LncRNA HOTAIRM1 promotes dental follicle stem cell-mediated bone regeneration by regulating HIF-1α/KDM6/EZH2/H3K27me3 axis
LncRNA HOTAIRM1 promotes dental follicle stem cell-mediated bone regeneration by regulating HIF-1α/KDM6/EZH2/H3K27me3 axis
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DOI：
10.1002/jcp.31028
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发表时间：
2023-04-30
影响因子：
5.6
通讯作者：
Cao, Yang
中科院分区：
文献类型：
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作者：
Chen, Zhengyuan;Gan, Liyi;Cao, Yang
大型骨缺损区的重建经历了低氧，这仍然是一个主要的实际挑战。具有更有前景的干细胞来源的骨组织工程促进了更好的治疗结果的发展。人牙囊干细胞(HDFSCs)具有良好的多能性、成骨能力和可获得性，已被证明是一种很有前途的骨再生细胞来源。我们以前发现了一个新的长非编码RNA(LncRNA)，HOTAIRM1，在hDFSCs中高表达。在此，我们发现HOTAIRM1过表达的hDFSCs促进了大鼠临界大小颅骨缺损模型的骨再生。在缺氧条件下，hDFSCs机械地诱导HOTAIRM1，并激活HIF-1α。RNA测序分析表明，HOTAIRM1通过靶向HIF-1α上调氧敏感组蛋白去甲基酶KDM6A/B，抑制甲基转移酶EZH2。HDFSCs的成骨分化伴随着H3K27去甲基化，HOTAIRM1过表达使H3K27me3在成骨基因ALP、M-CSF、Wnt-3a、Wnt-5a、Wnt-7a和β-catenin中的分布减少，从而促进其转录。我们的研究为HOTAIRM1上调KDM6A/B和抑制EZH2提供了证据，这种上调以HIF-1α依赖的方式促进hDFSCs的成骨。HOTAIRM1介导的hDFSCs在临床上可能成为促进骨再生的一种有前途的治疗方法。
Large bone defect reconstruction undergoes hypoxia and remains a major practical challenge. Bone tissue engineering with a more promising stem cell source facilitates the development of better therapeutic outcomes. Human dental follicle stem cells (hDFSCs) with superior multipotency, osteogenic capacity, and accessibility have been proven a promising cell source for bone regeneration. We previously identified a novel long noncoding RNA (lncRNA), HOTAIRM1, to be highly expressed in hDFSCs. Here we found that HOTAIRM1 overexpressed hDFSCs promoted bone regeneration in rat critical-size calvarial defect model. Mechanically, HOTAIRM1 was induced in hDFSCs under hypoxic conditions and activated HIF-1 alpha. RNA-sequencing analysis indicated that HOTAIRM1 upregulated oxygen-sensing histone demethylases KDM6A/B and suppressed methyltransferase EZH2 via targeting HIF-1 alpha. The osteogenic differentiation of hDFSCs was accompanied with demethylation of H3K27, and HOTAIRM1 overexpression decreased the distribution of H3K27me3 in osteogenic genes, including ALP, M-CSF, Wnt-3a, Wnt-5a, Wnt-7a, and beta-catenin, thus promoted their transcription. Our study provided evidence that HOTAIRM1 upregulated KDM6A/B and inhibited EZH2 in a HIF-1 alpha dependent manner to enhance the osteogenesis of hDFSCs. HOTAIRM1-mediated hDFSCs may serve as a promising therapeutic approach to promote bone regeneration in clinical practice.