Markedly Decreased Blood Perfusion of Pancreatic Islets Transplanted Intraportally Into the Liver

Abstract

Experimental studies indicate low revascularization of intraportally transplanted islets. This study aimed to quantify, for the first time, the blood perfusion of intrahepatically transplanted islets and elucidate necessary factors for proper islet graft revascularization at this site. Yellow chameleon protein 3.0 islets expressing fluorescent protein in all cells were transplanted. Graft blood perfusion was determined by microspheres. The vascular density and relative contribution of donor blood vessels in revascularization was evaluated using islets expressing green fluorescent protein under the Tie-2 promoter. Blood perfusion of intrahepatic islets was as a mean only 5% of that of native islets at 1-month posttransplantation. However, there was a marked heterogeneity where blood perfusion was less decreased in islets transplanted without prior culture and in many cases restored in islets with disrupted integrity. Analysis of vascular density showed that distorted islets were well revascularized, whereas islets still intact at 1-month posttransplantation were almost avascular. Few donor endothelial cells were observed in the new islet vasculature. The very low blood perfusion of intraportally transplanted islets is likely to predispose for ischemia and hamper islet function. Since donor endothelial cells do not expand posttransplantation, disruption of islet integrity is necessary for revascularization to occur by recipient blood vessels.

Survival of encapsulated islets: More than a membrane story

“…The endocrine tissue, which in humans includes approximately 1 million IOL, is scattered in the exocrine pancreas and constitutes only 1%2% of its biomass, while utilizing 10%20% of the total blood flow into the organ [113115] . The proportion of arteriole endings and of vascular density in IOL and exocrine tissue is similar [116,117] . IOL are supplied with arterial blood via one or more arterioles which, after penetrating the capsule, form dense, glomerularlike network of capillaries.…”

“…This architecture is dramatically changed following transplantation. Capillary densities of rodent islet grafts implanted under the kidney capsule average 500700 capillaries/mm 2[121124] , which is approximately half the density of native pancreatic islets (1300 capillaries/mm 2 ) [123] and vascular density of murine islets transplanted into the liver is not more than 20% of the original density [117] . The vascular density of the human subcutis is lower by an additional order of magnitude averaging only 60100 capillaries/ mm 2[125127] .…”

Endothelial chimerism and vascular sequestration protect pancreatic islet grafts from antibody-mediated rejection

“…In contrast with transplantation, where perfusion is immediately reestablished by surgical reconnection of the arterial and venous vessels of the organ to the recipient's circulation, the restoration of blood flow to grafted islets involves angiogenesis (25)(26)(27)(28)(29). We postulated that this difference might explain the resistance of islet graft vasculature to the deleterious impact of DSA.…”

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

“…However, the long-term results have been hampered by substantial early cell death due to hypoxic [1] and inflammatory events [2], and later to insufficient engraftment [3,4], gluco-/lipotoxicity [5], islet amyloid formation [6,7] and immunological events [8]. The exaggerated cell death occurring in the islet grafts necessitates transplantation of large numbers of islets to restore and maintain normoglycaemia in the recipients, which is largely problematic when considering the worldwide lack of organs for transplantation.…”