF4α, C/EBPα and FOXA2 form a hierarchical regulatory network that ensures stable albumin expression even in pathophysiological conditions.

2022-04-06 | GSE181201 | GEO

Oct4 and Hnf4alpha-induced hepatic stem cells attenuated hepatic function in liver injury model

Project description:Generation of expandable induce hepatic stem cells (iHSCs) has a potential for cell-based therapy and drug screening in liver disease. Recently many groups reported reprogramming of somatic cells into hepatocyte-like cells by direct conversion. However, the induced hepatocytes have limitations in proliferation, function and viability for cell therapy and drug development. We generated iHSCs which have properties including self-renewal and bipotency into hepatocytes and cholangiocytes. iHSCs-derived hepatocytes showed typical morphology and functions which include glycogen storage, low-density lipoprotein (LDL) uptake, Indocyanine green (ICG) metabolism, and Albumin secretion, and iHSCs-derived cholangiocytes also have functional characteristics of cholangiocytes, including cyst and tubules formation, cyst polarity, and the secretion of small substances by transmembrane channel protein. In addition, iHSCs attenuated liver injury, such as alcohol induced steatosis and carbon tetrachloride (CCl4) induced fibrosis models. Taken together, generation of functional iHSCs would be used in therapeutic applications.

2019-08-21 | GSE106347 | GEO

Hepatocytes obtained from mouse GPSCs are functional and show similar expression profiles to fetal primary hepatocytes

Project description:Germline cell-derived pluripotent stem cells (GPSCs) are similar to embryonic stem (ES) cells in that they can proliferate intensively and differentiate into a variety of cell types, including cardiomyocytes and neurons. In this report, mouse GPSCs were induced to differentiate into hepatocytes with very high efficiency, and demonstrated, for the first time, to be functional. These hepatocytes were characterised at cellular and molecular levels. The GPSC-derived hepatocytes not only expressed hepatic markers, but were also metabolically active as shown by albumin and haptoglobin secretion, urea synthesis, glycogen storage and indocyanine green uptake. Previous studies have revealed some inherent differences in gene expression between undifferentiated mouse ES cells and GPSCs. We wanted to investigate whether this difference may impact on the hepatocyte differentiation capacity of the GPSCs. Large-scale gene expression profiling revealed a strong similarity between GPSC and ES cells at different stages of induced hepatic differentiation. Moreover, Pearson correlation analysis of the microarray datasets revealed that, at late hepatic differentiation stages, the in vitro-derived cells were closer to fetal mouse primary hepatocytes. Thus, adult GPSCs offer great potential for cell ment therapy for a wide variety of liver diseases. Mouse ES cells and GPSCs at various times of hepatocyte differentiation, compared to embryonal (E16) and postnatal (PN1) mouse primary hepatocytes. The supplementary file 'GSE19044_non-normalized.txt' contains non-normalized data for Samples GSM471318-GSM471359.

2010-06-08 | E-GEOD-19044 | biostudies-arrayexpress

Transcriptional profiling of PNPase KO liver hepatocytes

Project description:Transcriptional profiling of PNPase KO liver hepatocytes (HepKO) generated from Albumin-Cre/wt (liver-specific) Pnpt1 fl/fl C57BL/6J mice. Samples comparing liver hepatocyte PNPase KO (HepKO) cells to litter-, age-, and sex-matched wildtype hepatocyte control cells. The goal of this experiment was to determine effects of PNPase loss on the total RNA transcriptome under physiologic in vivo conditions.

2018-05-03 | GSE109210 | GEO

Hepatocytes obtained from mouse GPSCs are functional and show similar expression profiles to fetal primary hepatocytes

2010-06-01 | GSE19044 | GEO

In vitro culture at 39° C during hepatic maturation of human ES cells facilitates hepatocyte-like cell functions

Project description:Hepatocyte-like cells derived from human pluripotent stem cells (hPSC-HLCs) offer an alternative to primary hepatocytes commonly used for drug screenings and toxicological tests. However, these cells do not have hepatic functions comparable to those of hepatocytes in vivo due to insufficient hepatic differentiation. Here we showed that the hepatic functions of hPSC-HLCs were facilitated by applying physiological liver temperatures during hepatic differentiation. We identified the optimal temperature by treating HLCs derived from H9 human embryonic stem cells (hESC-HLCs) at 39 °C; the 42 °C treatment caused significantly greater cell death than the 39 °C treatment. We confirmed the improvement of hepatic functions, such as albumin secretion, cytochrome P450 3A activity, and collagen production, without severe cell damage. In combination with existing hepatic differentiation protocols, the method proposed here may further improve hepatic functions for hPSCs and lead to the realization of drug discovery efforts and drug toxicological tests.

2022-03-29 | GSE172227 | GEO

High temporal resolution proteome and phosphoproteome profiling of stem cell-derived hepatocyte development

Project description:Primary human hepatocytes are widely used to evaluate liver toxicity of drugs, but they are scarce and demanding to culture. Stem cell-derived hepatocytes are increasingly discussed as alternatives. To obtain a better appreciation of the molecular processes during the differentiation of induced pluripotent stem cells into hepatocytes, we employ a quantitative proteomic approach to follow the expression of 9,000 proteins, 12,000 phosphorylation sites, and 800 acetylation sites over time. The analysis reveals stage-specific markers, a major molecular switch between hepatic endoderm versus immature hepatocyte-like cells impacting e.g. metabolism, the cell cycle, kinase activity, and the expression of drug transporters. Comparing the proteomes of 2D and 3D-derived hepatocytes to fetal and adult liver, indicate a fetal-like status of the in vitro models and lower expression of important ADME/Tox proteins. The collective data enable constructing a molecular roadmap of hepatocyte development that serve as a valuable resource for future research.

2022-04-01 | PXD027439 | Pride

Highly Efficient generation of Human Hepatic Cells from Induced Pluripotent Stem Cells.

Project description:Reprogrammed somatic cells offer a valuable source of pluripotent cells that have the potential to differentiate into many cells types and provide a new tool for regenerative medicine. In the present study we differentiated induced pluripotent stem cells (iPS cells) into hepatic cells. We first showed that mouse iPS cells could from a complete liver in mouse embryo (E14.5) including hepatocytes, endothelial cells, sinusoidal cells and resident macrophages. We then designed a highly efficient hepatocyte differentiation protocol using defined factors on human embryonic stem cells (ES cells). This protocol was found to generate more than 80% albumin expressing cells that show hepatic functions and express most of liver genes as shown by microarray analyses. Similar results were obtained when human iPS cells were induced to differentiate following the same procedure.

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