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Organoid optimization: Engineering a better cell therapy to treat type 1 diabetes

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Science Translational Medicine  15 Jan 2020:
Vol. 12, Issue 526, eaba2909
DOI: 10.1126/scitranslmed.aba2909

Abstract

Islet organoids reaggregated in endothelialized collagen constructs improve engraftment and function in the subcutaneous space in diabetic mice.

Islet transplantation is a cell-based therapy that can restore physiological insulin signaling in patients with type 1 diabetes. Although four decades of research in this field has demonstrated some improvement in achieving insulin independence in islet transplant recipients, the current intrahepatic delivery method results in up to 60% graft loss during and immediately after islet transplantation, necessitating the use of multiple donor organs to achieve insulin independence and severely limiting the feasibility of this therapy. Islet death post-transplantation is a result of multiple factors inherent to intrahepatic delivery, as well as the delayed revascularization of islet organoids, which are heavily vascularized and highly metabolic cell clusters that vary in size from 50 to 400 μm in diameter. Previous research has demonstrated that larger islets struggle to vascularize efficiently post-transplantation, resulting in organoid central necrosis and failure to engraft.

There has been substantial interest in transplanting islets in the subcutaneous space due to its accessibility and reduced operative risks; however, subcutaneous islet survival and function has historically been limited by poor graft revascularization. A new study from Vlahos and colleagues reports an engineering approach to improving islet survival and engraftment in the subcutaneous site. The authors created “pseudo-islets” by disassociating and reaggregating islets within collagen scaffolds and including supportive cells, such as endothelial cells and mesenchymal stromal cells. These pseudo-islets could be engineered for an ideal size and composition to maximize islet revascularization—and therefore survival and function—in the subcutaneous transplant site in diabetic mice.

The approach described in this study demonstrated promising diabetes reversal, but the substantial manipulation of primary islets to achieve these pseudo-islets, combined with the necessity of a second cell type to achieve engraftment, may limit the translational potential of this approach. Despite this caveat, this work represents progress toward achieving islet engraftment and function in extrahepatic transplant sites and, in particular, the challenging subcutaneous site.

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