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Chemical reprogramming of mouse embryonic and adult fibroblast into endoderm lineage.

ABSTRACT: We report here an approach to redirecting somatic cell fate under chemically defined conditions without transcription factors. We start by converting mouse embryonic fibroblasts to epithelial-like cells with chemicals and growth factors. Subsequent cell fate mapping reveals a robust induction of SOX17 in the resulting epithelial-like cells that can be further reprogrammed to endodermal progenitor cells. Interestingly, these cells can self-renew in vitro and further differentiate into albumin-producing hepatocytes that can rescue mice from acute liver injury. Our results demonstrate a rational approach to convert mouse embryonic fibroblasts to hepatocytes and suggest that this mechanism-driven approach may be generalized for other cells.

SUBMITTER: Cao S

PROVIDER: S-EPMC5704493 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Chemical reprogramming of mouse embryonic and adult fibroblast into endoderm lineage.

Cao Shangtao S Yu Shengyong S Chen Yan Y Wang Xiaoshan X Zhou Chunhua C Liu Yuting Y Kuang Junqi J Liu He H Li Dongwei D Ye Jing J Qin Yue Y Chu Shilong S Wu Linlin L Guo Lin L Li Yinxiong Y Shu Xiaodong X Chen Jiekai J Liu Jing J Pei Duanqing D

The Journal of biological chemistry 20170921 46

We report here an approach to redirecting somatic cell fate under chemically defined conditions without transcription factors. We start by converting mouse embryonic fibroblasts to epithelial-like cells with chemicals and growth factors. Subsequent cell fate mapping reveals a robust induction of SOX17 in the resulting epithelial-like cells that can be further reprogrammed to endodermal progenitor cells. Interestingly, these cells can self-renew <i>in vitro</i> and further differentiate into albu ...[more]

PMID: 28935668

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Chemical reprogramming of mouse embryonic and adult fibroblast into endoderm lineage

Project description:We report here an approach to redirect somatic cell fate under chemically defined conditions without transcription factors. We start by converting mouse embryonic fibroblasts (MEFs) to epithelial-like cells (ciELC) with chemicals and growth factors. Subsequent cell fate mapping reveals a robust induction of SOX17 in the resulting ELCs that can be further reprogrammed to endodermal progenitor cells (ciEPC). Interestingly, these cells can self-renew in vitro and further differentiate into albumin-producing hepatocytes that can rescue mice from acute live injury. Our results demonstrate a rational approach to convert MEFs to hepatocytes and suggest that this mechanism-driven approach may be generalized for other cells.

2017-10-04 | GSE104555 | GEO

Chemical reprogramming of mouse embryonic and adult fibroblast into endoderm lineage

Project description:Chemical reprogramming of mouse embryonic and adult fibroblast into endoderm lineage

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Pluripotent state induction in mouse embryonic fibroblast using mRNAs of reprogramming factors.

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A role for PDGF signaling in expansion of the extra-embryonic endoderm lineage of the mouse blastocyst.

Project description:The inner cell mass (ICM) of the implanting mammalian blastocyst comprises two lineages: the pluripotent epiblast (EPI) and primitive endoderm (PrE). We have identified platelet-derived growth factor receptor alpha (PDGFRα) as an early marker of the PrE lineage and its derivatives in both mouse embryos and ex vivo paradigms of extra-embryonic endoderm (ExEn). By combining live imaging of embryos and embryo-derived stem cells expressing a histone H2B-GFP fusion reporter under the control of Pdgfra regulatory elements with the analysis of lineage-specific markers, we found that Pdgfra expression coincides with that of GATA6, the earliest expressed transcriptional regulator of the PrE lineage. We show that GATA6 is required for the activation of Pdgfra expression. Using pharmacological inhibition and genetic inactivation we addressed the role of the PDGF pathway in the PrE lineage. Our results demonstrate that PDGF signaling is essential for the establishment, and plays a role in the proliferation, of XEN cells, which are isolated from mouse blastocyst stage embryos and represent the PrE lineage. Implanting Pdgfra mutant blastocysts exhibited a reduced number of PrE cells, an effect that was exacerbated by delaying implantation. Surprisingly, we also noted an increase in the number of EPI cells in implantation-delayed Pdgfra-null mutants. Taken together, our data suggest a role for PDGF signaling in the expansion of the ExEn lineage. Our observations also uncover a possible role for the PrE in regulating the size of the pluripotent EPI compartment.

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High-Resolution Dissection of Chemical Reprogramming from Mouse Embryonic Fibroblasts into Fibrocartilaginous Cells.

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Project description:Recent studies have highlighted the functional diversity of dermal fibroblast populations in health and disease, with part of this diversity linked to fibroblast lineage and embryonic origin. Fibroblasts derived from foxd1-expressing progenitors contribute to the myofibroblast populations present in lung and kidney fibrosis in mice but have not been investigated in the context of dermal wound repair. Using a Cre/Lox system to genetically track populations derived from foxd1-expressing progenitors, lineage-positive fibroblasts were identified as a subset of the dermal fibroblast population. During development, lineage-positive cells were most abundant within the dorsal embryonic tissues, contributing to the developing dermal fibroblast population, and remaining in this niche into adulthood. In adult mice, assessment of fibrosis-related gene expression in lineage-positive and lineage-negative populations isolated from wounded and unwounded dorsal skin was performed, identifying an enrichment of transcripts associated with matrix synthesis and remodeling in the lineage-positive populations. Using a novel excisional wound model, ventral skin healed with a greatly reduced frequency of foxd1 lineage-positive cells. This work supports that the embryonic origin of fibroblasts is an important predictor of fibroblast function, but also highlights that within disparate regions, fibroblasts of different lineages likely undergo convergent differentiation contributing to phenotypic similarities.

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Somatic MIWI2 Hinders Direct Lineage Reprogramming From Fibroblast to Hepatocyte.

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