长链非编码RNA MIR22HG在人骨髓间充质干细胞成骨向分化中的作用及机制研究

With the aging of the population, osteoporosis has become a global health problem. However, there are no effective ways for treating osteoporosis currently. Osteoporosis is believed to have a strong correlation with reduced osteogenic potential of bone marrow mesenchymal stem cells (BMMSCs). Hence, improving osteogenic capability of BMMSCs is important for repair and regeneration of bone. However, the detailed mechanism of osteogenic differentiation of BMMSCs remains elusive. Recent studies have found long non-coding RNA (lncRNA) is involved in cell proliferation and differentiation, and plays important roles in development and progression of various kinds of diseases. In this study, we screened differentially expressed lncRNAs in osteogenic differentiation of BMMSCs with RNA sequencing. We found the expression of MIR22HG was significantly upregulated after osteogenic induction of BMMSCs. MIR22HG has been found to play vital roles in carcinogenesis, but its effect on osteogenic differentiation has not been reported. In this study, we aim to investigate the role of MIR22HG on osteogenic differentiation of BMMSCs which will facilitate to uncover the mechanism of osteogenic differentiation of BMMSCs and provide an experimental basis for bone repair and regeneration.

随着社会老龄化的加重，骨质疏松已经成为全球公共卫生问题，但目前尚无有效的治疗手段。研究显示骨质疏松与骨髓间充质干细胞（BMMSCs）成骨向分化能力下降有关。因此提高BMMSCs成骨向分化的能力对于骨修复和骨再生治疗至关重要，然而目前BMMSCs成骨向分化的机制仍未研究透彻。近年来研究发现长链非编码RNA（lncRNA）参与细胞增殖、分化和多种疾病的发生发展等过程。本研究通过使用RNA测序对BMMSCs成骨分化前后差异表达的lncRNAs进行筛选，发现MIR22HG表达水平在成骨诱导后明显增加，MIR22HG以往被发现与肿瘤发生发展关系密切，但在成骨过程中的作用还未见报道，因此本研究旨在探索MIR22HG对间充质干细胞成骨向分化的作用及调控机制，从而更好的阐明骨髓间充质干细胞成骨向分化的过程，为骨修复和骨再生治疗打下基础。

该项目探索了长链非编码RNA MIR22HG在间充质干细胞成骨向分化中的调控作用。本研究发现MIR22HG在成骨分化过程中明显增加，敲低MIR22HG抑制间充质干细胞体内外成骨向分化，过表达则促进间充质干细胞体内外成骨向分化。机制研究发现MIR22HG通过AKT通路调控间充质干细胞成骨向分化。通过构建骨质疏松动物模型，我们发现MIR22HG在骨质疏松小鼠骨髓间充质干细胞中表达明显下降，提示了其在骨代谢中的重要作用及其在骨质疏松疾病中的潜在治疗价值。基于以上研究，我们还发现MIR22HG在间充质干细胞成脂向分化中也具有重要调控作用，实验发现MIR22HG通过WNT/β-catenin通路抑制MIR22HG成脂向分化。除了上述研究之外，我们还扩展研究了热休克蛋白B7（HSPB7）和维甲酸诱导基因3（RAI3）在间充质干细胞成骨分化中的作用及分子机制。本项目研究丰富了间充质干细胞成骨分化的理论知识，为骨缺损修复及骨相关疾病治疗提供了新的治疗靶点。