MicroRNA-365-3p inhibits bone marrow mesenchymal stem cell differentiation into islet-like cell clusters via targeting Pax6 and inhibiting the MEK/ERK pathway.

IF 2.5 Q3 ENDOCRINOLOGY & METABOLISM Minerva endocrinology Pub Date : 2023-12-01 Epub Date: 2021-06-23 DOI:10.23736/S2724-6507.21.03389-3
Wenting Wang, Shu Li, Yankun Hao, Baixiang Cui, Xuezhi Zheng, Lei Yan, Xufang Yang
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Abstract

Background: Diabetes has severe impacts on the health of patients. The differentiation of mesenchymal stem cells (MSCs) into islet-like cell clusters (ICCs) is an effective protocol for the treatment of diabetes. microRNAs (miRs) regulate multiple cellular processes including cell differentiation. This study sought to identify the mechanism of miR-365-3p in the differentiation of bone marrow MSCs (bMSCs) into ICCs.

Methods: Initially, the differentiation of bMSCs into ICCs was induced. Then, the miR-365-3p expression pattern in the bMSCs and ICCs was detected. Next, the miR-365-3p expression pattern was silenced in bMSCs to assess the effect on differentiation efficiency and measure the expressions of ICC marker genes during the differentiation of bMSCs into ICCs. The miR-365-3p downstream target genes were predicted and verified. Paired box protein 6 (Pax6) was downregulated in bMSCs with silenced miR-365-3p to evaluate the differentiation of bMSCs into ICCs. Furthermore, the Pax6 downstream pathway was evaluated.

Results: The differentiation of bMSCs into ICCs was successfully induced. The miR-365-3p expression in bMSCs was higher than that in ICCs. miR-365-3p downregulation in bMSCs facilitated the differentiation of bMSCs into ICCs, as evidenced by elevated releases of insulin and C-peptide in ICCs and elevated expressions of ICC marker genes. Our findings denoted that miR-365-3p targeted Pax6. Inhibition of Pax6 expression annulled the promotion of miR-365-3p downregulation on the differentiation of bMSCs into ICCs. Increased phosphorylation levels of MEK and ERK were identified in ICCs after downregulation of miR-365-3p however they were decreased after downregulation of Pax6.

Conclusions: This study supported that miR-365-3p inhibited the differentiation of bMSCs into ICCs via targeting Pax6 and inhibiting the MEK/ERK pathway.

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MicroRNA-365-3p通过靶向Pax6和抑制MEK/ERK通路抑制骨髓间充质干细胞分化成小岛状细胞簇。
背景:糖尿病严重影响患者的健康。间充质干细胞(MSCs)分化成小岛样细胞团(ICCs)是治疗糖尿病的有效方案。microRNAs(miRs)调控多种细胞过程,包括细胞分化。本研究试图确定 miR-365-3p 在骨髓间充质干细胞(bMSCs)分化为 ICCs 过程中的作用机制:方法:首先诱导骨髓间充质干细胞分化为 ICCs。方法:首先,诱导 bMSCs 分化为 ICCs,然后检测 bMSCs 和 ICCs 中 miR-365-3p 的表达模式。然后,在bMSCs中沉默miR-365-3p的表达模式,以评估其对分化效率的影响,并测量bMSCs分化成ICCs过程中ICC标记基因的表达。对 miR-365-3p 下游靶基因进行了预测和验证。在沉默了 miR-365-3p 的 bMSCs 中,配对盒蛋白 6(Pax6)被下调,以评估 bMSCs 向 ICCs 的分化。此外,还评估了 Pax6 的下游通路:结果:成功诱导了 bMSCs 向 ICCs 的分化。miR-365-3p在bMSCs中的表达量高于在ICCs中的表达量。miR-365-3p在bMSCs中的下调促进了bMSCs向ICCs的分化,ICCs中胰岛素和C肽的释放量升高以及ICC标志基因的表达量升高证明了这一点。我们的研究结果表明,miR-365-3p 以 Pax6 为靶标。抑制 Pax6 的表达可消除 miR-365-3p 下调对 bMSCs 向 ICCs 分化的促进作用。miR-365-3p下调后,ICCs中MEK和ERK的磷酸化水平升高,而Pax6下调后磷酸化水平降低:这项研究证实,miR-365-3p 通过靶向 Pax6 和抑制 MEK/ERK 通路,抑制了 bMSCs 向 ICCs 的分化。
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