He Bo, Su Shouwen, Zhang Zeyu, Lin Zhongpei, Qiu Qinglin, Yang Yan, Wen Xiaoyue, Zhu Zhaowei
Orthopaedic Trauma and Joint Department, Department of Orthopedics, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510000, China.
Department of Dermatology, Guangzhou Dermatology Hospital, No. 56 Hengfu Road, Guangzhou, 510095, Guangdong, China.
Mol Med. 2025 Mar 21;31(1):110. doi: 10.1186/s10020-025-01142-4.
BACKGROUND: The states of Schwann cells undergo significant shifts during nerve regeneration. Previous studies have shown the expression of Runx2 is locally upregulated within the affected areas. However, the regulatory mechanisms underlying its epigenetic control remain unclear. METHODS: To investigate the epigenetic mechanisms through which Runx2 influences the phenotypic transition of repair Schwann cells. Runx2 siRNA fragments and Runx2 overexpression plasmids were constructed. Healthy adult Sprague-Dawley (SD) rats weighted 100-150 g, regardless of sex, were randomly selected. Following the establishment of a sciatic nerve crush injury model, samples were collected for qPCR analysis at 4 and 7 days post-injury. In vitro, the alterations in cell morphology, proliferation, apoptosis, and the ability to promote neural regeneration following the downregulation or upregulation of Runx2 in Schwann cells were assessed. A comprehensive analysis of transcriptome data, ATAC sequencing, and CUT&Tag sequencing of histones and transcription factors in SCs after Runx2 overexpression, along with single-cell RNA sequencing data from GSE216665 and Sox2 overexpression data from RSC96 in GSE94590, was conducted to elucidate the mechanism of action of Runx2, which was subsequently validated using dual luciferase assays. RESULTS: Runx2 expression increased locally during the early stages of injury, primarily localized within Zhu Schwann cells (Zhu SCs). Runx2-overexpressing Schwann cells, when cultured in vitro, underwent a transformation from long, spindle-shaped He Schwann cells (He SCs) to flat, rounded Zhu SCs. Multi-omics analysis indicated that Runx2-OE may positively feedback-regulate its expression by opening transcriptional regulatory regions and binding to its own gene regulatory domains. Furthermore, it could also activate transcription factors such as Sox2, transitioning them from a transcriptionally silent to an active state, thereby enhancing Sox2 expression and synergistically regulating the phenotypic transition of Schwann cells. CONCLUSIONS: Runx2 can activate and recruit downstream stemness factors, such as Sox2, by modulating chromatin accessibility and histone modification status within Schwann cells, thereby promoting and maintaining the timely phenotypic transformation of Schwann cells following injury.
背景：雪旺细胞的状态在神经再生过程中会发生显著变化。先前的研究表明，Runx2的表达在受影响区域内局部上调。然而，其表观遗传调控的潜在机制仍不清楚。 方法：为了研究Runx2影响修复性雪旺细胞表型转变的表观遗传机制。构建了Runx2小干扰RNA片段和Runx2过表达质粒。随机选取体重100 - 150克的健康成年Sprague-Dawley（SD）大鼠，不限性别。建立坐骨神经挤压伤模型后，在损伤后4天和7天收集样本进行qPCR分析。在体外，评估雪旺细胞中Runx2下调或上调后细胞形态、增殖、凋亡以及促进神经再生能力的变化。对Runx2过表达后雪旺细胞的转录组数据、ATAC测序以及组蛋白和转录因子的CUT&Tag测序进行综合分析，同时结合来自GSE216665的单细胞RNA测序数据和来自GSE94590中RSC96的Sox2过表达数据，以阐明Runx2的作用机制，随后使用双荧光素酶测定法进行验证。 结果：Runx2表达在损伤早期局部增加，主要定位于珠状雪旺细胞（Zhu SCs）。体外培养时，过表达Runx2的雪旺细胞从长梭形的He雪旺细胞（He SCs）转变为扁平圆形的Zhu SCs。多组学分析表明，Runx2过表达可能通过打开转录调控区域并结合其自身基因调控域来正向反馈调节其表达。此外，它还可以激活转录因子如Sox2，使其从转录沉默状态转变为激活状态，从而增强Sox2表达并协同调节雪旺细胞的表型转变。 结论：Runx2可通过调节雪旺细胞内的染色质可及性和组蛋白修饰状态来激活和招募下游干性因子，如Sox2，从而促进和维持损伤后雪旺细胞及时的表型转变。
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