Function Of Setd4-expressing Quiescent β Cells

Type 1 diabetes is an autoimmune disease in which substantialβ-cells are lost leading to permanent endocrine deficiency.It is important for diabetes treatment to enhance or induce the intrinsic regenerative ability of endocrine islets and devising new strategies to produce insulin-secretingβ-cells.There is a class of quiescent cells in the adult mouse pancreas that can respond to the injury.As a conserved mechanism of adult stem cells in vivo,quiescent cells play an important role in homeostasis maintenance and response to the injury in some tissues.Previous research discovered an evolutionarily conserved mechanism of Setd4 regulating cell quiescence.Setd4~+cells in islets respond to the STZ-induced injury,but the specific characteristics and function of Setd4~+cells are not clear.In this study,we explored the function of Setd4~+cells forβ-cell regeneration.We found that Setd4~+cells were mainly expressed in Pdx1~+cells and did not express the proliferation indicator Ki67 in the islets,indicating that these cells were in quiescent state.Based on the mechanism of Setd4 regulating cell quiescence,we constructed SETD4 conditional knockout mice and achieved SETD4 conditional knockout in the Pdx1~+cells of adult mouse islets.One week after SETD4 conditional knockout in adult mice,the number of proliferating Pdx1~+cells increased.In streptozotocin-induced type1 diabetes model mice,the number of Setd4~+cells were found to remain constant and in quiescent state.In order to further investigate the function of Setd4 inβ-cell injury model,we performed SETD4 gene conditional knockout in Type 1 diabetes model mice,the results showed that SETD4 knock-out lead to increasing more proliferating Pdx1~+cells,but there were no significant differences in islet histology,insulin content,blood glucose and the number of functionalβ-cells.After treatment with GAD65,it was found that SETD4 knock-out decreased the concentrations of blood glucose,improved insulin content and histological morphology of islets and increased the number of proliferating Pdx1~+cells and functionalβcells.In summary,our study identified a population of quiescent Pdx1~+cells regulated by Setd4 protein in islets.SETD4 knock-out promoted the proliferation of Pdx1~+cells.In the model of type 1 diabetes induced by streptozotocin,Setd4~+cells resist the damage by maintaining quiescence.The specific SETD4 knock-out can promote the regeneration of Pdx1~+cells in response to injury induced by STZ.Our study provides a new therapeutic target for type 1 diabetes and provides new possibilities for the mechanism of pancreatic endocrine cell regeneration.