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

Ali Zafar, Jou Lee, Shameema Yesmin, Michelle B. Paget, Clifford J. Bailey, Hilary E. Murray, Richard Downing

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article numbere12508
JournalXenotransplantation
Volume26
Issue number4
Early online date8 Apr 2019
DOIs
Publication statusPublished - 1 Jul 2019

Bibliographical note

This is the peer reviewed version of the following article: Zafar, A, Lee, J, Yesmin, S, et al. 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. Xenotransplantation. 2019;e12508, which has been published in final form at https://doi.org/10.1111/xen.12508.  This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.

Keywords

  • T-cell
  • amniotic epithelial cells
  • immunomodulation
  • porcine islets
  • rotational cell culture
  • xenotransplantation

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