Exendin-4 enhances the differentiation of Wharton’s jelly mesenchymal stem cells into insulin-producing cells through activation of various β-cell markers

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Abstract

Background

Diabetes mellitus is a devastating metabolic disease. Generation of insulin-producing cells (IPCs) from stem cells, especially from Wharton’s jelly mesenchymal stem cells (WJ-MSCs), has sparked much interest recently. Exendin-4 has several beneficial effects on MSCs and β cells. However, its effects on generation of IPCs from WJ-MSCs specifically have not been studied adequately. The purpose of this study was therefore to investigate how exendin-4 could affect the differentiation outcome of WJ-MSCs into IPCs, and to investigate the role played by exendin-4 in this differentiation process.

Methods

WJ-MSCs were isolated, characterized and then induced to differentiate into IPCs using two differentiation protocols: protocol A, without exendin-4; and protocol B, with exendin-4. Differentiated IPCs were assessed by the expression of various β-cell-related markers using quantitative RT-PCR, and functionally by measuring glucose-stimulated insulin secretion.

Results

The differentiation protocol B incorporating exendin-4 significantly boosted the expression levels of β-cell-related genes Pdx-1, Nkx2.2, Isl-1 and MafA. Moreover, IPCs generated by protocol B showed much better response to variable glucose concentrations as compared with those derived from protocol A, which totally lacked such response. Furthermore, exendin-4 alone induced early differentiation markers such as Pdx-1 and Nkx2.2 but not Isl-1, besides inducing late markers such as MafA. In addition, exendin-4 showed a synergistic effect with nicotinamide and β-mercaptoethanol in the induction of these markers.

Conclusions

Exendin-4 profoundly improves the differentiation outcome of WJ-MSCs into IPCs, possibly through the ability to induce the expression of β-cell markers.

Electronic supplementary material

The online version of this article (doi:10.1186/s13287-016-0374-4) contains supplementary material, which is available to authorized users.

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Most cited references 40

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Generation of functional human pancreatic β cells in vitro.

Felicia W Pagliuca, Jeffrey Millman, Mads Gürtler … (2014)

The generation of insulin-producing pancreatic β cells from stem cells in vitro would provide an unprecedented cell source for drug discovery and cell transplantation therapy in diabetes. However, insulin-producing cells previously generated from human pluripotent stem cells (hPSC) lack many functional characteristics of bona fide β cells. Here, we report a scalable differentiation protocol that can generate hundreds of millions of glucose-responsive β cells from hPSC in vitro. These stem-cell-derived β cells (SC-β) express markers found in mature β cells, flux Ca(2+) in response to glucose, package insulin into secretory granules, and secrete quantities of insulin comparable to adult β cells in response to multiple sequential glucose challenges in vitro. Furthermore, these cells secrete human insulin into the serum of mice shortly after transplantation in a glucose-regulated manner, and transplantation of these cells ameliorates hyperglycemia in diabetic mice. Copyright © 2014 Elsevier Inc. All rights reserved.

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Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells.

Alireza Rezania, Jennifer Bruin, Payal Arora … (2014)

Transplantation of pancreatic progenitors or insulin-secreting cells derived from human embryonic stem cells (hESCs) has been proposed as a therapy for diabetes. We describe a seven-stage protocol that efficiently converts hESCs into insulin-producing cells. Stage (S) 7 cells expressed key markers of mature pancreatic beta cells, including MAFA, and displayed glucose-stimulated insulin secretion similar to that of human islets during static incubations in vitro. Additional characterization using single-cell imaging and dynamic glucose stimulation assays revealed similarities but also notable differences between S7 insulin-secreting cells and primary human beta cells. Nevertheless, S7 cells rapidly reversed diabetes in mice within 40 days, roughly four times faster than pancreatic progenitors. Therefore, although S7 cells are not fully equivalent to mature beta cells, their capacity for glucose-responsive insulin secretion and rapid reversal of diabetes in vivo makes them a promising alternative to pancreatic progenitor cells or cadaveric islets for the treatment of diabetes.

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Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats.

G Xu, D A Stoffers, J F Habener … (1999)

Diabetes is a disease of increasing prevalence in the general population and of unknown cause. Diabetes is manifested as hyperglycemia due to a relative deficiency of the production of insulin by the pancreatic beta-cells. One determinant in the development of diabetes is an inadequate mass of beta-cells, either absolute (type 1, juvenile diabetes) or relative (type 2, maturity-onset diabetes). Earlier, we reported that the intestinal hormone glucagon-like peptide I (GLP-I) effectively augments glucose-stimulated insulin secretion. Here we report that exendin-4, a long-acting GLP-I agonist, stimulates both the differentiation of beta-cells from ductal progenitor cells (neogenesis) and proliferation of beta-cells when administered to rats. In a partial pancreatectomy rat model of type 2 diabetes, the daily administration of exendin-4 for 10 days post-pancreatectomy attenuates the development of diabetes. We show that exendin-4 stimulates the regeneration of the pancreas and expansion of beta-cell mass by processes of both neogenesis and proliferation of beta-cells. Thus, GLP-I and analogs thereof hold promise as a novel therapy to stimulate beta-cell growth and differentiation when administered to diabetic individuals with reduced beta-cell mass.

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Author and article information

Contributors

Dina H. Kassem: dina_kassem@pharma.asu.edu.eg

Mohamed M. Kamal: Mohamed_kamal@pharma.asu.edu.eg

Abd El-Latif G. El-Kholy: drabdellatif_elkholy@med.asu.edu.eg

Hala O. El-Mesallamy: hala.elmesallamy@hotmail.com , hala_elmosalamy@hotmail.com

Journal

Journal ID (nlm-ta): Stem Cell Res Ther

Journal ID (iso-abbrev): Stem Cell Res Ther

Title: Stem Cell Research & Therapy

Publisher: BioMed Central (London )

ISSN (Electronic): 1757-6512

Publication date (Electronic): 11 August 2016

Publication date PMC-release: 11 August 2016

Publication date Collection: 2016

Volume: 7

Electronic Location Identifier: 108

Affiliations

[1 ]Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt

[2 ]Gynecology and Obstetrics Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Article

Publisher ID: 374

DOI: 10.1186/s13287-016-0374-4

PMC ID: 4981957

PubMed ID: 27515427

SO-VID: 42ea39ac-3ae5-4d1e-8669-7375c89f8c9a

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 22 April 2016

Date revision received : 13 July 2016

Date accepted : 25 July 2016

Funding

Funded by: Personal Funding

Custom metadata

ScienceOpen disciplines: Molecular medicine

Keywords: wharton’s jelly,mesenchymal stem cells,exendin-4,insulin-producing cells,diabetes mellitus

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ScienceOpen disciplines: Molecular medicine

Keywords: wharton’s jelly, mesenchymal stem cells, exendin-4, insulin-producing cells, diabetes mellitus

Exendin-4 enhances the differentiation of Wharton’s jelly mesenchymal stem cells into insulin-producing cells through activation of various β-cell markers

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Abstract

Background

Methods

Results

Conclusions

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Most cited references 40

Generation of functional human pancreatic β cells in vitro.

Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells.

Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats.

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