Session Time: 3:15pm-4:45pm
Presentation Time: 3:15pm-3:27pm
*Purpose: Human pluripotent stem cell-derived islet-like cells (SC-islets) represent a practical source for beta-cell replacement to achieve a functional cure for type 1 diabetes. Long-term survival and glycemic correction by SC-islets encapsulated in various biomaterials to avoid systemic immunosuppression has only been demonstrated in rodent models. Translation of these approaches in large animals and humans is often problematic, due to the robust foreign body and allo or xeno-immune responses that leading to early graft failure. We recently reported that SC-islets microencapsulated in alginate with CXCL12 restored long-term glycemic correction without systemic immunosuppression in mice. We now report long-term functional survival of SC-islets alginate-microencapsulated with CXCL12 in a non-diabetic (ND) and a diabetic NHP.
*Methods: Microencapsulated SC-islets were transplanted into the greater omental sac of a ND and a diabetic NHP. Microcapsules were also transplanted intraperitoneally in parallel in immunocompetent C57BL/6 diabetic mice. Biochemical, immunologic and hematologic parameters, blood glucose levels, serum C-peptide were measured during a 24 week period. Biopsies of microcapsules from the ND NHP were recovered at 4, 12 and at 24 weeks post-transplantation to analyze their survival, function and local immune responses to the microcapsules.
*Results: Blood glucose levels of the ND NHP were in the normal range throughout the study while insulin requirements of the diabetic NHP were consistently reduced from day 50 post transplantation onwards allowing exogenous insulin dosing to be reduced by 62% from pre transplant levels. Normoglycemia was restored in transplanted diabetic mice. Plasma C-peptide levels of the ND NHP were stable (~200 pM to 700 pM) and random and intravenous glucose-induced C-peptide was detectable in the diabetic NHP. Recovered SC-islets from ND NHP at 1, 12 and 24-weeks as well as those retrieved from the diabetic NHP at 23 weeks were glucose-responsive. The vast majority of recovered microcapsules at all time points in both animals showed no evidence of fibrotic overgrowth. mRNA transcript and protein expression of islet beta-cell markers were detectable, at 24 weeks post-transplant, albeit at decreased levels compared to pre-transplantation, by qPCR and immunohistochemistry, respectively.
*Conclusions: These preliminary findings support ongoing studies in additional diabetic NHPs transplanted with SC-islets microencapsulated in alginate containing CXCL12 without systemic immunosuppression.
To cite this abstract in AMA style:Poznansky MC, Alagpulinsa D, Lei J, Pop R, Sobell D, Chapin M, Collins S, Veres A, Deng H, Melton D, Markmann J. Long-term Functional Survival of Human Stem Cell-Derived Islets Microencapsulated in Alginate with CXCL12 in Non-Human Primates without Immunosuppression [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/long-term-functional-survival-of-human-stem-cell-derived-islets-microencapsulated-in-alginate-with-cxcl12-in-non-human-primates-without-immunosuppression/. Accessed July 23, 2021.
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