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Reprogramming fibroblasts into bi-potential hepatic stem cells by defined factors

ABSTRACT: Recent studies have demonstrated direct reprogramming of fibroblasts into a range of somatic cell types, but to date stem/progenitor cells have only been reprogrammed for the blood and neuronal lineages. We previously reported generation of induced hepatocyte-like (iHep) cells by transduction of Gata4, Hnf1α, and Foxa3 in p19 Arf null mouse embryonic fibroblasts (MEFs). Here, we show that Hnf1β and Foxa3, liver organogenesis transcription factors, are sufficient to reprogram MEFs into induced hepatic stem cells (iHepSCs). iHepSCs can be stably expanded in vitro and possess the potential of bi-directional differentiation into both hepatocytic and cholangiocytic lineages. In the injured liver of fumarylacetoacetate hydrolase (Fah)-deficient mice, repopulating iHepSCs become hepatocyte-like cells. They also engraft as cholangiocytes into bile ducts of mice with DDC-induced bile ductular injury. Lineage-conversion into bi-potential expandable iHepSCs provides a strategy to enable efficient derivation of both hepatocytes and cholangiocytes for use in disease modeling and tissue engineering.

ORGANISM(S): Mus musculus

PROVIDER: GSE48486 | GEO | 2013/07/19

SECONDARY ACCESSION(S): PRJNA210316

REPOSITORIES: GEO

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Reprogramming fibroblasts into bi-potential hepatic stem cells by defined factors

Project description:Recent studies have demonstrated direct reprogramming of fibroblasts into a range of somatic cell types, but to date stem/progenitor cells have only been reprogrammed for the blood and neuronal lineages. We previously reported generation of induced hepatocyte-like (iHep) cells by transduction of Gata4, Hnf1α, and Foxa3 in p19 Arf null mouse embryonic fibroblasts (MEFs). Here, we show that Hnf1β and Foxa3, liver organogenesis transcription factors, are sufficient to reprogram MEFs into induced hepatic stem cells (iHepSCs). iHepSCs can be stably expanded in vitro and possess the potential of bi-directional differentiation into both hepatocytic and cholangiocytic lineages. In the injured liver of fumarylacetoacetate hydrolase (Fah)-deficient mice, repopulating iHepSCs become hepatocyte-like cells. They also engraft as cholangiocytes into bile ducts of mice with DDC-induced bile ductular injury. Lineage-conversion into bi-potential expandable iHepSCs provides a strategy to enable efficient derivation of both hepatocytes and cholangiocytes for use in disease modeling and tissue engineering. iHepSCs were converted form fibroblasts by transduction of Hnf1β and Foxa3. iHepSCs were induced to differentiate into hepatocyte-like cells and cholangiocytes in vitro. Totally, 9 samples including four clones of iHepSCS, one clone of LEPCs, two samples of MEFs and two samples of iHepSCs-derived cholangocytes were analyzed.

2013-07-19 | E-GEOD-48486 | biostudies-arrayexpress

Direct conversion of mouse fibroblasts into cholangiocyte progenitor cells

Project description:We describe that Hnf1α and Foxa3 dramatically facilitate the robust generation of iHepSCs. Notably, the prolonged in vitro culture of Hnf1α and Foxa3 derived iHepSCs induce Notch signaling-mediated secondary conversion into cholangiocyte progenitor-like cells displaying the dramatically enhanced differentiation capacity into the mature cholangiocytes in vitro and in vivo. Our study provides the novel two-step approach for obtaining cholangiocyte progenitor-like cells using defined factors.

2018-03-06 | GSE97507 | GEO

Conversion of mouse fibroblast to hepatocyte-like cells by defined factors

Project description:Plasticity of differentiated cells has been proved by nuclear transfer, induced pluripotent cells and transdifferentiation. Here we show that by transduction of 3 factors (Hnf1alpha, Gata4, and Foxa3) and p19Arf inactivation, tail-tip fibroblasts can be converted to hepatocyte-like (iHep) cells, expressing hepatocyte marker genes, and acquiring many mature hepatocyte functions in vitro and in vivo. p19Arf-null TTFs were tranfected with 3 liver enriched transcription factors, then changed to modified Block's medium. To enrich iHep cells, epithelial cells were enriched by partial trypsin digestion.

