Intraportal islet transplantation: the impact of the liver microenvironment

Abstract

SUMMARYThe portal vein remains the preferred site for pancreatic islet transplantation due to its easy access and low morbidity. However, despite great progress in isolation and transplantation protocols over the past few years, it is still associated with the early loss of some 50-70% of transplanted islets. The complex liver microenvironment itself presumably plays an important role in this loss. The present review focuses on the specifics of the liver microenvironment, notably the localized hepatic ischemia/reperfusion injury following transplantation, the low oxygenation of the portal vein, the instant blood-mediated inflammatory reaction, the endogenous liver immune system, and the gut-liver axis, and how they can each have an impact on the transplanted islets. It identifies the potential, or already applied, clinical interventions for improving intraportal islet survival, and pinpoints those promising areas still lacking preclinical research. Future interventions on clinical intraportal islet transplantation need to take into account the global context of the liver microenvironment, with multi-point interventions being most likely to improve early islet survival and engraftment.

Integrated whole liver histologic analysis of the allogeneic islet distribution and characteristics in a nonhuman primate model

“…The liver is mainly considered a suitable site for islet transplantation 16 . Islets transplanted into the portal vein are considered transplanted into the entire liver via the bloodstream.…”

“…In islet transplantation studies, observing the transplanted islets in the recipient liver is very important because islets that have achieved insulin-independent normal glucose levels under various conditions during the early and extended periods after transplantation provide meaningful information that can aid progress in the islet transplantation field [12][13][14][15][16] . The most obvious method to observe islets transplanted into the recipient liver and surrounding environment is direct liver biopsy.…”

A novel model for in vivo quantification of immediate liver perfusion impairment after pancreatic islet transplantation

“…IBMIR starts within minutes and culminates about 120 min after islet transplantation. 3,4 Focal discolorations, which develop in suboptimally/insufficiently perfused liver tissue, are clearly visible immediately after islet transplantation with subsequent progression into focal necrosis of liver cells in order of hours. The consequent inflammation and thrombosis lead to a significant loss of transplanted islets early after infusion.…”

“…[3][4][5][6][7] that islet grafts isolated from more than one donor are required to achieve insulin independence of a diabetic patient in clinical practice. 4,[7][8][9] Several intervention strategies improving islet engraftment by inhibition of coagulation and/or inflammation have been reported, [8][9][10][11][12][13][14] however, a technique for quantification of ischemic liver tissue is still missing despite its critical need for the evaluation of efficiency of the diverse therapeutic interventions. Until now, IBMIR monitoring was based merely on the measurement of the level of thrombinantithrombin complex after pancreatic islet transplantation or in vitro using the blood loop system.…”

Chemical Strategies for Improving Islet Transplant Outcomes

“…Another important factor in islet destruction is hypoxia, which is experienced by the islets during isolation, culturing, and after implantation [23,33]. Studies have shown that insufficient oxygen levels lead to cell apoptosis, especially in highly metabolic cells such as β-cells [24][25][26][27][28].…”