Understanding pathways regulating liver versus pancreas fate decision and beta-cell regeneration

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Xu, Jin
Storici, Francesca
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The liver and pancreas originate from common endodermal progenitors in early development. It has been shown that Bone morphogenetic protein 2b (Bmp2b) signaling is essential for determining the fate of these bipotential progenitors towards the liver or pancreas. Our goal was to identify Bmp2b-mediated gene regulatory networks and to delineate their underlying mechanisms governing the liver versus pancreas fate decision. From microarray assays, we found four and a half LIM domains 1b (fhl1b) as a novel target of Bmp2b signaling. We observed that fhl1b is primarily expressed in the prospective liver primordium. By loss- and gain-of-function analyses combined with a single cell lineage tracing technique, we showed that fhl1b favors the specification of liver and suppresses the induction of pancreatic cells. Diabetes is characterized by compromised glucose regulation. Both type 1 and type 2 diabetes patients suffer from losing functional β-cells along the progression of the disease. Our goal was to expand the understanding on pathways potentially promoting β-cell regeneration. First, given its function in suppressing pancreas induction with concomitant stimulation of liver, we conducted loss- and gain-of-function studies of fhl1b using a zebrafish model of type 1 diabetes. We conclude that fhl1b regulates the regeneration of β-cells mainly via modulating ductal progenitor-to-β-cell neogenesis. In addition, we identified TBK1/IKKε inhibitors (TBK1/IKKε-Is) as enhancers of β-cell regeneration through a chemical screening. We demonstrated that these inhibitors enhance β-cell-specific proliferation and further investigated the gene regulatory networks mediating mitogenic effects of TBK1/IKKε-Is. In collaboration with Dr. Oyelere and Dr. García at Georgia Institute of Technology, we further explored the specificity and potency of these inhibitors in mammalian systems (rat and human islet culture in vitro and a mouse model of type 1 diabetes in vivo) to complement our findings in zebrafish. We showed the conserved effects of increasing function and proliferation of β-cells in mammalian systems.
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