Laboratory of Pluripotent Stem Cell Disease Modeling, Translational Medicine Department, Research Branch, Sidra Medicine, P.O. Box 26999, Doha, Qatar.
Stem Cell Core, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.
Stem Cell Rev Rep. 2024 Oct;20(7):1915-1931. doi: 10.1007/s12015-024-10752-0. Epub 2024 Jun 25.
The pathogenesis of diabetes involves complex changes in the expression profiles of mRNA and non-coding RNAs within pancreatic islet cells. Recent progress in induced pluripotent stem cell (iPSC) technology have allowed the modeling of diabetes-associated genes. Our recent study using FOXA2-deficient human iPSC models has highlighted an essential role for FOXA2 in the development of human pancreas. Here, we aimed to provide further insights on the role of microRNAs (miRNAs) by studying the miRNA-mRNA regulatory networks in iPSC-derived islets lacking the FOXA2 gene. Consistent with our previous findings, the absence of FOXA2 significantly downregulated the expression of islet hormones, INS, and GCG, alongside other key developmental genes in pancreatic islets. Concordantly, RNA-Seq analysis showed significant downregulation of genes related to pancreatic development and upregulation of genes associated with nervous system development and lipid metabolic pathways. Furthermore, the absence of FOXA2 in iPSC-derived pancreatic islets resulted in significant alterations in miRNA expression, with 61 miRNAs upregulated and 99 downregulated. The upregulated miRNAs targeted crucial genes involved in diabetes and pancreatic islet cell development. In contrary, the absence of FOXA2 in islets showed a network of downregulated miRNAs targeting genes related to nervous system development and lipid metabolism. These findings highlight the impact of FOXA2 absence on pancreatic islet development and suggesting intricate miRNA-mRNA regulatory networks affecting pancreatic islet cell development.
糖尿病的发病机制涉及胰岛细胞内 mRNA 和非编码 RNA 表达谱的复杂变化。诱导多能干细胞（iPSC）技术的最新进展使得模拟与糖尿病相关的基因成为可能。我们最近使用 FOXA2 缺陷型人 iPSC 模型的研究强调了 FOXA2 在人类胰腺发育中的重要作用。在这里，我们旨在通过研究缺乏 FOXA2 基因的 iPSC 衍生胰岛中的 miRNA-mRNA 调控网络，进一步探讨 miRNA 的作用。与我们之前的发现一致，FOXA2 的缺失显著下调了胰岛激素 INS 和 GCG 的表达，以及胰岛中其他关键发育基因的表达。相应地，RNA-Seq 分析显示与胰腺发育相关的基因显著下调，与神经系统发育和脂质代谢途径相关的基因上调。此外，FOXA2 缺失的 iPSC 衍生胰岛中 miRNA 的表达也发生了显著改变，有 61 个 miRNA 上调，99 个下调。上调的 miRNA 靶向与糖尿病和胰岛细胞发育相关的关键基因。相反，胰岛中 FOXA2 的缺失显示出一个下调 miRNA 靶向与神经系统发育和脂质代谢相关的基因的网络。这些发现强调了 FOXA2 缺失对胰岛发育的影响，并提示复杂的 miRNA-mRNA 调控网络影响胰岛细胞的发育。
