lncRNA Gm10451 regulates PTIP to facilitate iPSCs-derived β-like cell differentiation by targeting miR-338-3p as a ceRNA
lncRNA Gm10451 regulates PTIP to facilitate iPSCs-derived β-like cell differentiation by targeting miR-338-3p as a ceRNA
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lncRNA Gm10451 通过靶向 miR-338-3p 作为 ceRNA 调节 PTIP 以促进 iPSC 衍生的 β 样细胞分化
DOI：
10.1016/j.biomaterials.2019.119266
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发表时间：
2019-09-01
期刊：
影响因子：
14
通讯作者：
Wang, Zhiwei
中科院分区：
文献类型：
--
作者：
Huang, Yan;Xu, Yang;Wang, Zhiwei
iPSC 衍生的胰岛素产生细胞移植是一种有前途的糖尿病治疗策略。尽管在过去的几年里已经有许多体外诱导成熟、葡萄糖反应性β细胞的方案，但许多潜在的问题仍有待解决。作为重要的调节因子，长非编码 RNA (lncRNA) 参与许多生物过程，包括多能性的维持和干细胞分化。在这项研究中，我们发现了一种新型 lncRNA Gm10451 作为 β 样细胞分化的功能调节剂。 Gm10451 定位于细胞质，通过靶向 miR-338-3p 作为竞争性内源 RNA (ceRNA)，调节组蛋白 H3K4 甲基转移酶复合物 PTIP，以促进胰岛素(+)/Nkx6.1(+) β 样细胞分化。 miR-338-3p 还被证明可以通过靶向 PTIP 来抑制 Nkx6.1(+) 早期 β 样细胞分化。移植到链脲佐菌素 (STZ) 小鼠后，β 样细胞中 Gm10451 的缺失阻止了成熟 β 细胞制造者的表达，例如胰岛素、Nkx6.1 和 Mafa。因此，小鼠的高血糖症并未得到解决。总而言之，这项研究为产生更成熟和功能性的 iPSC 衍生的 β 样细胞提供了一个有效的表观遗传靶点。我们预计，由人类干细胞、生物材料和表观遗传修饰产生的胰腺类器官在未来可以作为一种新型的糖尿病治疗选择。
iPSCs-derived insulin-producing cell transplantation is a promising strategy for diabetes therapy. Although there have been many protocols of mature, glucose-responsive beta cells induced in vitro over the past few years, many underlying problems remain to be resolved. As a crucial regulator, long noncoding RNAs (lncRNAs) participate in numerous biological processes, including the maintenance of pluripotency, and stem cell differentiation. In this study, we identified a novel lncRNA Gm10451 as a functional regulator for beta-like cell differentiation. Localized to the cytoplasm, Gm10451 regulates histone H3K4 methyltransferase complex PTIP to facilitate Insulin(+)/Nkx6.1(+) beta-like cell differentiation by targeting miR-338-3p as a competing endogenous RNA (ceRNA). miR-338-3p has also been shown to suppress Nkx6.1(+) early-stage beta-like cell differentiation by targeting PTIP. Following transplantation into streptozotocin (STZ)-mice, Gm10451 loss in beta-like cells prevented the expression of mature beta-cell makers, such as Insulin, Nkx6.1, and Mafa. Accordingly, hyperglycemia in the mice was not resolved. Taken together, this study provides an efficient epigenetic target for generating more mature and functional iPSCs-derived beta-like cells. We anticipate that pancreatic organoids, which are generated from human stem cells, biological materials, and epigenetic modifications, can be used in the future as a novel diabetes treatment option.