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Am J Transplant. 2019 Feb 12. doi: 10.1111/ajt.15308. [Epub ahead of print]

Alginate-microencapsulation of human stem cell-derived β cells with CXCL12 prolongs their survival and function in immunocompetent mice without systemic immunosuppression.

Author information

1
Vaccine and Immunotherapy Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
2
Department of Pathology and School of Clinical Medicine, University of Cambridge, Cambridge, UK.
3
Department of Microbiology and Molecular Biology, Brigham Young University, Provo, Utah.
4
Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts.
5
Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Abstract

Pancreatic β-cell replacement by islet transplantation for the treatment of type 1 diabetes (T1D) is currently limited by donor tissue scarcity and the requirement for lifelong immunosuppression. The advent of in vitro differentiation protocols for generating functional β-like cells from human pluripotent stem cells, also referred to as SC-β cells, could eliminate these obstacles. To avoid the need for immunosuppression, alginate-microencapsulation is widely investigated as a safe path to β-cell replacement. Nonetheless, inflammatory foreign body responses leading to pericapsular fibrotic overgrowth often causes microencapsulated islet-cell death and graft failure. Here we used a novel approach to evade the pericapsular fibrotic response to alginate-microencapsulated SC-β cells; an immunomodulatory chemokine, CXCL12, was incorporated into clinical grade sodium alginate to microencapsulate SC-β cells. CXCL12 enhanced glucose-stimulated insulin secretion activity of SC-β cells and induced expression of genes associated with β-cell function in vitro. SC-β cells co-encapsulated with CXCL12 showed enhanced insulin secretion in diabetic mice and accelerated the normalization of hyperglycemia. Additionally, SC-β cells co-encapsulated with CXCL12 evaded the pericapsular fibrotic response, resulting in long-term functional competence and glycemic correction (>150 days) without systemic immunosuppression in immunocompetent C57BL/6 mice. These findings lay the groundwork for further preclinical translation of this approach into large animal models of T1D.

KEYWORDS:

basic (laboratory) research/science; diabetes: type 1; endocrinology/diabetology; fibrosis; immune regulation; immunosuppression/immune modulation; insulin/C-peptide; islet transplantation; islets of Langerhans; translational research/science

PMID:
30748094
DOI:
10.1111/ajt.15308

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