The Role Of Mesp1 In Regulating Islet Cells Development

Objective:Mesp1 is an important transcriptional factor in regulating cardiac mesoderm development,without which will cause cardiac dysplasia in the knockout mouse model.Our preliminary research indicates that Mesp1 progeny cells are expressed in the region of endoderm and specifically expressed in the pancreas.But the mechanism of Mesp1 in regulating pancreas development remains to be studied.Methods:We set up Foxa₂ knockout（MCFFA）mice model,identify the genotype,and measure the blood level of glucose、insulin and glucagon.We also measured the quantity of different islet cells in mouse pancreas tissue section by immunofluorescence staining in different groups（homozygous,heterozygous and control group）.We locate the Mesp1 progeny cells in pancreatic islet by lineage tracing.We have cultured the Mesp1-knockout embryonic stem cells which were injected into the blastocysts and then transplant them into the uterus of psudopregnant mice to form the chimeric mice.We evaluate the difference of genetic expression between two ESC samples by PCA and hotmap after RNA-seq.We also did the functional analysis of the two different genes.We transplant the embryonic stem cells into the islet of STZ induced diabetic mice to investigate the glucose levels and the mechanism of Mesp1 on diabetic mouse model.Results:Knocking out Foxa₂ in Mesp1-expressed progeny cells can lead to hyperinsulinemic hypoglycemia,which make a change in the quantity of islet cells and fate switch between different islet cells.Mesp1 can inhibit the endodermal transcription factor（including Foxa₂）,which indicates the endodermal transcription factor（Foxa₂）will be upregulated when Mesp1 are removed.There are significant differences between two ESC samples on genetic expression by PCA and hotmap analysis after RNA-Seq.Functional analysis indicates that the discrepancy between the two genetic ESCs involves in organism development、membrane component and ion channel activity.Mesp1 is related to pancreatic secretion by KEGG.By STRING software,the TCF3、TCF4 and TCF12 are related to Mesp1.The transplantation of ESC cells onto the pancreas of diabetic mouse will have some impact on the blood glucose level.Conclusions:Mesp1 plays an important role on regulating islet cells development and fate switch between different islet cells.The transplantation of Mesp1 knoukout ESC cells onto the pancreas of diabetic mouse provides a new experimental consideration for diabetic treatment.