Insulin-positive ductal cells do not migrate into preexisting islets during pregnancy

Qun Liu,Xiangwei Xiao,Tianlun Yang,Lingyan Zhu,George K Gittes,Jieqi Qian,Krishna Prasadan,Chaoban Wang,Yinan Jiang

doi:10.1038/s12276-021-00593-z

Abstract

The adult pancreatic ductal system was suggested to harbor facultative beta-cell progenitors similar to the embryonic pancreas, and the appearance of insulin-positive duct cells has been used as evidence for natural duct-to-beta-cell reprogramming. Nevertheless, the phenotype and fate of these insulin-positive cells in ducts have not been determined. Here, we used a cell-tagging dye, CFDA-SE, to permanently label pancreatic duct cells through an intraductal infusion technique. Representing a time when significant increases in beta-cell mass occur, pregnancy was later induced in these CFDA-SE-treated mice to assess the phenotype and fate of the insulin-positive cells in ducts. We found that a small portion of CFDA-SE-labeled duct cells became insulin-positive, but they were not fully functional beta-cells based on the in vitro glucose response and the expression levels of key beta-cell genes. Moreover, these insulin-positive cells in ducts expressed significantly lower levels of genes associated with extracellular matrix degradation and cell migration, which may thus prevent their budding and migration into preexisting islets. A similar conclusion was reached through analysis of the Gene Expression Omnibus database for both mice and humans. Together, our data suggest that the contribution of duct cells to normal beta-cells in adult islets is minimal at best.

Highlights

The short supply of donor pancreases prevents extensive clinical application of islet transplantation as a cure for diabetes[1,2,3], which heightens the need for alternative sources of insulin (INS)-producing beta-cells
Previous studies have shown that very few INS+ cells are detected in the normal adult pancreatic duct, and these rare cells have been suggested to be vestiges of the embryonic pancreas, where some beta-cells fail to bud from the duct trunk, possibly due to inadequate expression of buddingdependent gene clusters at the single-cell level
We found that the percentage of INS+ cells out of the total carboxyfluorescein diacetate succinimidyl ester (CFDA-SE)+ cell population was significantly higher in the pancreas of gestational day 16 (G16) mice than in the pancreas of NP mice (Fig. 2d), which was consistent with our quantification of the percentage of INS+ duct cells based on DBA/INS staining (Fig. 1a, b)

Summary

Introduction

The short supply of donor pancreases prevents extensive clinical application of islet transplantation as a cure for diabetes[1,2,3], which heightens the need for alternative sources of insulin (INS)-producing beta-cells. Beta-cell expansion in adults is mainly attributable to beta-cell replication. Adult pancreatic duct cells have been extensively studied for their potential to generate functional beta-cells, since embryonic pancreatic ductal structures clearly harbor endocrine precursors[10,11,12]. Official journal of the Korean Society for Biochemistry and Molecular Biology. Liu et al Experimental & Molecular Medicine (2021) 53:605–614 technique. Pregnancy is a wellaccepted model for physiologic beta-cell growth in adult mice in which beta-cell mass nearly doubles at its peak[20]. Pregnancy was later induced in these CFDA-SEtreated mice to assess the phenotype and fate of the insulin-positive cells in ducts

Methods

Results

Conclusion