Vascular heterogeneity between native rat pancreatic islets is responsible for differences in survival and revascularisation post transplantation

Abstract

Aims/hypothesis Highly blood-perfused islets have been observed to be the most functional islets in the native pancreas. We hypothesised that differences in vascular support of islets in donor pancreases influence their susceptibility to cellular stress and capacity for vascular engraftment after transplantation. Methods Highly blood-perfused islets in rats were identified by injection of microspheres into the ascending aorta before islet isolation. Cell death was evaluated after in vitro cytokine or hypoxia exposure, and 2 days post transplantation. One month post transplantation, islet engraftment, including vascular density, blood perfusion and oxygen tension ( pO 2 ) in the tissue, was evaluated. Results Microsphere-containing islets had a similar frequency of cell death during standard culture conditions but increased cell death after exposure to cytokines and hypoxia in comparison with other islets. Two days after transplantation the percentage of apoptotic or necrotic cells was also higher in grafts of such islets and 1 month post transplantation these grafts were composed of substantially more connective tissue. Grafts of highly blood-perfused islets in the native pancreas regained a higher vascular density, blood perfusion and pO 2 in comparison with grafts of other islets. Conclusions/interpretation Native islets that are highly blood-perfused regained this feature after transplantation, indicating a superior capacity for revascularisation and posttransplant function. However, the same group of islets was more vulnerable to different kinds of cellular stress, which limited their early survival post transplantation. Preferential death of these most active islets may contribute to the high number of islets needed to provide cure with islet transplantation.

Quantification of β-Cell Mass in Intramuscular Islet Grafts Using Radiolabeled Exendin-4

“…36 The insulin area was determined manually using a Leica LMD6000-microscope (Leica Microsystems, Wetzlar, Germany). The total area of the islet graft was calculated as an area under the curve by plotting the known areas.…”

The dark side of islet vasculature

“…In their present study, reported in this issue of Diabetologia [13], Ullsten and colleagues report that highly perfused islets are more susceptible to cell death induced by the inflammatory cytokines TNFα, IFNγ and IL-1β or hypoxia in vitro. In addition, despite being better vascularised and oxygenated in the host, the highly perfused, microparticle-containing islets were found to be more prone to cell death and fibrosis.…”

“…If islets with the highest perfusion rate are also the islets that have the highest sensitivity to cytokines and hypoxia, as suggested by Ullsten and colleagues [13], this has many implications for our understanding of islet endocrine function, islet transplantation and islet pathology. Heterogeneity with regard to perfusion, function and sensitivity to cytotoxic conditions could conceivably help explain some of the histopathological observations that have until now had no clear explanation.…”

Islet amyloid deposits preferentially in the highly functional and most blood-perfused islets

“…On an inter-islet level, we have previously described two subpopulations of islets distinguished by their differences in blood supply; one low blood-perfused, low-oxygenated population with dormant metabolic activity (7), and another population with a high blood supply exhibiting superior functionality and beta cell proliferation indexes (8). Noteworthy, the latter population of high-functioning islets exhibited an increased sensitivity to hypoxia and cytokines leading to reduced survival upon stress (9). …”