Dataset Information

Combining TGF-? signal inhibition and connexin43 silencing for iPSC induction from mouse cardiomyocytes.

ABSTRACT: The reprogramming of differentiated cells into induced pluripotent stem cells (iPSCs) can be achieved by ectopic expression of defined transcription factors (Oct3/4, Sox2, Klf4 and c-Myc). However, to date, some iPSCs have been generated using viral vectors; thus, unexpected insertional mutagenesis in the target cells would be a potential risk. Here we report reprogramming of siPSCs (gene silencing-induced pluripotent stem cells) from mouse neonatal cardiomyocytes (CMs) by combining TGF-? signal inhibition and connexin43 (Cx43) silencing, and show that siPSCs show pluripotency in vitro and in vivo. Our novel non-insertional mutagenesis technique may provide a means for iPSC generation.

SUBMITTER: Dai P

PROVIDER: S-EPMC4255192 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Publications

Combining TGF-β signal inhibition and connexin43 silencing for iPSC induction from mouse cardiomyocytes.

Dai Ping P Harada Yoshinori Y Miyachi Hitoshi H Tanaka Hideo H Kitano Satsuki S Adachi Tetsuya T Suzuki Tomoyuki T Hino Hitoshi H Takamatsu Tetsuro T

Scientific reports 20141204

The reprogramming of differentiated cells into induced pluripotent stem cells (iPSCs) can be achieved by ectopic expression of defined transcription factors (Oct3/4, Sox2, Klf4 and c-Myc). However, to date, some iPSCs have been generated using viral vectors; thus, unexpected insertional mutagenesis in the target cells would be a potential risk. Here we report reprogramming of siPSCs (gene silencing-induced pluripotent stem cells) from mouse neonatal cardiomyocytes (CMs) by combining TGF-β signal ...[more]

PMID: 25471520

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Project description:Prevailing insulin resistance and the resultant hyperglycemia elicits a compensatory response from pancreatic islet beta cells (β-cells) that involves increases in β-cell function and β-cell mass. However, the sustained metabolic stress eventually leads to β-cell failure characterized by severe β-cell dysfunction and progressive loss of β-cell mass. Whereas, β-cell dysfunction is relatively well understood at the mechanistic level, the avenues leading to loss of β-cell mass are less clear with reduced proliferation, dedifferentiation, and apoptosis all potential mechanisms. Butler and colleagues documented increased β-cell apoptosis in pancreas from lean and obese human Type 2 diabetes (T2D) subjects, with no changes in rates of β-cell replication or neogenesis, strongly suggesting a role for apoptosis in β-cell failure. Here, we describe a permissive role for TGF-β/Smad3 in β-cell apoptosis. Human islets undergoing β-cell apoptosis release increased levels of TGF-β1 ligand and phosphorylation levels of TGF-β's chief transcription factor, Smad3, are increased in human T2D islets suggestive of an autocrine role for TGF-β/Smad3 signaling in β-cell apoptosis. Smad3 phosphorylation is similarly increased in diabetic mouse islets undergoing β-cell apoptosis. In mice, β-cell-specific activation of Smad3 promotes apoptosis and loss of β-cell mass in association with β-cell dysfunction, glucose intolerance, and diabetes. In contrast, inactive Smad3 protects from apoptosis and preserves β-cell mass while improving β-cell function and glucose tolerance. At the molecular level, Smad3 associates with Foxo1 to propagate TGF-β-dependent β-cell apoptosis. Indeed, genetic or pharmacologic inhibition of TGF-β/Smad3 signals or knocking down Foxo1 protects from β-cell apoptosis. These findings reveal the importance of TGF-β/Smad3 in promoting β-cell apoptosis and demonstrate the therapeutic potential of TGF-β/Smad3 antagonism to restore β-cell mass lost in diabetes.

Dataset Information

Combining TGF-? signal inhibition and connexin43 silencing for iPSC induction from mouse cardiomyocytes.

Publications

Combining TGF-β signal inhibition and connexin43 silencing for iPSC induction from mouse cardiomyocytes.

Similar Datasets

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