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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

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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.

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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.

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

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

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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.

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HNF1 regulates critical functions of the human epididymis epithelium. [RNA-Seq]

Project description:HNF1α and HNF1β recognize the same DNA consensus sequence in the genome, to which they bind as homodimers or heterodimers. Both factors share a high degree of homology their DNA binding and dimerization (N-terminus) regions but have a more divergent C-terminal transactivation domain. HNF1β is essential for the generation of a functional male reproductive tract in mice and genital tract abnormalities are evident in humans with recessive mutations in HNF1β. The functions of HNF1α and HNF1β have been studied in epithelia from other several tissues (liver, kidney, intestine, and pancreas) but their role in the adult human epididymis epithelium (HEE) remains unexplored. We established that HNF1α/β are expressed in caput HEE cells and are predicted to occupy cis-regulatory elements in these cells. To investigate the contribution of HNF1 in controlling gene expression in caput cells we performed siRNA-mediated depletion of HNF1α and HNF1β together, followed by RNA-seq analysis. Three replicas of caput cells were transfected with the specific siRNAs or with a non-targeting control siRNA. RNA-seq after HNF1 depletion showed significant alterations in the expression of genes encoding ion channels and exchangers that are involved in controlling the luminal environment in the caput epididymis.

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