The Moss laboratory is focused on understanding how pancreatic beta cell neogenesis and function can be potentiated in vivo using zebrafish and other animal models of beta cell regeneration in adults. Our experiments are ultimately directed towards providing translational information that can be used as diabetes therapeutics in humans. Previous analysis of mammalian insulin (1,2) and cardiac actin (3) promoters in cell lines has led to our development of in vivo models where relevant changes in gene expression or cell signaling represent physiological changes (4). Although developmental paradigms can instruct organogenesis and metabolism (5,6), we have redirected our focus on generating adult models of diabetes and obesity (7,8). We have found that islet tissue can be regenerated after conditional genetic, chemical or surgical ablation without the need for insulin therapy in living adult zebrafish (8). Using transparent, conditional knock-out adults as a platform for small molecule manipulation of important signaling pathways in the beta cell, we are discovering critical signal transduction nodes necessary for regeneration. This economical and efficient zebrafish model, where beta cells can be evaluated directly in the same animal over time using fluorescent markers, provides a framework for understanding how small molecules affect beta cell growth and function in vivo. Interestingly, an unexpected source of auto-fluorescence in zebrafish provides a cautionary tale for researchers using whole animal models (9). Recently, we have expanded our inquiry into beta cell regeneration by generating a dual reporter zebrafish where both beta cells and the islet microvasculature are labeled with fluorescent proteins (10). In vivo changes in both cell types are being evaluated in the presence of small molecule inhibitors or activators during regeneration.
Pancreatic beta cells are lost due to insulin resistance, inflammation, hyperglycemia or autoimmune attack and are not significantly replenished by endogenous progenitors in mammals. In contrast, we observe a robust regeneration of beta cells in contact with islet vasculature that restores function in adult zebrafish within two weeks (10). To determine if small molecules promoting beta cell regeneration in zebrafish might benefit humans, we are developing vascularized hydrogels to improve islet cell growth compared with conventional cultures. Cadaveric human islets are available for research, however their limited survival in culture after severance from pancreatic vasculature introduces significant errors in evaluating experimental outcomes from multiple donors. In contrast, vascularized hydrogels can sustain long-term culture of beta cells and when transplanted, rescue induced diabetes in rodent models more effectively than islets transplanted alone. In collaboration with Duke's Biomedical Engineering, small molecules potentiating regeneration in vivo are being used to test human islet tissue surrogates in vitro, directing new analysis and treatment paradigms for diabetes.
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