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

Pancreatic ß-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 ß-like cells from human pluripotent stem cells, also referred to as SC-ß cells, could eliminate these obstacles. To avoid the need for immunosuppression, alginate-microencapsulation is widely investigated as a safe path to ß-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-ß cells; an immunomodulatory chemokine, CXCL12, was incorporated into clinical grade sodium alginate to microencapsulate SC-ß cells. CXCL12 enhanced glucose-stimulated insulin secretion activity of SC-ß cells and induced expression of genes associated with ß-cell function in vitro. SC-ß cells co-encapsulated with CXCL12 showed enhanced insulin secretion in diabetic mice and accelerated the normalization of hyperglycemia. Additionally, SC-ß 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.

Harnessing CXCL12 signaling to protect and preserve functional ß-cell mass and for cell replacement in type 1 diabetes.

Type 1 diabetes (T1D) is a complex multifactorial disease characterized by autoimmune destruction of insulin-producing pancreatic ß cells. Our understanding of the pathogenic mechanisms and natural history of T1D has evolved significantly over the past two decades; we can efficiently predict high-risk individuals, early diagnose the disease and stage progression. Fortuitously, novel in vitro differentiation protocols for generating functional ß-like cells from human pluripotent stem cells have been developed. These advances provide a definitive roadmap to implement realistic preventive and ß-cell replacement therapies in T1D. Immunoprotection and preservation of functional ß-cell mass are a sine qua non for the success of these interventions. The chemokine, stromal cell-derived factor-1alpha, known as CXCL12-α, is an attractive therapeutic target molecule in this context. CXCL12-α signaling promotes ß-cell development, survival and regeneration and can mediate local immunomodulation in the pancreatic islets. Interestingly, CXCL12-α is robustly expressed in maturing insulin-producing ß cells and in adult ß cells during periods of injury and regeneration. However, under normal physiological settings, CXCL12-α is repressed in terminally differentiated mature ß cells and islets. Here, we provide a comprehensive overview of the role of CXCL12-α signaling in ß-cell biology, physiology and immune regulation. We discuss CXCL12-α signaling mechanisms that could be harnessed to modulate ß-cell autoimmunity, protect and preserve functional ß-cell mass and for cell replacement therapy in T1D.