Retinoic acid (RA) signaling is essential for multiple developmental processes, including appropriate pancreas formation from the foregut endoderm. RA is also required to generate pancreatic progenitors from human pluripotent stem cells. However, the role of RA signaling during endocrine specification has not been fully explored. In this study, we demonstrate that the disruption of RA signaling within the NEUROG3-expressing endocrine progenitor population impairs mouse β cell differentiation and induces ectopic expression of crucial δ cell genes, including somatostatin. In addition, the inhibition of the RA pathway in hESC-derived pancreatic progenitors downstream of NEUROG3 induction impairs insulin expression. We further determine that RA-mediated regulation of endocrine cell differentiation occurs through Wnt pathway components. Together, these data demonstrate the importance of RA signaling in endocrine specification and identify conserved mechanisms by which RA signaling directs pancreatic endocrine cell fate.

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Diabetes is an epidemic with increasing incidence across the world. Most individuals who are afflicted by this disease have type 2 diabetes, but there are many who suffer from type 1, an autoimmune disorder. Both types of diabetes have complex genetic underpinnings that are further complicated by epigenetic and environmental factors. A less prevalent and often under diagnosed subset of diabetes cases are characterized by single genetic mutations and include Maturity Onset Diabetes of the Young (MODY) and Neonatal Diabetes Mellitus (NDM). While the mode of action and courses of treatment for all forms of diabetes are distinct, the diseases all eventually result in the dysfunction and/or death of the pancreatic β cell - the body’s source of insulin. With loss of β cell function, blood glucose homeostasis is disrupted, and life-threatening complications arise. In this review, we focus on how model systems provide substantial insights into understanding β cell biology to inform our understanding of all forms of diabetes. The strengths and weaknesses of animal, hPSC derived β-like cell, and organoid models are considered along with discussion of GATA6, a critical transcription factor frequently implicated in pancreatic dysfunction with developmental origins; experimental studies of GATA6 have highlighted the advantages and disadvantages of how each of these model systems can be used to inform our understanding of β cell specification and function in health and disease.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of antibodies to double stranded DNA (dsDNA) that can deposit in the kidney leading to nephritis. Our laboratory has previously been studying the association of SLE with the Epstein Barr Virus (EBV). We generated two monoclonal antibodies designated 3D4 and 16D2, that bind to a peptide (PFM-15) in the carboxyl region of a major nuclear protein of EBV (EBNA-1) and cross-react with dsDNA. In the present study, we demonstrate that both of these monoclonal antibodies can bind to fixed preparations of rat glomeruli suggesting pathogenic potential. Immunostaining is dramatically reduced when glomeruli are pre-treated with DNase indicating that these antibodies recognize chromatin associated structures. In addition, the PFM-15 peptide inhibits 3D4 and 16D2 from binding to glomeruli and inhibits both antibodies from binding to dsDNA coated plates by ELISA. This suggests that PFM-15 can act as a molecular mimic of dsDNA. Our results demonstrate that antibodies that recognize a viral peptide and cross-react with dsDNA can bind to glomeruli and therefore have pathogenic potential. This study further supports an association between EBV and SLE and supports the role of molecular mimicry in autoimmune disease.

Lipids have been implicated as mediators of insulitis and β-cell death in type 1 diabetes development, but it is poorly understood how islet lipid profiles are changed in response to the signaling pathways triggered by insulitis. Here, we investigated the changes in islet/β-cell lipid composition using three models of insulitis and type 1 diabetes progression: isolated human islets and EndoC-βH1 β-cells treated with the proinflammatory cytokines IL-1β and IFN-γ, and islets from non-obese diabetic (NOD) mice isolated before the onset of diabetes. Lipidomic analyses of these three models showed a consistent change in abundance of the lysophosphatidylcholine, phosphatidylcholine and triacylglycerol species. Immunohistochemistry and fluorescence in-situ hybridization showed an enrichment of lysophosphatidylcholine biosynthetic enzyme PLA2G6 in mouse islets. These results were consistent with the lipid profiles obtained using mass spectrometry imaging, which showed an enrichment of lysophosphatidylcholine in mouse islets. Furthermore, we determined that the ADPribosyl-acceptor glycohydrolase ARH3 is regulated by cytokines downstream of PLA2G6 and that this regulation may represent a negative feedback mechanism that reduces cytokine-induced apoptosis. Overall, these data show the importance of lipid metabolism in regulating β-cell death in type 1 diabetes.