LncRNA HOTAIRM1 promotes dental follicle stem cell‐mediated bone regeneration by regulating HIF‐1α/KDM6/EZH2/H3K27me3 axis

Abstract 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‐1α. RNA‐sequencing analysis indicated that HOTAIRM1 upregulated oxygen‐sensing histone demethylases KDM6A/B and suppressed methyltransferase EZH2 via targeting HIF‐1α. 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 β‐catenin, thus promoted their transcription. Our study provided evidence that HOTAIRM1 upregulated KDM6A/B and inhibited EZH2 in a HIF‐1α 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.