ISL1 Promotes Pancreatic Islet Cell Proliferation

Abstract

BackgroundIslet 1 (ISL1), a LIM-homeodomain transcription factor is essential for promoting pancreatic islets proliferation and maintaining endocrine cells survival in embryonic and postnatal pancreatic islets. However, how ISL1 exerts the role in adult islets is, to date, not clear.Methodology/Principal FindingsOur results show that ISL1 expression was up-regulated at the mRNA level both in cultured pancreatic cells undergoing glucose oxidase stimulation as well in type 1 and type 2 diabetes mouse models. The knockdown of ISL1 expression increased the apoptosis level of HIT-T15 pancreatic islet cells. Using HIT-T15 and primary adult islet cells as cell models, we show that ISL1 promoted adult pancreatic islet cell proliferation with increased c-Myc and CyclinD1 transcription, while knockdown of ISL1 increased the proportion of cells in G1 phase and decreased the proportion of cells in G2/M and S phases. Further investigation shows that ISL1 activated both c-Myc and CyclinD1 transcription through direct binding on their promoters.Conclusions/SignificanceISL1 promoted adult pancreatic islet cell proliferation and probably by activating c-Myc and CyclinD1 transcription through direct binding on their promoters. Our findings extend the knowledge about the crucial role of ISL1 in maintaining mature islet cells homeostasis. Our results also provide insights into the new regulation relationships between ISL1 and other growth factors.

Elevation of transcription factor Islet-1 levels in vivo increases β-cell function but not β-cell mass

“…Alternatively, these genes might be direct targets of additional transcriptional regulator(s) yet to be identified using PCR-based transcription factor screens or RNA-Seq. 32 Furthermore, while Guo and colleagues had reported that Isl-1 can promote cell proliferation and attenuate cell death against oxidative stress in isolated rat islets and HIT-T15 cells, 16 we did not detect significant changes in cell proliferation or cell survival in our transgenic mouse model. The discrepancy between these findings might simply due to the high levels of Isl-1 expression achieved in the lentivirus-based in vitro model, which might lead to activation of different gene programs.…”

“…The discrepancy between these findings might simply due to the high levels of Isl-1 expression achieved in the lentivirus-based in vitro model, which might lead to activation of different gene programs. 16 In conclusion, these novel findings provide the islet biology community with the gene expression profile of enhanced β-cell function. Future experiments designed to manipulate these genes in mouse models or cell cultures will lead to better understanding of how insulin secretion is regulated and how glucose homeostasis is maintained in adult animals.…”

“…Recently, it has been shown that rat islets, when transduced with lentivirus overexpressing Isl-1, increased cell proliferation, which was the result of an upregulation of c-Myc and CyclinD1. 16 Therefore, we tested whether increased Isl-1 expression in vivo affected β-or α-cell mass in the Pdx1 PB -Isl-1-Myc mice. Unlike what was reported, we found no significant differences in β-or α-cell mass between control and Pdx1 PB -Isl-1-Myc mice likely due to the lower level of Isl-1 expression ( Fig.…”

ISL1 expression is not restricted to pancreatic well-differentiated neuroendocrine neoplasms, but is also commonly found in well and poorly differentiated neuroendocrine neoplasms of extrapancreatic origin

“…In the pancreas, where ISL1 is expressed in the normal islet cells, it is known to represent a differentiation marker. [4][5][6][7][8] Thus, expression of ISL1 in pancreatic NETs most likely reflects the high differentiation status of these neoplasms. 10,11 Accordingly, it is not surprising that ISL1 is lacking or only weakly expressed in poorly differentiated pancreatic neuroendocrine carcinomas.…”

“…3 ISL1 has an important role in the embryogenesis and differentiation of the insulinproducing pancreatic beta cells within the islets of Langerhans. [4][5][6][7] Deficiency of ISL1 was associated with absence of neural tube motor neuron differentiation in mouse experiments. 8 Apart from its role in the cell line development of the endocrine pancreas, ISL1 was found to have a major role as a marker of cardiac progenitor cell lineage.…”