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Sequential Reprogramming Leads to a Specific Hepatic Expression Pattern during Mouse Bone Marrow Derived Hepatocyte Formation In Vivo

ABSTRACT: The fusion of bone marrow (BM) hematopoietic cells with hepatocytes to generate BM derived hepatocytes (BMDH) is a natural process, which is enhanced in damaged tissues. However, the reprogramming needed to generate BMDH and the identity of the resultant cells are essentially unknown. In a mouse model of chronic liver damage, here we identify a modification in the chromatin structure of the hematopoietic nucleus during BMDH formation, accompanied by the sequential loss of the key hematopoietic transcription factor PU.1/Sfpi1 (SFFV proviral integration 1) and gain of the key hepatic transcriptional regulator HNF-1A homeobox A (HNF-1A/Hnf1a). Through genome-wide expression analysis of laser captured BMDH, a differential gene expression pattern was detected and the chromatin changes observed were confirmed at the chromatin regulator gene level. Similarly, Tranforming Growth Factor-β1 (TGF-β1) and neurotransmitter (e.g. Prostaglandin E Receptor 4 [Ptger4]) pathway genes were over-expressed. In summary, in vivo BMDH generation is a sequential process in which the hematopoietic cell nucleus changes its identity and acquires hepatic features. These BMDHs have their own cell identity characterized by an expression pattern different from hematopoietic cells or hepatocytes. The role of these BMDHs in the liver requires further investigation.

ORGANISM(S): Mus musculus

PROVIDER: GSE29878 | GEO | 2012/04/01

SECONDARY ACCESSION(S): PRJNA140997

REPOSITORIES: GEO

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Project description:A network of transcription factors (TFs) determines cell identity, but identity can be altered by overexpressing a combination of TFs. In principle, this opens the possibility of achieving one of the goals of regenerative medicine generating the desired differentiated cells from pluripotent stem cells, such as embryonic stem (ES) cells and induced pluripotent stem (iPS) cells. However, choosing and verifying combinations of TFs for specific cell differentiation has been daunting due to a large number of possible combinations of ~2,000 TFs. Here we report an unbiased systematic approach identifying individual TFs that can direct efficient and rapid specific lineage differentiation. We start from a correlation matrix of global gene expression responses to the induction of single TFs and global gene expression profiles of a variety of tissues and organs. Based on the correlation matrix, we select TFs as examples and show that their overexpression differentiates ES cells into cells of specific organs, as predicted: Sfpi1 for blood cells, Hnf4a or Foxa1 for hepatocytes, and Ascl1 for neurons. Furthermore, we show that transfection of synthetic mRNAs of Sfpi1, Hnf4a, or Ascl1 generate correspondingly specific target cells. These results demonstrate both the wide-ranging utility of this approach to identify potent TFs for cell differentiation, and also the unanticipated capacity of single TFs to directly guide differentiation to specific lineage fates. Previously, we generated the global gene expression profiles obtained by overexpressing single TFs using the NIA mouse ES cell bank, which consists of 137 mouse ES cell lines carrying a doxycycline-regulatable TF. We then generated the correlation matrix by comparing TF-induced gene expression profiles and the expression profiles of a variety of cell types. TFs predicted by the correlation matrix for specific cell differentiation were selected and subjected to the detailed differentiation assays. ES cell lines were cultured in the GMEM with 1% FBS, 10% knockout serum (invitrogen), and LIF (Millipore). To induce differentiation, ES cell lines were cultured in the differentiation medium (DM) [(alpha minimal essential medium, aMEM) supplemented with 10% fetal calf serum and 5 × 10–5 M 2-mercaptoethanol] with or without doxycycline (1 g/ml). The following organ-specific cell culture media were also used: StemPro-34 Serum Free Media (invitrogen) for blood cells, Hepatocyte culture media kit (BD Biosciences) for hepatocytes, and NeuroCult differentiation kit (StemCell Technologies Inc) for neurons.

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Sequential Reprogramming Leads to a Specific Hepatic Expression Pattern during Mouse Bone Marrow Derived Hepatocyte Formation In Vivo

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