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ALK5 inhibition maintains islet endothelial cell survival but does not enhance islet graft revascularisation or function

ALK5 inhibition maintains islet endothelial cell survival but does not enhance islet graft revascularisation or function
ALK5 inhibition maintains islet endothelial cell survival but does not enhance islet graft revascularisation or function
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.
sb-431542, a-83-01, islet transplantation, tgf-?
0018-5043
78-83
King, A.J.F.
33799cb8-cf5d-4061-b69f-5a68ecaf2a9c
Clarkin, C.E.
05cd2a88-1127-41aa-a29b-7ac323b4f3c9
Austin, A.L.F.
f85a17c2-ebaa-4c06-b44f-90b6a189677c
Ajram, L.
d4be0e46-756e-4265-b874-542eb0c1e4e1
Dhunna, J.K.
51f17a35-1444-4363-abeb-5f141ec6b4c5
Jamil, M.O.
8d5c581c-5056-4242-b139-4de1f46ffcbd
Ditta, S.I.
10ed7463-13e9-481e-bc0a-d9b3558a29a5
Ibrahim, S.
9b41a1e1-919c-44f9-922b-9bbc5bf47eae
Raza, Z.
1b1cce86-d521-4374-bfe9-eb913e9ca434
Jones, P.M.
cfa35894-2bdd-452e-ba73-7efbee348e55
King, A.J.F.
33799cb8-cf5d-4061-b69f-5a68ecaf2a9c
Clarkin, C.E.
05cd2a88-1127-41aa-a29b-7ac323b4f3c9
Austin, A.L.F.
f85a17c2-ebaa-4c06-b44f-90b6a189677c
Ajram, L.
d4be0e46-756e-4265-b874-542eb0c1e4e1
Dhunna, J.K.
51f17a35-1444-4363-abeb-5f141ec6b4c5
Jamil, M.O.
8d5c581c-5056-4242-b139-4de1f46ffcbd
Ditta, S.I.
10ed7463-13e9-481e-bc0a-d9b3558a29a5
Ibrahim, S.
9b41a1e1-919c-44f9-922b-9bbc5bf47eae
Raza, Z.
1b1cce86-d521-4374-bfe9-eb913e9ca434
Jones, P.M.
cfa35894-2bdd-452e-ba73-7efbee348e55

King, A.J.F., Clarkin, C.E., Austin, A.L.F., Ajram, L., Dhunna, J.K., Jamil, M.O., Ditta, S.I., Ibrahim, S., Raza, Z. and Jones, P.M. (2015) ALK5 inhibition maintains islet endothelial cell survival but does not enhance islet graft revascularisation or function. Hormone and Metabolic Research, 47 (1), 78-83. (doi:10.1055/s-0034-1395567). (PMID:25429440)

Record type: Article

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.

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More information

e-pub ahead of print date: 27 November 2014
Published date: January 2015
Keywords: sb-431542, a-83-01, islet transplantation, tgf-?
Organisations: Biomedicine

Identifiers

Local EPrints ID: 375381
URI: https://eprints.soton.ac.uk/id/eprint/375381
ISSN: 0018-5043
PURE UUID: c039e581-0474-4fb3-bccf-6f855aa4140b

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Date deposited: 23 Mar 2015 13:05
Last modified: 15 Jul 2019 21:26

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