Repository of Research and Investigative Information

Repository of Research and Investigative Information

Ahvaz Jundishapur University of Medical Sciences

Sonic hedgehog pathway suppression and reactivation accelerates differentiation of rat adipose-derived mesenchymal stromal cells toward insulin-producing cells

Dayer, D. and Tabar, M. H. and Moghimipour, E. and Tabandeh, M. R. and Ghadiri, A. A. and Bakhshi, E. A. and Orazizadeh, M. and Ghafari, M. A. (2017) Sonic hedgehog pathway suppression and reactivation accelerates differentiation of rat adipose-derived mesenchymal stromal cells toward insulin-producing cells. Cytotherapy, 19 (8). pp. 937-946. ISSN 1465-3249

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Official URL: <Go to ISI>://WOS:000405936900004

Abstract

Background aims. Sonic hedgehog (Shh) is an intercellular signaling molecule that regulates pancreas development in mammals. Manipulation of Shh signaling pathway can be used as reliable approach to improve the generation of functional insulin-producing cells (IPCs) from mesenchymal stromal cells (MSCs). Methods. In the present study, a novel differentiation protocol was used to produce IPCs from adipose tissue-derived MSCs (ATDMSCs) based on sequential inhibition and reactivation of Shh pathway. ATDMSCs were differentiated into IPCs via a 14-day basic protocol using 1 insulin transferrin selenium (ITS) and 1 nicotinamide in Dulbecco's Modified Eagle's Medium medium. A mixture of 0.25 mu mol/L cyclopamine + 64 ng/mL basic fibroblast growth factor at day 3 of differentiation and 150 ng/mL recombinant Shh at day 11 of differentiation were used, respectively, to promote sequential inhibition and reactivation of Shh pathway. Insulin granule formation, glucose-stimulated insulin secretion and gene expression pattern related to the pancreatic endocrine development and function were analyzed in manipulated and unmanipulated IPCs. Results. IPCs obtained after Shh manipulation secreted higher amounts of insulin in vitro. This phenotype was accompanied by increased expression of both genes critical for beta-cell function and transcription factors associated with their mature phenotype including Pdx1, MafA, Nkx2.2, Nkx6.1, Ngn3, Isl1 and insulin at day 14 of differentiation. Conclusions. Our findings indicated that the early inhibition and late reactivation of Shh signaling pathway during the differentiation of ATDMSCs improved the functional properties of IPCs, a novel method that could be considered as an alternative approach for cell-based therapy for type 1 diabetes.

Item Type: Article
Keywords: adipose tissue-derived mesenchymal stromal cells insulin-producing cells sonic hedgehog manipulation embryonic stem-cells beta-cells in-vitro expression generation endoderm
Subjects: R Medicine > R Medicine (General)
Divisions: Faculty of Medicine, Health and Life Sciences
Depositing User: مهندس مهدی شریفی
Last Modified: 01 Jun 2018 13:08
URI: http://eprints.ajums.ac.ir/id/eprint/17282

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