Subcutaneously transplanted islet-embedded endothelialized modules restore normoglycemia in diabetic SCID/Bg mice

The transplantation of pancreatic islets via the hepatic portal vein (Edmonton Protocol)1
is a promising treatment for type 1 diabetics1. However, this therapy has limitations2, two of which include: (1) the need for multiple donors for each transplant to achieve insulin independence3 and (2) insulin independence is not sustained2. Finding an alternative transplant site that is both minimally invasive and able to support a large transplant volume is necessary for restoring normoglycemia in diabetes. Although the subcutaneous site satisfies both of these criteria, the site is poorly vascularized. Modular tissue
engineering is a “bottom-up” approach which uses collagen gel rods, mesenchymal stromal cells (MSC) and endothelial cells (EC) to form a subcutaneous vascularized bed and can be used to deliver pancreatic islets4. In this study, the subcutaneous transplantation of Wistar rat islets (750 IEQ, islet equivalents) embedded in endothelialized modules (mixed with EC modules, with or without MSC) were sufficient
to restore and maintain normoglycemia in streptozotocin induced diabetic SCID/Bg mice for up to 21 days. Free islets had no effect. Islets embedded in collagen but without endothelial cells were able to return diabetic animals to normoglycemia, but insulin independence was not sustained (animals became hyperglycemic within 21 days). Islets embedded within endothelialized modules were able to drive vascularization of the subcutaneous implant by recruiting host-derived vessels within 14 days of
transplantation.
In addition, we assessed the intra-islet vasculature and found that embedded islets in endothelialized modules had become re-vascularized and integrated with the host’s vasculature. The presence of an integrated and perfuseable vasculature is not a feature of previous the relatively few previous subcutaneous implant studies(e.g., 5).
Embedded islets drove a more robust and prolonged inflammatory response observed by a large recruitment of neutrophils at day 7. A shift towards a CD206+MHCII- (M2-like) macrophage was also observed at day 7 in islet-embedded modular implants, which continued to day 14. While we have demonstrated that module-associated vasculature is sufficient to support islet function and viability over 21 days, it remains to reduce the number of islets required to achieve normoglycemia. To this end, we are using modules to pre-vascularize the subcutaneous site before islet transplantation.

References:

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