2011-05-11 | E-GEOD-23635 | biostudies-arrayexpress

Targets of Hnf4alpha during conversion from mouse embryonic fibroblasts (MEFs) to hepatocyte-like (iHep) cells.

Project description:We have found three specific combinations of two transcription factors, comprising Hnf4alpha plus Foxa1, Foxa2 or Foxa3, could convert mouse embryonic fibroblasts (MEFs) into cells that closely resemble hepatocytes in vitro. Then we used ChIP-seq to explore the targets of Hnf4alpha during conversion event from MEFs to iHep cells.

2020-08-06 | GSE119880 | GEO

Conversion of mouse fibroblast to hepatocyte-like cells by defined factors

2011-05-11 | GSE23635 | GEO

Transcriptome analysis of the induced hepatocyte-like (iHep) cells

Project description:We have found three specific combinations of two transcription factors, comprising Hnf4alpha plus Foxa1, Foxa2 or Foxa3, could convert mouse embryonic fibroblasts (MEFs) into cells that closely resemble hepatocytes in vitro. Then we used RNA-seq to explore the conversion event to the iHep cells.

2020-08-06 | GSE90534 | GEO

Genome-wide maps of the chromatin and transcription state transition during conversion from mouse embryonic fibroblasts (MEFs) to hepatocyte-like cells (iHep)

Project description:We have found three specific combinations of two transcription factors, comprising Hnf4alpha plus Foxa1, Foxa2, or Foxa3, could convert mouse embryonic fibroblasts (MEFs) into cells that closely resemble hepatocytes (iHep cells) in vitro. Then we mapped 2 histone modification marks (H3K9ac and H3K27me3) and 2 states of Pol2 (with phosphorylated serine 5 and phosphorylated both of serine 5 and serine 2) during the conversion event. Besides we performed FAIRE-Seq to explore the chromatin accessbility in the iHep cells.

2020-08-06 | GSE119877 | GEO

Foxa and Hnf4alpha targets during conversion from mouse embryonic fibroblasts (MEFs) to hepatocyte-like (iHep) cells

Project description:We have found three specific combinations of two transcription factors, comprising Hnf4alpha plus Foxa1, Foxa2 or Foxa3, could convert mouse embryonic fibroblasts (MEFs) into cells that closely resemble hepatocytes in vitro. Then we used ChIP-seq to explore the targets of Foxa and Hnf4alpha during conversion event to iHep cells.

2020-08-06 | GSE90536 | GEO

Targets of DNA binding, N-terminal, or C-terminal domain swapped mutant forms fo Foxa proteins in induced hepatocyte-like (iHep) cells.

Project description:We have found that three specific combinations of two transcription factors, comprising Hnf4alpha plus Foxa1, Foxa2 or Foxa3, could convert mouse embryonic fibroblasts (MEFs) into cells that closely resemble hepatocytes in vitro, and DNA binding, N-terminal, and C-terminal domains (DBD, NTD, and CTD, respectively) of Foxa proteins are swappable in the direct reprogramming of the iHep cells. Then we used ChIP-seq to explore the targets of the domain swapped mutant forms of Foxa proteins during conversion event to iHep cells.

2020-08-06 | GSE117332 | GEO

Foxa and Hnf4alpha targets during conversion from mouse embryonic fibroblasts (MEFs) to hepatocyte-like (iHep) cells and hepatocytes (Hep).

Project description:We have found three specific combinations of two transcription factors, comprising Hnf4alpha plus Foxa1, Foxa2 or Foxa3, could convert mouse embryonic fibroblasts (MEFs) into cells that closely resemble hepatocytes in vitro. Then we used ChIP-seq to explore the targets of Foxa and Hnf4alpha during conversion event to iHep cells. Besides we performed for hepatocytes.

2020-08-06 | GSE90538 | GEO

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