| Maintenance of blood glucose levels are important to normal organism functions.They are regulated by the hormone producing pancreatic endocrine cells of the islets.The isletscompriseinsulin-expressing?-cells,somatostatin-expressing?-cells,glucagon-expressing?-cells and ghrelin-expressing?-cells.?-cell loss or failure causes diabetes,a health issue suffering by an increasing proportion of the world's population.Type 1 diabetic patients can possibly be cured by restoration of?-cell mass.For treatment of insulin-dependent diabetes,islet transplant is proven to be a better option to insulin therapy for adult patients.Transplantation of islets requires at least a single donor.Thus transplant rejection and availability of islets are critical,calling for endogenous sources for?-cells.Researches on normal endocrine pancreas development and regeneration of?-cell are providing more and more leads to efficient restoration of functional?-cells.Extensive researches have been published focusing on?-cell regeneration.Animal models are established to study cellular origins and regulators of?-cell regeneration for the diabetes cure.Using these models,several endogenous sources like?-cells and?-cells have been revealed to contribute to restoration of the lost?-cell mass.These studies showed endocrine cells maintained plasticity to some degree while rising from the common ancient progenitor and committing to different lineages.Comparing to the knowledge of several origins of?-cell neogenesis,little is known about the mechanism of?-cell regeneration.Here,we employed a zebrafish?-cell ablation and regeneration model to investigate?-cell neogenesis in the first few days after a near-total?-cell loss.Regeneration of?-cells first occurred within 7 hours post treatment.neurod,pdx1,mnx1and nkx2.2a are among the key regulators of zebrafish?-cell development.In Tg(neuroD:GFP)and Tg(ins:CFP-NTR)double transgenic embryos,100%of the new?-cells were GFP and CFP double positive,indicating?-cell regeneration happened within the neurod positive endocrine pool.By Tg(pdx1:GFP),Tg(mnx1:GFP)and Tg(nkx2.2a:GFP),we were able to illustrate pdx1,mnx1,nkx2.2a expression in?-cell regeneration.Statistics showed only 89.2%of the new?-cell are pdx1~+,54.11%were mnx1~+,while 56.67%were nkx2.2a~+.We used triple transgenic embryos with Tg(pdx1:GFP;mnx1:GFP;ins:CFP-NTR)andTg(pdx1:GFP;nkx2.2a:GFP;ins:CFP-NTR)to further observe?-cell regeneration.Data turned out that all regenerated?-cell were GFP~+.However,in Tg(mnx1:GFP;nkx2.2a:GFP;ins:CFP-NTR)triple transgenic embryos,only 61.9%of the regenerated?-cells were GFP~+.Together,neurod,pdx1,mnx1and nkx2.2a all participated in zebrafish?-cell regeneration.Differential expression pattern of these developmental regulators may suggest variant routes to the?-cell regeneration.Using Cre/loxP-based lineage tracing,we showed that intra-pancreatic duct cells resisted to give rise to regenerating?-cell.Given that transdifferentiation of?-cell and?-cell can regenerate?-cell,here we have provided further molecular evidences that the regenerating?-cells originate from multiple cellular origins. |
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