Diabetes Is Reversed in a Murine Model by Marginal Mass Syngeneic Islet Transplantation Using a Subcutaneous Cell Pouch Device

Abstract

BackgroundIslet transplantation is a successful β-cell replacement therapy for selected patients with type 1 diabetes mellitus. Although high rates of early insulin independence are achieved routinely, long-term function wanes over time. Intraportal transplantation is associated with procedural risks, requires multiple donors, and does not afford routine biopsy. Stem cell technologies may require potential for retrievability, and graft removal by hepatectomy is impractical. There is a clear clinical need for an alternative, optimized transplantation site. The subcutaneous space is a potential substitute, but transplantation of islets into this site has routinely failed to reverse diabetes. However, an implanted device, which becomes prevascularized before transplantation, may alter this equation.MethodsSyngeneic mouse islets were transplanted subcutaneously within Sernova Corp's Cell Pouch (CP). All recipients were preimplanted with CPs 4 weeks before diabetes induction and transplantation. After transplantation, recipients were monitored for glycemic control and glucose tolerance.ResultsMouse islets transplanted into the CP routinely restored glycemic control with modest delay and responded well to glucose challenge, comparable to renal subcapsular islet grafts, despite a marginal islet dose, and normoglycemia was maintained until graft explantation. In contrast, islets transplanted subcutaneously alone failed to engraft. Islets within CPs stained positively for insulin, glucagon, and microvessels.ConclusionsThe CP is biocompatible, forms an environment suitable for islet engraftment, and offers a potential alternative to the intraportal site for islet and future stem cell therapies.

β-cell replacement sources for type 1 diabetes: a focus on pancreatic ductal cells

“…Unwanted 'off-target' mesodermal formation was reported with human ESCs in transplantation sites [Kroon et al 2008;Rezania et al 2012]. Many groups have tried selection of ESC-derived endocrine cells [Kelly et al 2015;Jiang and Morahan, 2015] or the use of micro-and macroencapsulation devices [Motte et al 2014;Agulnick et al 2015;Song and Roy, 2015] such as the Theracyte TM (Inc. manufactures, Laguna Hills, California) system to circumvent the undesired cell growth, but also to promote angiogenesis of the cells and to protect those from the host immune system [Pepper et al 2015]. PSC-derived functional insulin-producing cells were recently injected into a Theracytebased device (called Encaptra TM , San Diego, California) and subsequently transplanted subcutaneously [Agulnick et al 2015].…”

Finding a New Home for Islet Cell Transplants

“…Recently, however, success in improving vascularisation for murine islet transplantation has been achieved within a macropolymer device implanted subcutaneously. 4 In this issue of Transplantation, Pepper et al 5 from the Edmonton group, extend their previous studies 6 showing evidence of creation of a vascularized subcutaneous space in mice using a novel "deviceless (DL) approach" to create a prevascularized site for islet implantation and transplanting a marginal mass of islets. Two-centimeter segments of a 5-French (Fr.)…”

Long-term function and optimization of mouse and human islet transplantation in the subcutaneous device-less site

“…8,12,[14][15][16] It has been suggested that the lack of graft viability post-subcutaneous transplantation is due to the tissue's relatively low superficial tissue oxygen tension compared to other vascularized organs. 16 To thwart endogenous hypoxia and improve islet engraftment, subcutaneous engraftment strategies have employed growth factors, 17 scaffolds, 18-20 encapsulation polymers, 15,21 immunoisolating and non-immunoisolating devices, 11,[22][23][24][25][26] and oxygen delivery technologies. 17,24 While attractive due to the potential of avoiding systemic immunosuppression, a drawback of immunoisolating devices is the physical separation between host nutrient supply and the therapeutic cells within the device.…”