Reprogramming of pancreatic exocrine cells AR42J into insulin-producing cells using mRNAs for Pdx1, Ngn3, and MafA transcription factors

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00023001%3A_____%2F16%3A00059976" target="_blank" >RIV/00023001:_____/16:00059976 - isvavai.cz</a>

Výsledek na webu

<a href="http://www.nature.com/mtna/journal/v5/n5/pdf/mtna201633a.pdf" target="_blank" >http://www.nature.com/mtna/journal/v5/n5/pdf/mtna201633a.pdf</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/mtna.2016.33" target="_blank" >10.1038/mtna.2016.33</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Reprogramming of pancreatic exocrine cells AR42J into insulin-producing cells using mRNAs for Pdx1, Ngn3, and MafA transcription factors

Popis výsledku v původním jazyce

Direct reprogramming of pancreatic nonendocrine cells into insulin-producing beta-cells represents a promising approach for the treatment of insulin-dependent diabetes. However, its clinical application is limited by the potential for insertional mutagenesis associated with the viral vectors currently used for cell reprogramming. With the aim of developing a nonintegrative reprogramming strategy for derivation of insulin-producing cells, here, we evaluated a new approach utilizing synthetic messenger RNAs encoding reprogramming transcription factors. Administration of synthetic mRNAs encoding three key transcription regulators of beta-cell differentiation-Pdx1, Neurogenin3, and MafA-efficiently reprogrammed the pancreatic exocrine cells into insulin-producing cells. In addition to the insulin genes expression, the synthetic mRNAs also induced the expressions of genes important for proper pancreatic beta-cell function, including Sur1, Kir6.2, Pcsk1, and Pcsk2. Pretreating cells with the chromatin-modifying agent 5-Aza-2'-deoxycytidine further enhanced reprogramming efficiency, increasing the proportion of insulin-producing cells from 3.5 +/- 0.9 to 14.3 +/- 1.9% (n = 4). Moreover, 5-Aza-2'-deoxycytidine pretreatment enabled the reprogrammed cells to respond to glucose challenge with increased insulin secretion. In conclusion, our results support that the reprogramming of pancreatic exocrine cells into insulin-producing cells, induced by synthetic mRNAs encoding pancreatic transcription factors, represents a promising approach for cell-based diabetes therapy.

Název v anglickém jazyce

Reprogramming of pancreatic exocrine cells AR42J into insulin-producing cells using mRNAs for Pdx1, Ngn3, and MafA transcription factors

Popis výsledku anglicky

Direct reprogramming of pancreatic nonendocrine cells into insulin-producing beta-cells represents a promising approach for the treatment of insulin-dependent diabetes. However, its clinical application is limited by the potential for insertional mutagenesis associated with the viral vectors currently used for cell reprogramming. With the aim of developing a nonintegrative reprogramming strategy for derivation of insulin-producing cells, here, we evaluated a new approach utilizing synthetic messenger RNAs encoding reprogramming transcription factors. Administration of synthetic mRNAs encoding three key transcription regulators of beta-cell differentiation-Pdx1, Neurogenin3, and MafA-efficiently reprogrammed the pancreatic exocrine cells into insulin-producing cells. In addition to the insulin genes expression, the synthetic mRNAs also induced the expressions of genes important for proper pancreatic beta-cell function, including Sur1, Kir6.2, Pcsk1, and Pcsk2. Pretreating cells with the chromatin-modifying agent 5-Aza-2'-deoxycytidine further enhanced reprogramming efficiency, increasing the proportion of insulin-producing cells from 3.5 +/- 0.9 to 14.3 +/- 1.9% (n = 4). Moreover, 5-Aza-2'-deoxycytidine pretreatment enabled the reprogrammed cells to respond to glucose challenge with increased insulin secretion. In conclusion, our results support that the reprogramming of pancreatic exocrine cells into insulin-producing cells, induced by synthetic mRNAs encoding pancreatic transcription factors, represents a promising approach for cell-based diabetes therapy.

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

FB - Endokrinologie, diabetologie, metabolismus, výživa

OECD FORD obor

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Projekt

<a href="/cs/project/NT12190" target="_blank" >NT12190: Příprava inzulín produkujících buněčných linií pro léčbu diabetu z prekursorových buněk dospělého pankreatu pomocí rekombinantních transkripčních faktorů</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2016

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Molecular therapy-nucleic acids

ISSN

2162-2531

e-ISSN

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Svazek periodika

5

Číslo periodika v rámci svazku

May 2016

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

12

Strana od-do

"art. no. e320"

Kód UT WoS článku

000376427500001

EID výsledku v databázi Scopus

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