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      Endothelial and beta cell composite aggregates for improved function of a bioartificial pancreas encapsulation device

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          Abstract

          Introduction:

          Encapsulation of pancreatic islets or beta cells is a promising strategy for treatment of type 1 diabetes by providing an immune isolated environment and allowing for transplantation in a different location than the liver. However, islets used for encapsulation often show lower functionality due to the damaging of islet endothelial cells during the isolation procedure. Factors produced by endothelial cells have great impact on beta cell insulin secretion. Therefore, mutual signaling between endothelial cells and beta cells should be considered for the development of encapsulation systems to achieve high insulin secretion and maintain beta cell viability. Here, we investigate whether co-culture of beta cells with endothelial cells could improve beta cell function within encapsulation devices.

          Materials and methods:

          Mouse insulinoma MIN6 cells and human umbilical vein endothelial cells were used for creating composite aggregates on agarose microwell platform. The composite aggregates were encapsulated within flat poly(ether sulfone)/polyvinylpyrrolidone device. Their functionality was assessed by glucose-induced insulin secretion test and compared to non-encapsulated free-floating aggregates.

          Results:

          We created composite aggregates of 80–100 µm in diameter, closely mimicking pancreatic islets. Upon glucose stimulation, their insulin secretion is improved in comparison to aggregates consisting of only MIN6 cells. Moreover, the composite aggregates encapsulated within a device secrete more insulin than aggregates consisting of only MIN6 cells.

          Conclusion:

          Composite aggregates of MIN6 cells with human umbilical vein endothelial cells have improved insulin secretion in comparison to MIN6 aggregates showing that the interaction of beta cell and endothelial cell is crucial for a functional encapsulation system.

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          Most cited references 35

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          The vascular basement membrane: a niche for insulin gene expression and Beta cell proliferation.

          Endocrine pancreatic beta cells require endothelial signals for their differentiation and function. However, the molecular basis for such signals remains unknown. Here, we show that beta cells, in contrast to the exocrine pancreatic cells, do not form a basement membrane. Instead, by using VEGF-A, they attract endothelial cells, which form capillaries with a vascular basement membrane next to the beta cells. We have identified laminins, among other vascular basement membrane proteins, as endothelial signals, which promote insulin gene expression and proliferation in beta cells. We further demonstrate that beta1-integrin is required for the beta cell response to the laminins. The proposed mechanism explains why beta cells must interact with endothelial cells, and it may apply to other cellular processes in which endothelial signals are required.
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            Pancreatic islet production of vascular endothelial growth factor--a is essential for islet vascularization, revascularization, and function.

            To investigate molecular mechanisms controlling islet vascularization and revascularization after transplantation, we examined pancreatic expression of three families of angiogenic factors and their receptors in differentiating endocrine cells and adult islets. Using intravital lectin labeling, we demonstrated that development of islet microvasculature and establishment of islet blood flow occur concomitantly with islet morphogenesis. Our genetic data indicate that vascular endothelial growth factor (VEGF)-A is a major regulator of islet vascularization and revascularization of transplanted islets. In spite of normal pancreatic insulin content and beta-cell mass, mice with beta-cell-reduced VEGF-A expression had impaired glucose-stimulated insulin secretion. By vascular or diffusion delivery of beta-cell secretagogues to islets, we showed that reduced insulin output is not a result of beta-cell dysfunction but rather caused by vascular alterations in islets. Taken together, our data indicate that the microvasculature plays an integral role in islet function. Factors modulating VEGF-A expression may influence islet vascularity and, consequently, the amount of insulin delivered into the systemic circulation.
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              Pancreatic beta cell lines and their applications in diabetes mellitus research.

              During the past 30 years great effort has been put into establishing an insulin-secreting beta cell line that retains normal regulation of insulin secretion, but only few of these attempts have been successful. To overcome the limited availability of primary beta cells and to include the principles of the 3Rs into the field of diabetes mellitus research, numerous investigators used X-rays or viruses to induce insulinomas, in vitro transformation, derivation of cells from transgenic mice or even non-islet cells to produce immortalised beta cell lines. The most widely used insulin-secreting cell lines are RIN, HIT, MIN, INS-1 and TC cells. These cells produce insulin and small amounts of glucagon and somatostatin. Some of them are only poorly responsive to glucose, others respond to glucose well, but their concentration-dependence curve is markedly shifted to higher sensitivity. Despite problems associated with beta cell cultures, these cell lines have provided some valuable information about physiological processes. However, an urgent need to establish a "normal" beta cell line of human or pig origin remains.
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                Author and article information

                Journal
                Int J Artif Organs
                Int J Artif Organs
                JAO
                spjao
                The International Journal of Artificial Organs
                SAGE Publications (Sage UK: London, England )
                0391-3988
                1724-6040
                20 February 2018
                March 2018
                : 41
                : 3
                : 152-159
                Affiliations
                [1 ]Bioartificial Organs, Biomaterials Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands
                [2 ]Biomedical Materials Group and Institute of Pharmacy, Martin Luther University of Halle-Wittenberg, Halle, Germany
                [3 ]Interdisciplinary Centre of Material Sciences, Martin Luther University of Halle-Wittenberg, Halle, Germany
                Author notes
                Dimitrios Stamatialis, Bioartificial Organs, Biomaterials Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands. Email: d.stamatialis@ 123456utwente.nl
                Article
                10.1177_0391398817752295
                10.1177/0391398817752295
                6161570
                29546813
                © The Author(s) 2018

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

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