Harnessing CXCL12 signaling to protect and preserve functional β-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 beta 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 beta-like cells from human pluripotent stem cells have been developed. These advances provide a definitive roadmap to implement realistic preventive and beta-cell replacement therapies in T1D. Immunoprotection and preservation of functional beta-cell mass are a sine qua non for the success of these interventions. The chemokine, stromal cell-derived factor-1 alpha, known as CXCL12-alpha, is an attractive therapeutic target molecule in this context. CXCL12-a signaling promotes (beta-cell development, survival and regeneration and can mediate local immunomodulation in the pancreatic islets. Interestingly, CXCL12-alpha is robustly expressed in maturing insulin producing beta cells and in adult beta cells during periods of injury and regeneration. However, under normal physiological settings, CXCL12-alpha is repressed in terminally differentiated mature beta cells and islets. Here, we provide a comprehensive overview of the role of CXCL12-a signaling in beta-cell biology, physiology and immune regulation. We discuss CXCL12-alpha signaling mechanisms that could be harnessed to modulate beta-cell autoimmunity, protect and preserve functional beta-cell mass and for cell replacement therapy in T1D. (C) 2018 Elsevier Inc. All rights reserved.