Engraftment, function and beta cell regulation in the adrenal transplant model
Final Report Abstract
Pancreatic islet transplantation is a viable treatment option for selected patients with type 1 diabetes mellitus. However, a number of factors hamper widespread utilization of this therapeutic modality. A major limiting factor for long-term survival and function of islet transplants are still insufficient. A major determinant is the microenvironment of is in regard to the inappropriate microenvironment after intraportal transplantation. We aim to evaluate the microenvironment of the adrenal as a beneficial transplantation site that promotes beta cell engraftment, survival and long-term function as the adrenal offers extensive vascularization, anti-apoptotic and pro-proliferative effects of various signalling molecules and a local anti-inflammatory and immunosuppressive microenvironment. For in vitro analysis of islet viability, function and reactive oxygen species (ROS) a co-culture system of adrenal cells and pancreatic islets was established. The co-culture setting did not significantly impact on islet viability, insulin content and secretion and there is evidence that oxidative stress is markedly reduced in the presence of adrenal cells. For islet transplantation, the adrenal of diabetic NuNu-mice was exteriorized and 300 islets were injected through the upper pole of the gland or the kidney. Animals showed a fast decrease in blood glucose levels within the first days after transplantation in both groups, at around 10 days the curves between adrenal and kidney site drifted apart in favor of the adrenal site. Regardless of the transplantation site, islets showed a well preserved morphology and intense insulin staining. The intra-adrenally engrafted islets show higher vascularization compared to the kidney capsule control. The preliminary work underlined the feasibility of islet transplantation into the adrenal with first promising results on the restoration of normoglycemia in streptozotocin-induced diabetic mice. The results achieved could prove the beneficial effect of the adrenal microenvironment on islet engraftment and function in vitro and in vivo and elucidate the underlying mechanisms in regards to promoting islet revascularization, protection from oxidative stress, and enhancement of islet proliferative capacity. This novel concept might allow reducing the islet mass that is currently needed to reverse diabetes.
Publications
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Modulation of pancreatic islets-stress axis by hypothalamic releasing hormones and 11betahydroxysteroid dehydrogenase. Proc Natl Acad Sci USA. 2011 Aug 16;108(33):13722-7
Schmid J, Ludwig B, Schally AV, Steffen A, Ziegler CG, Block NL, Koutmani Y, Brendel MD, Karalis KP, Simeonovic CJ, Licinio J, Ehrhart-Bornstein M, Bornstein SR
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„Agonists of Growth Hormone Releasing Hormone as Effectors for Survival and Proliferation of Pancreatic Islets“. International Patent Application number: PCT/US2011/039,162
Andrew Schally, Norman Block, Stefan Bornstein, Barbara Ludwig
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Acromegaly and oxidative stress: impact on endothelial dysfunction and atherosclerosis. Horm. Metab. Res., 2013 45:255-256
Morawietz H
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Impact of Hey2 and COUP-TFII on genes involved in arteriovenous differentiation in primary human arterial and venous endothelial cells. Basic Res. Cardiol., 2013 Jul;108(4):362
Korten S, Brunssen C, Poitz DM, Grossklaus S, Brux M, Schnittler HJ, Strasser RH, Bornstein SR, Morawietz H, Goettsch W
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Lipoprotein apheresis of hypercholesterolemic patients mediates vasoprotective gene expression in human endothelial cells. Atherosclerosis (Supplements), 2013 14:107-113
Morawietz H, Goettsch W, Brux M, Reimann M, Bornstein SR, Julius U, Ziemssen T
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Transplantation of pancreatic islets to adrenal gland is promoted by agonists of growth-hormonereleasing hormone. Proc Natl Acad Sci USA. 2013 Feb 5;110(6):2288-93
Schubert U, Schmid J, Lehmann S, Zhang XY, Morawietz H, Block NL, Kanczkowski W, Schally AV, Bornstein SR, Ludwig B
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Increased gene expression of the cardiac endothelin system in obese mice. Horm Metab Res. 2015 Jun;47(7):509-15
Catar RA, Muller G, Brandt A, Langbein H, Brunssen C, Goettsch C, Frenzel A, Hofmann A, Goettsch W, Steinbronn N, Strasser RH, Schubert U, Ludwig B, Bornstein SR, Morawietz H
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Transplantation of bovine adrenocortical cells encapsulated in alginate. Proc Natl Acad Sci USA. 2015 Feb 24;112(8):2527-32
Balyura M, Gelfgat E, Ehrhart-Bornstein M, Ludwig B, Gendler Z, Barkai U, Zimerman B, Rotem A, Block NL, Schally AV, Bornstein SR
