Engineered islet cell clusters transplanted into subcutaneous space are superior to pancreatic islets in diabetes

Abstract

An alternative route for pancreatic islet transplantation is the subcutaneous space; however, inadequate vascularization in the subcutaneous space limits the availability of oxygen and nutrients to the subcutaneously transplanted islets, which leads to the development of a necrotic core in the islets, thereby causing islet dysfunction. Thus, we aimed to prevent the early apoptosis of pancreatic islets after transplantation into subcutaneous space by preparing islet clusters of appropriate size. We prepared fully functional islet cell clusters (ICCs) by using the hanging-drop technique. We optimized the size of ICCs on the basis of viability and functionality after culture in an hypoxic environment. We transplanted ICCs into the subcutaneous space of diabetic mice and evaluated the viability of the islets at the transplantation site. In an hypoxic environment, ICCs exhibited improved viability and functionality compared with control islets. ICCs, upon transplantation into the hypoxic subcutaneous space of diabetic mice, showed better glycemic control compared with control islets. Live/dead imaging of the islets after retrieval from the transplanted area revealed significantly reduced apoptosis in ICCs. Transplantation of ICCs may be an attractive strategy to prevent islet cell apoptosis that results from nonimmune-mediated physiologic stress at the transplantation site.-Pathak, S., Regmi, S., Gupta, B., Pham, T. T., Yong, C. S., Kim, J. O., Yook, S., Kim, J.-R., Park, M. H., Bae, Y. K., Jeong, J.-H. Engineered islet cell clusters transplanted into subcutaneous space are superior to pancreatic islets in diabetes.

Fibrin supports subcutaneous neonatal porcine islet transplantation without the need for pre‐vascularization

“…Though the subcutaneous space is an attractive ectopic islet transplant site with numerous merits, 4,15,32 it lacks adequate blood supply and exhibits a hypoxic environment. 14,[38][39][40][41][42][43] We report that NPIs transplanted into the dorsal subcutaneous space of diabetic B6/Rag -/mice failed to engraft and correct hyperglycemia. However, all mice transplanted subcutaneously with NPI pre-embedded in fibrin (SC + F) achieved Fibrin(ogen) is a proangiogenic plasma transglutaminase 46 that has a proliferative effect on fibroblasts, 47 which is pivotal in hemostasis, and wound healing.…”

Increase Functional β-Cell Mass in Subcutaneous Alginate Capsules With Porcine Prenatal Islet Cells but Loss With Human Adult Islet Cells

“…This benefit, however, did not prevent a 70% decline in b-cell number over 20 weeks, which contrasts with the fourfold increase in b-cell number in capsules containing prenatal porcine islet cells. This opposing outcome is attributable to differences in b-cell functional state: human adult b-cells in the graft do not exhibit signs of proliferative activity and do not survive well in the subcutaneous space, possibly caused by their higher susceptibility to its hypoxic microenvironment (35)(36)(37). It is thus far unknown whether this is also the case in intraperitoneal capsules.…”

The Fate of Allogeneic Pancreatic Islets following Intraportal Transplantation: Challenges and Solutions

“…This phenomenon is defined as central cell necrosis, which is often associated with reduced islet function [ 9 ]. Smaller islets are therefore favorable for transplantation and might lead to better graft survival [ 10 ]. Even after vascularization is complete, the vascular density, oxygen tension, and blood perfusion of the engrafted islets remain in an anoxic state compared with native islets [ 11 – 13 ].…”

“…Uematsu et al used a novel scaffold, recombinant peptide to optimize prevascularization procedures to augment subcutaneous islet function in mice [ 29 ]. A 3D-printed vascularized device has been invented and has enabled the long-term survival of human islets subcutaneously in immune-deficient mice [ 10 ]. Oxygen feeding to the transplanted islet is an intuitive means to overcome hypoxia.…”