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Rotational culture and integration with amniotic stem cells reduce porcine islet immunoreactivity in vitro and slow xeno‐rejection in a murine model of islet transplantation
Author(s) -
Zafar Ali,
Lee Jou,
Yesmin Shameema,
Paget Michelle B.,
Bailey Clifford J.,
Murray Hilary E.,
Downing Richard
Publication year - 2019
Publication title -
xenotransplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.052
H-Index - 61
eISSN - 1399-3089
pISSN - 0908-665X
DOI - 10.1111/xen.12508
Subject(s) - islet , transplantation , xenotransplantation , stem cell , in vitro , immune system , microbiology and biotechnology , immunology , amniotic epithelial cells , biology , andrology , medicine , endocrinology , diabetes mellitus , adult stem cell , endothelial stem cell , biochemistry
Background Pre‐transplant modification of porcine islets may improve their suitability for clinical use in diabetes management by supporting graft function and reducing the potential for xeno‐rejection. The present study investigates intra‐graft incorporation of stem cells that secrete beta (β)‐cell trophic and immunomodulatory factors to preserve function and alter immune cell responsiveness to porcine islets. Methods Isolated porcine islets were maintained in a three‐dimensional rotational cell culture system (RCCS) to facilitate aggregation with human amniotic epithelial cells (AECs). Assembled islet constructs were assessed for functional integrity and ability to avoid xeno‐recognition by CD4+ T‐cells using mixed islet:lymphocyte reaction assays. To determine whether stem cell‐mediated modification of porcine islets provided a survival advantage over native islets, structural integrity was examined in a pig‐to‐mouse islet transplant model. Results Rotational cell culture system supported the formation of porcine islet:AEC aggregates with improved insulin‐secretory capacity compared to unmodified islets, whilst the xeno‐response of purified CD4+ T‐cells to AEC‐bearing grafts was significantly ( P < 0.05) attenuated. Transplanted AEC‐bearing grafts demonstrated slower rejection in immune‐competent recipients compared to unmodified islets. Conclusions/interpretation Rotational culture enables pre‐transplant modification of porcine islets by integration with immunomodulatory stem cells capable of subduing xeno‐reactivity to CD4+ T‐cells. This reduces islet rejection and offers translational potential to widen availability and improve the clinical effectiveness of islet transplantation.