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

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.

Publication DOI: https://doi.org/10.1111/xen.12508
Divisions: College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences > School of Biosciences > Cell & Tissue Biomedical Research
College of Health & Life Sciences
College of Health & Life Sciences > Chronic and Communicable Conditions
Additional Information: 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.
Uncontrolled Keywords: T-cell,amniotic epithelial cells,immunomodulation,porcine islets,rotational cell culture,xenotransplantation,Immunology,Transplantation
Publication ISSN: 1399-3089
Full Text Link:
Related URLs: https://onlinel ... .1111/xen.12508 (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2019-07-01
Published Online Date: 2019-04-08
Accepted Date: 2019-03-07
Authors: Zafar, Ali
Lee, Jou
Yesmin, Shameema
Paget, Michelle B.
Bailey, Clifford J. (ORCID Profile 0000-0002-6998-6811)
Murray, Hilary E.
Downing, Richard

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