MicroRNAs: An adaptive mechanism in the pancreatic β-cell…and beyond?

Abstract

Recent protocols have been developed to differentiate human stem cells and fibroblasts into insulin-producing cells capable of releasing the hormone in a glucosestimulated manner. Limitations remain which prevent bringing these protocols to a clinical setting as these models must still undergo complete characterization. Advances in sequencing technologies have driven the identification of several noncoding RNA species including microRNAs (miRNAs). While their diversity and unique expression patterns across different tissues have made deciphering their precise functional role a significant challenge, studies using both cell lines and transgenic mouse models have made substantial progress in understanding their regulatory role on exocytosis and proliferation of the β-cell. These results also indicate miRNAs play an integral role in the fundamental mechanics of how the cell manages the balance between these independent functions. Continued investigation into miRNA function may uncover mechanisms which can be exploited to improve differentiation protocols in producing fully mature β-cells.

Restoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction

“…Notably, we observed inhibition of PITPNA in ND human islets incurred a reduction of AGO2 expression and this may indicate (1) the beta-cell neutralizes miRNA-mediated gene regulation to counter hyperglycemia during T2D and (2) loss of AGO2 expression in T2D islets may characterize a late phase of the disease where compensatory proliferation of the beta-cell has been compromised 42 . These findings reinforce the notion that the miRNA pathway is a critical component for how cells adapt to changes in their metabolic environment as well as demonstrate how disruption of this pathway renders the beta cell incapable of maintaining a proper homeostatic balance with the ultimate result of diabetic disease 84 , 85 .…”

“…Inclusion of Pitpna in this regulon amply illustrates the functional diversity of miRNA-targeted genes that mediate exocytosis. We posit that suppression of these genes by miR-375 provides broad regulatory control over the beta-cell secretory machinery and ‘secretome’ under normal steady state conditions and this circuit may prevent excess insulin release and safeguards the central nervous system from hypoglycemia 84 . Notably, we observed inhibition of PITPNA in ND human islets incurred a reduction of AGO2 expression and this may indicate (1) the beta-cell neutralizes miRNA-mediated gene regulation to counter hyperglycemia during T2D and (2) loss of AGO2 expression in T2D islets may characterize a late phase of the disease where compensatory proliferation of the beta-cell has been compromised 42 .…”

Restoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction

“…Inclusion of Pitpna in this regulon amply illustrates the functional diversity of microRNA-targeted genes that mediate exocytosis. We posit that suppression of these genes by miR-375 provides broad regulatory control over the beta-cell secretory machinery and ‘secretome’ under normal steady state conditions and this circuit may prevent excess insulin release and safeguards the central nervous system from hypoglycemia (Poy, 2016). These findings reinforce the notion that the microRNA pathway is a critical component for how cells adapt to changes in their metabolic environment as well as demonstrate how disruption of this pathway renders the beta cell incapable of maintaining a proper homeostatic balance with the ultimate result of diabetic disease (LaPierre and Stoffel, 2017; Poy, 2016).…”

Enteroendocrine Progenitor Cell–Enriched miR-7 Regulates Intestinal Epithelial Proliferation in an Xiap-Dependent Manner

“…Notably, class C miRNAs include miR-7b, which has been previously extensively studied in the context of endocrine pancreatic development and function. [8][9][10][11][12][13][14][15] MiR-7 was also shown to be enriched in a specific subtype of mature EECs and cholecystokininproducing EECs, 16 and also in enterochromaffin cellderived tumors 17 ; however, importantly, the expression pattern of miR-7 (or any other miRNA) across the entire EEC lineage trajectory has never before been reported.…”