Zhang Yize, Zhang Yujia, Wang Catherine, Heo Yuna, Tumenbayar Bat-Ider, Lee Se-Hwan, Bae Yongho, Chin Heo Su
McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA.
bioRxiv. 2024 Jul 23:2024.07.22.604178. doi: 10.1101/2024.07.22.604178.
Meniscus injuries pose significant challenges in clinical settings, primarily due to the intrinsic heterogeneity of the tissue and the limited efficacy of current treatments. Endogenous cell migration is crucial for the healing process, yet the regulatory mechanisms of meniscus cell migration and its zonal dependency within the meniscus are not fully understood. Thus, this study investigates the role of epigenetic mechanisms in governing meniscus cell migration under inflammatory conditions, with a focus on their implications for injury healing and regeneration. Here, we discovered that a proinflammatory cytokine, TNF-α treatment significantly impedes the migration speed of inner meniscus cells, while outer meniscus cells are unaffected, underscoring a zonal-dependent response within the meniscus. Our analysis identified distinct histone modification patterns and chromatin dynamics between inner and outer meniscus cells during migration, highlighting the necessity to consider these zonal-dependent properties in devising repair strategies. Specifically, we found that TNF-α differentially influences histone modifications, particularly H3K27me3, between the two cell types. Transcriptome analysis further revealed that TNF-α treatment induces substantial gene expression changes, with inner meniscus cells exhibiting more pronounced alterations than outer cells. Gene cluster analysis pointed to distinct responses in chromatin remodeling, extracellular matrix assembly, and wound healing processes between the zonal cell populations. Moreover, we identified potential therapeutic targets by employing existing epigenetic drugs, GSKJ4 (a histone demethylase inhibitor) and C646 (a histone acetyltransferase inhibitor), to successfully restore the migration speed of inner meniscus cells under inflammatory conditions. This highlights their potential utility in treating meniscus tear injuries. Overall, our findings elucidate the intricate interplay between epigenetic mechanisms and meniscus cell migration, along with its meniscus zonal dependency. This study provides insights into potential targets for enhancing meniscus repair and regeneration, which may lead to improved clinical outcomes for patients with meniscus injuries and osteoarthritis.
半月板损伤在临床环境中带来了重大挑战，主要原因是组织本身的异质性以及当前治疗方法的疗效有限。内源性细胞迁移对愈合过程至关重要，但半月板细胞迁移的调控机制及其在半月板内的区域依赖性尚未完全了解。因此，本研究调查了表观遗传机制在炎症条件下控制半月板细胞迁移中的作用，重点关注其对损伤愈合和再生的影响。在这里，我们发现促炎细胞因子TNF-α处理显著阻碍了内侧半月板细胞的迁移速度，而外侧半月板细胞不受影响，这突出了半月板内的区域依赖性反应。我们的分析确定了迁移过程中内侧和外侧半月板细胞之间不同的组蛋白修饰模式和染色质动态，强调了在设计修复策略时考虑这些区域依赖性特性的必要性。具体而言，我们发现TNF-α对两种细胞类型之间的组蛋白修饰有不同影响，特别是H3K27me3。转录组分析进一步表明，TNF-α处理会诱导大量基因表达变化，内侧半月板细胞的变化比外侧细胞更明显。基因聚类分析指出，区域细胞群体在染色质重塑、细胞外基质组装和伤口愈合过程中的反应不同。此外，我们通过使用现代表观遗传药物GSKJ4（一种组蛋白去甲基化酶抑制剂）和C646（一种组蛋白乙酰转移酶抑制剂）确定了潜在的治疗靶点，成功恢复了炎症条件下内侧半月板细胞的迁移速度。这突出了它们在治疗半月板撕裂损伤中的潜在效用。总体而言，我们的研究结果阐明了表观遗传机制与半月板细胞迁移之间的复杂相互作用及其半月板区域依赖性。本研究为增强半月板修复和再生的潜在靶点提供了见解，这可能会改善半月板损伤和骨关节炎患者的临床结局。
