Pancreatic Islets Engineered with Thrombomodulin Show Enhanced Engraftment in an Intraportal Transplantation Model by Mitigating Instant Blood-Mediated Inflammatory Reactions
1Molecular Microbiology and Immunology, University of Missouri at Columbia, Columbia, MO, 2Department of Child Health, University of Missouri at Columbia, Columbia, MO, 3Child Health and Molecular Microbiology and Immunology, University of Missouri at Columbia, Columbia, MO
Meeting: 2022 American Transplant Congress
Abstract number: 176
Keywords: Engraftment, Graft failure, Insulin, Islets
Topic: Basic Science » Basic Science » 05 - Translational Cellular Therapies: Islet and Stem Cell Transplantation
Session Information
Session Name: Cellular/Islet Therapies and Tissue Engineering
Session Type: Rapid Fire Oral Abstract
Date: Sunday, June 5, 2022
Session Time: 5:30pm-7:00pm
Presentation Time: 5:30pm-5:40pm
Location: Hynes Room 310
*Purpose: IBMIR is a major culprit of early islet loss post-transplant. Thrombomodulin (TM) is an anti-coagulant and cofactor of activated Protein C (APC) that perpetuates homeostasis of thrombosis, leading to reduction in the release of proinflammatory molecules and inactivation of neutrophils and macrophages. We herein engineered islets to transiently display on their surface TM as a means of mitigating IBMIR to enhance islet engraftment
*Methods: A novel form of TM chimeric with streptavidin (SA-TM) was generated, expressed in insect cells, and protein was characterized for structure and function. Islets were biotinylated following by engineering with SA-TM protein taking the advantage of high interaction between biotin and streptavidin (SA). Engineered islets were assessed for viability and function as well as mitigating IBMIR using an in vitro loop assay. SA-TM-engineered islets were transplanted intraportally at a minimal mass into STZ-diabetic syngeneic recipients (n=7). Islets engineered with SA served as controls (n=7). Animals were monitored for blood glucose levels for an observation period of 60 days and assessed for graft function using intraperitoneal glucose tolerance test.
*Results: SA-TM was effectively displayed on the surface of islets without impacting their viability or insulin secretion. SA-TM-engineered islets mitigated IBMIR in an in vitro loop assay by significantly increasing APC levels and decreasing various inflammatory mediators, including high mobility group box protein 1 (HMGB1), tissue factor, IL-6, and IL-1β, as compared to SA-engineered islets. SA-TM on the surface of xenogeneic splenocytes inhibited their phagocytosis by macrophages. Importantly, SA-TM-engineered islets showed improved engraftment and long-term function in a syngeneic minimal mass model of intraportal islet transplantation as compared to controls (83% vs 29% survival). Enhanced survival was correlated with decreased levels of various proinflammatory mediators, including HMGB1, MCP-1 and IL-1β, involved in IBMIR.
*Conclusions: Engineering islets to positionally and transiently display SA-TM protein on their surface serves an effective platform to mitigate IBMIR with important clinical implications for islet transplantation to treat type 1 diabetes.
To cite this abstract in AMA style:
Turan A, Zhang L, Tarique M, Ulker V, Yolcu E, Shirwan H. Pancreatic Islets Engineered with Thrombomodulin Show Enhanced Engraftment in an Intraportal Transplantation Model by Mitigating Instant Blood-Mediated Inflammatory Reactions [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/pancreatic-islets-engineered-with-thrombomodulin-show-enhanced-engraftment-in-an-intraportal-transplantation-model-by-mitigating-instant-blood-mediated-inflammatory-reactions/. Accessed May 18, 2025.« Back to 2022 American Transplant Congress