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Pharmacological Induction of a Progenitor State for the Efficient Expansion of Primary Human Hepatocytes

ABSTRACT: Transplantation of genetically corrected hepatocytes is an attractive alternative to liver transplantation but is hampered by the low amplification potential of these cells in vitro. Here, we describe a method for generating proliferative hepatic progenitor cells (iHPC) from human hepatocytes as an expandable cell source for liver therapy. Dedifferentiation of primary hepatocytes to iHPC was achieved in less than 7 days by culturing the cells in medium with a cocktail of growth factors and small molecules. In culture, iHPC expressed a combination of endoderm hepatic progenitor and mesenchymal stem cell markers and proliferated vigorously, allowing for their expansion by at least 104 times. RNA sequencing of iHPC demonstrated that they displayed far more subtle changes in both transcriptome and transposcriptome, compared to hepatocyte-derived iPSC. Finally, transplantation of iHPC into the liver of immuno-deficient mice showed iHPC differentiation potential in vivo, without triggering detectable tumor development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE87559 | GEO | 2019/09/25

REPOSITORIES: GEO

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Pharmacological Induction of a Progenitor State for the Efficient Expansion of Primary Human Hepatocytes

Project description:Transplantation of genetically corrected hepatocytes is an attractive alternative to liver transplantation but is hampered by the low amplification potential of these cells in vitro. Here, we describe a method for generating proliferative hepatic progenitor cells (iHPC) from human hepatocytes as an expandable cell source for liver therapy. Dedifferentiation of primary hepatocytes to iHPC was achieved in less than 7 days by culturing the cells in medium with a cocktail of growth factors and small molecules. In culture, iHPC expressed a combination of endoderm hepatic progenitor and mesenchymal stem cell markers and proliferated vigorously, allowing for their expansion by at least 104 times. RNA sequencing of iHPC demonstrated that they displayed far more subtle changes in both transcriptome and transposcriptome, compared to hepatocyte-derived iPSC. Finally, transplantation of iHPC into the liver of immuno-deficient mice showed iHPC differentiation potential in vivo, without triggering detectable tumor development.

2019-09-25 | GSE87558 | GEO

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Project description:We discover IL6, combined with EGF and HGF, promotes long-term expansion (>30 passages in ~150 days with theoretical expansion of ~1E+35 times) of primary mouse hepatocytes in vitro in simple 2D culture, by converting hepatocytes into induced hepatic progenitor cells (iHPCs), which maintain the capacity of differentiation into hepatocytes. IL6 also supports the establishment of single hepatocyte-derived iHPC clones. The summation of the downstream STAT3, ERK and AKT pathways induces a number of transcription factors which support the rapid growth.

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Conversion of Human Gastric Epithelial Cells to Multipotent Endodermal Progenitors using Defined Small Molecules [array]

Project description:Endodermal stem/progenitor cells have diverse potential applications in research and regenerative medicine, so a readily available source could have widespread uses. Here we describe derivation of human induced endodermal progenitor cells (hiEndoPCs) from gastrointestinal epithelial cells using a cocktail of defined small molecules along with support from tissue-specific mesenchymal feeders. The hiEndoPCs show clonal expansion in culture and give rise to hepatocytes, pancreatic endocrine cells, and intestinal epithelial cells when treated with defined soluble molecules directing differentiation. The hiEndoPC-derived hepatocytes are able to rescue liver failure in Fah-/-Rag2-/- mice after transplantation, and, unlike hESCs, transplanted hiEndoPCs do not give rise to teratomas. Since human gastric epithelial cells are readily available from donors of many ages, this conversion strategy can generate clonally expandable cell populations with a variety of potential applications, including personalized drug screening and therapeutic strategies for liver failure and diabetes.

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Conversion of Human Gastric Epithelial Cells to Multipotent Endodermal Progenitors using Defined Small Molecules [gene expression]

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Human Embryonic Stem Cell-derived Expandable Hepatic Organoids Enable Pathophysiological Model of Alcoholic Liver Injury

Project description:We report the generation of human pluripotent-stem-cell-derived (hPSC), expandable hepatic organoids (hEHOs) using a newly established method that consists of subjecting hPSCs to a sequence of distinct wholly defined (serum-free, feeder free) media lineage restricting the cells to become determined hepatic stem cells followed by a process of shifting the cells from monolayer (2D) to organoid (3D ) cultures. The hEHOs stably keep phenotypic features of a bi-potent hepatic lineage that can differentiate into functional hepatocytes or cholangiocytes. The hEHOs can expand for over 20 passages enabling industrial scaling to amounts requisite for industry or clinical programs. The cells from culture are able to engraft rapidly into injured liver parenchyma of FRG mice following transplantation and to differentiate in vivo into mature hepatocytes. If implanted into the epididymis fat pads of immune-deficiency mice, they do not generate non-hepatic lineages nor teratomas. We further developed a derivative model by incorporating human fetal liver mesenchymal cells (hFLMCs) into the hEHOs, referred as hFLMC/hEHO, and used the organoids to model alcohol liver disease-associated pathophysiologic changes, such as oxidative stress generation, steatosis, inflammatory mediators release and fibrosis, following treatment with alcohol. Our work demonstrates that the hFLMC/hEHO provide a novel ex vivo pathophysiological model for studying alcohol liver disease as well as many other non-genetic liver diseases.

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