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Differentiating neural crest stem cells induce proliferation of cultured rodent islet beta cells
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neuroanatomi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
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2012 (Engelska)Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 55, nr 7, s. 2016-2025Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Aims/hypothesis

Efficient stimulation of cycling activity in cultured beta cells would allow the design of new strategies for cell therapy in diabetes. Neural crest stem cells (NCSCs) play a role in beta cell development and maturation and increase the beta cell number in co-transplants. The mechanism behind NCSC-induced beta cell proliferation and the functional capacity of the new beta cells is not known.

Methods

We developed a new in vitro co-culture system that enables the dissection of the elements that control the cellular interactions that lead to NCSC-dependent increase in islet beta cells.

Results

Mouse NCSCs were cultured in vitro, first in medium that stimulated their proliferation, then under conditions that supported their differentiation. When mouse islet cells were cultured together with the NCSCs, more than 35% of the beta cells showed cycle activity. This labelling index is more than tenfold higher than control islets cultured without NCSCs. Beta cells that proliferated under these culture conditions were fully glucose responsive in terms of insulin secretion. NCSCs also induced beta cell proliferation in islets isolated from 1-year-old mice, but not in dissociated islet cells isolated from human donor pancreas tissue. To stimulate beta cell proliferation, NCSCs need to be in intimate contact with the beta cells.

Conclusions/interpretation

Culture of islet cells in contact with NCSCs induces highly efficient beta cell proliferation. The reported culture system is an excellent platform for further dissection of the minimal set of factors needed to drive this process and explore its potential for translation to diabetes therapy.

Ort, förlag, år, upplaga, sidor
2012. Vol. 55, nr 7, s. 2016-2025
Nyckelord [en]
Beta cell, Cell culture, Diabetes, Neural crest, Proliferation
Nationell ämneskategori
Endokrinologi och diabetes
Identifikatorer
URN: urn:nbn:se:uu:diva-178542DOI: 10.1007/s00125-012-2542-0ISI: 000305215200020OAI: oai:DiVA.org:uu-178542DiVA, id: diva2:542428
Anmärkning

De 2 förstaförfattarna delar förstaförfattarskapet

De 2 sistaförfattarna delar sistaförfattarskapet

Tillgänglig från: 2012-08-01 Skapad: 2012-07-31 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
Ingår i avhandling
1. The beneficial Effects of Neural Crest Stem Cells on Pancreatic      β–cells
Öppna denna publikation i ny flik eller fönster >>The beneficial Effects of Neural Crest Stem Cells on Pancreatic      β–cells
2014 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2014. s. 67
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1037
Nyckelord
Neural Crest Stem Cells, Pancreatic Islets, β-cell proliferation, β-cell survival, Cadherin
Nationell ämneskategori
Neurovetenskaper
Forskningsämne
Medicinsk vetenskap
Identifikatorer
urn:nbn:se:uu:diva-233157 (URN)978-91-554-9056-0 (ISBN)
Disputation
2014-11-18, B/B7:113a, Biomedical center, Husargatan 3, Uppsala, 13:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2014-10-27 Skapad: 2014-09-29 Senast uppdaterad: 2018-01-11

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Vasylovska, SvitlanaOlerud, JohanNgamjariyawat, AnongnadJansson, LeifKozlova, Elena N.

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Vasylovska, SvitlanaOlerud, JohanNgamjariyawat, AnongnadJansson, LeifKozlova, Elena N.
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NeuroanatomiInstitutionen för neurovetenskapInstitutionen för medicinsk cellbiologi
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Diabetologia
Endokrinologi och diabetes

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