The science behind Betalin Theraputics
Islet transplantation has become a feasible cell therapy procedure that aims to achieve normoglycemia in severe diabetic patients. Currently, one of the greatest challenges in this approach is early islet cell death. The natural microenvironment is lost during islet isolation, resulting in β-cell dysfunction and often death. Therefore, the importance of extracellular matrix (ECM) for islet viability and function has been repeatedly documented. Specifically, interactions between β-cells and the basement membrane of the vasculature are important for correct function.
Increased islet function in vitro has been documented for islets grown on several individual ECM components. Islet endothelial cells support insulin secretion and β-cell differentiation by their secretion of basement membrane components, especially laminin and the glycoprotein thrombospondin-1 sequestered to the islet matrix and hepatocyte growth factor. The high number of islet capillaries results in each β -cell being located directly adjacent to at least one endothelial cell, thereby enabling a direct interaction with endothelium-derived factors.
Tissue and organ engineering recognizes the need for a complex stroma and thus several approaches use natural decellularized scaffolds derived from the target tissue or organ.
Pancreatic microscaffolds, while an intuitive option, were not ideal for our therapeutic purposes due to the discrepancy in the vasculature between the exocrine part – where the pancreatic matrix is derived, and endocrine part – where the islets of Langerhans are located.
Decellularized lung microscaffolds, however, are derived from the lung's huge surface area of alveolar matrix, which is lined in its entirety by a basement membrane produced by the highly infiltrating fine vasculature. Because the interaction between β-cells and the basement membrane produced by endothelial cells has been shown to be critical for β-cell function, we reasoned that decellularized lung microscaffolds should provide a suitable milieu for β-cells.
Islet (red) onto micro-scaffold (green)
We further reason that utilizing three-dimensional decellularized scaffolds of minute size with a thickness not exceeding 300 µm, should allow free diffusion of gases and nutrients to all of its components, thereby avoiding hypoxia and malnutrition. This could also prove critical in eventual transplantation attempts as it would avoid the need to vascularize before angiogenesis takes place.
Indeed, EMPs prepared in our lab with whole islets (I0-EMPs) secreted high levels of insulin in a glucose-regulated manner. Cultures were periodically assayed for viability and function by performing on the same I0-EMPs time course Glucose-Stimulated Insulin Secretion (GSIS) analyses. Surprisingly, I0-EMPs continued to secrete large quantities of insulin even after almost 4 months in culture, the longest periods tested. The figure below shows, that I0-EMPs continue to secrete insulin in a glucose-regulated manner at levels comparable to those secreted by freshly isolated islets. The amount of insulin secreted by I0-EMPs under high glucose (HG) concentration was statistically indistinguishable from the insulin secretion values obtained from fresh islets (I0) -under the same glucose conditions- at any culture point even after 94 days in culture (p > 0.15). The insulin secretion values under low glucose (LG) conditions in I0-EMPs were also found not to be statistically significant from those secreted by fresh islets either (p > 0.15). Yet, for fresh islets (I0) and for all culture points of I0-EMPs except at 94 days there was a significant difference between the insulin secreted at HG and that secreted under LG conditions (p < 0.05) testifying further for the capacity of I0-EMPs to regulate insulin secretion.
These exciting findings lay the foundation for Betalin Therapeutics' solution, which is currently being developed towards clinical application.
More about the science behind Betalin Therapeutics' solution:
Lung-Derived Microscaffolds Facilitate Diabetes Reversal after Mouse and Human Intraperitoneal Islet Transplantation, Abualhassan Nasser, Sapozhnikov Lena, Pawlick Rena L, Kahana Meygal, Pepper Andrew R, Bruni Antonio, Gala-Lopez Boris, Kin Tatsuya, Mitrani Eduardo, Shapiro A.M. James, PLoS ONE, 2016, 11(5). (Link)
Beta Cells Secrete Significant and Regulated Levels of Insulin for Long Periods when Seeded onto Acellular Micro-Scaffolds, Sionov Ronit Vogt, Finesilver Gershon, Sapozhnikov Lena, Soroker Avigail, Zlotkin-Rivkin Efrat, Saad Yocheved, Kahana Meygal, Bodaker Matan, Alpert Evgenia, and Mitrani Eduardo. Tissue Engineering Part A. November 2015, 21(21-22): 2691-2702. (Link)
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