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Co-culture of insulin producing human EndoC-βH1 cells with boundary cap neural crest stem cells protects partially against cytokine-induced cell death
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (Regenerative Neurobiology)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (Regenerative Neurobiology)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

We have recently observed that co-culture of mouse and rat beta-cells with mouse boundary cap neural crest stem cells (bNCSCs) protected against inflammatory cytokine-induced cell death, possibly via direct cadherin-mediated cell-to-cell junctions. However, it has not been addressed whether also human beta-cells can be protected via this strategy. The aim of this investigation was therefore to study the effect of bNCSC co-culture with insulin producing human EndoC-βH1 cells on cytokine-induced cell death. For this purpose GFP-positive bNCSCs were cultured together with GFP-negative EndoC-βH1 cells in the presence of the cytokines IL-1b (50 U/ml) and IFN-g (1000 U/ml). Cells were then stained with propidium iodide and trypsinized for flow cytometry analysis. Analysis of propidium iodide fluorescence in GFP-positive and GFP-negative cells revealed that EndoC-βH1 cells died to a lower extent when co-cultured with bNCSCs than when cultured without bNCSCs. We also observed that EndoC-βH1 cells formed N-cadherin, but not E-cadherin junctions with the bNCSCs. The bNCSC cell population contained a large proportion of beta-tubulin expressing cells indicating neuronal differentiation. A protective function of the N-cadherin junctions was suggested by one experiment in which a neutralizing N-cadherin antibody counteracted the effect of co-culture. We conclude that the interaction between human insulin producing cells and bNCSCs results in a lowered susceptibility of insulin producing cells to pro-inflammatory cytokines in vitro

National Category
Medical and Health Sciences
Research subject
Biomedical Laboratory Science
Identifiers
URN: urn:nbn:se:uu:diva-233153OAI: oai:DiVA.org:uu-233153DiVA: diva2:750720
Available from: 2014-09-29 Created: 2014-09-29 Last updated: 2015-01-23
In thesis
1. The beneficial Effects of Neural Crest Stem Cells on Pancreatic      β–cells
Open this publication in new window or tab >>The beneficial Effects of Neural Crest Stem Cells on Pancreatic      β–cells
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Patients with type-1 diabetes lose their β-cells after autoimmune attack. Islet transplantation is a co-option for curing this disease, but survival of transplanted islets is poor. Thus, methods to enhance β-cell viability and function as well as methods to expand β-cell mass are required. The work presented in this thesis aimed to study the roles of neural crest stem cells or their derivatives in supporting β-cell proliferation, function, and survival.

In co-culture when mouse boundary cap neural crest stem cells (bNCSCs) and pancreatic islets were in direct contact, differentiating bNCSCs strongly induced β-cell proliferation, and these proliferating β-cells were glucose responsive in terms of insulin secretion. Moreover, co-culture of murine bNCSCs with β-cell lines RIN5AH and β-TC6 showed partial protection of β-cells against cytokine-induced β-cell death. Direct contacts between bNCSCs and β-cells increased β-cell viability, and led to cadherin and β-catenin accumulations at the bNCSC/β-cell junctions. We proposed that cadherin junctions supported signals which promoted β-cell survival. We further revealed that murine neural crest stem cells harvested from hair follicles were unable to induce β-cell proliferation, and did not form cadherin junctions when cultured with pancreatic islets. Finally, we discovered that the presence of bNCSCs in co-culture counteracted cytokine-mediated insulin-producing human EndoC-βH1 cell death. Furthermore, these two cell types formed N-cadherin, but not E-cadherin, junctions when they were in direct contact. In conclusion, the results of these studies illustrate how neural crest stem cells influence β-cell proliferation, function, and survival which may improve islet transplantation outcome.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 67 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1037
Keyword
Neural Crest Stem Cells, Pancreatic Islets, β-cell proliferation, β-cell survival, Cadherin
National Category
Neurosciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-233157 (URN)978-91-554-9056-0 (ISBN)
Public defence
2014-11-18, B/B7:113a, Biomedical center, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2014-10-27 Created: 2014-09-29 Last updated: 2015-01-23

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