LAUSR

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.