Identification of miRNAs Involved in Reprogramming Acinar Cells into Insulin Producing Cells

Abstract

Reprogramming acinar cells into insulin producing cells using adenoviral (Ad)-mediated delivery of Pdx1, Ngn3 and MafA (PNM) is an innovative approach for the treatment of diabetes. Here, we aimed to investigate the molecular mechanisms involved in this process and in particular, the role of microRNAs. To this end, we performed a comparative study of acinar-to-β cell reprogramming efficiency in the rat acinar cell line AR42J and its subclone B13 after transduction with Ad-PNM. B13 cells were more efficiently reprogrammed than AR42J cells, which was demonstrated by a strong activation of β cell markers (Ins1, Ins2, IAPP, NeuroD1 and Pax4). miRNome panels were used to analyze differentially expressed miRNAs in acinar cells under four experimental conditions (i) non-transduced AR42J cells, (ii) non-transduced B13 cells, (iii) B13 cells transduced with Ad-GFP vectors and (iv) B13 cells transduced with Ad-PNM vectors. A total of 59 miRNAs were found to be differentially expressed between non-transduced AR42J and B13 cells. Specifically, the miR-200 family was completely repressed in B13 cells, suggesting that these cells exist in a less differentiated state than AR42J cells and as a consequence they present a greater plasticity. Adenoviral transduction per se induced dedifferentiation of acinar cells and 11 miRNAs were putatively involved in this process, whereas 8 miRNAs were found to be associated with PNM expression. Of note, Ad-PNM reprogrammed B13 cells presented the same levels of miR-137-3p, miR-135a-5p, miR-204-5p and miR-210-3p of those detected in islets, highlighting their role in the process. In conclusion, this study led to the identification of miRNAs that might be of compelling importance to improve acinar-to-β cell conversion for the future treatment of diabetes.

MicroRNA expression profile and identification of novel microRNA biomarkers for metabolic syndrome

“…These miRNAs may be involved in the development of MetS. Previous studies have suggested that miR-137-3p may be associated with the production of insulin as well as the metabolism of lipids [ 21 , 22 ]. Ventriglia et al demonstrated that the expression of miR-409-3p was downregulated in the plasma samples of diabetic mice [ 23 ].…”

MicroRNA‐210 is increased and it is required for dedifferentiation of osteosarcoma cell line

“…However, few studies indicated that miR‐210 was involved in cell reprogramming. For instance, miR‐210 was reported to be involved in the reprogramming of acinar cells into insulin‐producing cells (Teichenne et al, ), and modulating the EMT of ovarian cancer cells (Ding et al, ). Our results indicated that miR‐210 accelerated the dedifferentiation of Stro‐1 − /CD117 − non‐OSC cells into Stro‐1 + CD117 + OSCs.…”

Circulating microRNAs in young individuals with long-duration type 1 diabetes in comparison with healthy controls

“…The observed upregulation of hsa-miR-135a suggests a mechanism that could, directly or indirectly, influence the development of renal fibrosis in individuals with diabetes. It has also been shown that hsa-miR-135a, among other miRNAs, is of importance for reprogramming acinar cells into insulin producing cells 34 , which suggests a therapeutic potential for this miRNA. Hsa-miR-135a is a pivotal miRNA in biogenesis and regulation in various forms of cancer 35 .…”