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

Type 1 diabetes (T1D) is a complex multifactorial disease characterized by autoimmune destruction of insulin-producing pancreatic β 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 β-like cells from human pluripotent stem cells have been developed. These advances provide a definitive roadmap to implement realistic preventive and β-cell replacement therapies in T1D. Immunoprotection and preservation of functional β-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 β-cell development, survival and regeneration and can mediate local immunomodulation in the pancreatic islets. Interestingly, CXCL12-α is robustly expressed in maturing insulin-producing β cells and in adult β cells during periods of injury and regeneration. However, under normal physiological settings, CXCL12-α is repressed in terminally differentiated mature β cells and islets. Here, we provide a comprehensive overview of the role of CXCL12-α signaling in β-cell biology, physiology and immune regulation. We discuss CXCL12-α signaling mechanisms that could be harnessed to modulate β-cell autoimmunity, protect and preserve functional β-cell mass and for cell replacement therapy in T1D.