Abstract
Islet transplantation is a potential treatment for Type 1 diabetes but long term graft
function is suboptimal. The rich supply of intraislet endothelial cells diminishes
rapidly after islet isolation and culture, which affects the revascularisation rate
of islets after transplantation. The ALK5 pathway inhibits endothelial cell proliferation
and thus inhibiting ALK5 is a potential target for improving endothelial cell survival.
The aim of the study was to establish whether ALK5 inhibition prevents the loss of
intraislet endothelial cells during islet culture and thus improves the functional
survival of transplanted islets by enhancing their subsequent revascularisation after
implantation. Islets were cultured for 48 h in the absence or presence of 2 different
ALK inhibitors: SB-431542 or A-83-01. Their vascular density after culture was analysed
using immunohistochemistry. Islets pre-cultured with the ALK5 inhibitors were implanted
into streptozotocin-diabetic mice for either 3 or 7 days and blood glucose concentrations
were monitored and vascular densities of the grafts were analysed. Islets cultured
with ALK5 inhibitors had higher vascular densities than control-cultured islets. Three
days after implantation, endothelial cell numbers in islet grafts were minimal, irrespective
of treatment during culture. Seven days after implantation, endothelial cells were
evident within the islet grafts but there was no difference between control-cultured
islets and islets pre-treated with an ALK5 inhibitor. Blood glucose concentrations
were no different between the treatment groups. In conclusion, inhibition of ALK5
improved intraislet endothelial cell numbers after islet culture, but this effect
was lost in the early post-transplantation period.
Key words
SB-431542 - A-83-01 - islet transplantation - TGF-β
