A prevascularized subcutaneous device-less site for islet and cellular transplantationby Andrew R Pepper, Boris Gala-Lopez, Rena Pawlick, Shaheed Merani, Tatsuya Kin, A M James Shapiro

Nat Biotechnol

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A rt i c l e s

Cellular transplantation is an attractive and growing treatment strategy for a variety of disease processes, including diabetes, Parkinson’s disease, myocardial ischemia, stroke, metabolic liver disease and hemophilia.

A prototypic example of cellular replacement therapy is intrahepatic transplantation of donor-derived pancreatic islets of Langerhans in individuals with type 1 diabetes mellitus who have unstable glucose control. The ‘Edmonton protocol’ for administering this therapy achieved high rates of insulin independence1. Initial long-term analysis indicated that insulin independence was not durable, as most recipients eventually returned to requiring moderate amounts of insulin, although they remained protected from recurrent hypoglycemia2.

Recent results from six islet centers suggest marked improvement in durable graft function, with insulin independence now seen in more than half of recipients at five years after transplantation3. However, the procedure often results in acute or gradual graft attrition, and carries risks of bleeding, thrombosis and localized steatosis. Moreover, intrahepatic transplantation does not permit imaging or retrieval of donor islets. The ability to retrieve the graft is especially important for current efforts to replace donor-derived islets with cells produced from human pluripotent stem cells, which may have unwanted effects.

These considerations suggest that the liver is not the optimal site for islet transplantation4,5.

Islets isolated for transplantation have lost their natural vascularized and specialized extracellular matrix6,7 and, for successful engraftment, must receive nutritional and physical support from the host through the formation of new blood vessels around and within the graft. The density of newly formed vessels after transplantation is much lower than that in native islets8,9, irrespective of whether islets are delivered to the human liver, kidney or spleen9. Research on the development of alternative transplant sites9–11 (Supplementary Tables 1 and 2) has suggested that an optimal site for islet transplantation should (i) have an adequate tissue volume capacity, (ii) be in close proximity to vascular networks, ensuring a sufficient oxygen supply to the graft before revascularization, (iii) allow for dynamic communication between the graft and the systemic circulation in a physiologically relevant manner, (iv) facilitate minimally invasive methods to transplant, biopsy and retrieve the graft, and (v) elicit minimal inflammation to reduce immunogenicity and promote long-term graft survival11.

In theory, subcutaneous transplantation should be superior to portal vein infusion as it provides ready access to the graft and the possibility of monitoring function through imaging12–14. However, islet transplantation into an unmodified subcutaneous site has never reversed diabetes in animals or humans as the microenvironment is inhospitable to cell survival owing to poor oxygen tension and inadequate vascularization15. Stimulation of angiogenesis is critical to successful subcutaneous islet transplantation9,11,14,16. Oxygen generators, polymers, meshes, encapsulation devices, matrices, growth factors (including fibroblast growth factor, hepatocyte growth factor and vascular endothelial growth factor) and co-transplantation of mesenchymal stem cells have all been explored with variable success (Supplementary Table 1).

Strategies for subcutaneous transplantation that rely on biomaterials often fail because of the foreign-body and inflammatory reaction— a complex, dynamic process that can persist for the lifetime of the implant17. Physical contact of the implant with host blood, lymph, exudate or other fluids triggers an instant inflammatory response that leads to spontaneous adsorption to the biomaterial of host blood proteins, including albumin, fibrinogen, complement, fibronectin and γ-globulin17–19. Host cells responsible for wound healing encounter this layer and release cytokines, chemokines, reactive oxygen species and other enzyme products that recruit tissue-resident macrophages and undifferentiated monocytes to the wound site17–19. As macrophages

A prevascularized subcutaneous device-less site for islet and cellular transplantation

Andrew R Pepper1, Boris Gala-Lopez1, Rena Pawlick1, Shaheed Merani1, Tatsuya Kin1,2 & A M James Shapiro1,2

Transplantation of donor-derived islets into the liver is a successful cellular replacement therapy for individuals with diabetes.

However, the hepatic vasculature is not an optimal transplant site for several reasons, including graft attrition and the inability to retrieve or image the islets. Here we describe islet transplantation into a prevascularized, subcutaneous site created by temporary placement of a medically approved vascular access catheter. In mice with streptozotocin (STZ)-induced diabetes, transplantation of ~500 syngeneic islets into the resulting ‘device-less’ space reversed diabetes in 91% of mice and maintained normoglycemia for >100 days. The approach was also effective in mice with pre-existing diabetes, in another mouse strain that mounts a more vigorous inflammatory response, and across an allogeneic barrier. These results demonstrate that transient priming of a subcutaneous site supports diabetes-reversing islet transplantation in mouse models without the need for a permanent cell-encapsulation device. 1Clinical Islet Transplant Program, Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada. 2Department of Surgery, University of Alberta,

Edmonton, Alberta, Canada. Correspondence should be addressed to: A.M.J.S. (amjs@islet.ca).

Received 6 October 2014; accepted 12 March 2015; published online 20 April 2015; doi:10.1038/nbt.3211 © 20 15

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A ll rig ht s re se rv ed .   advance online publication nature biotechnology