Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Department of Electron Microscopy Unit, Weizmann Institute of Science, Rehovot, Israel.
Am J Pathol. 2022 Aug;192(8):1122-1135. doi: 10.1016/j.ajpath.2022.05.008. Epub 2022 Jun 1.
Wound healing typically recruits the immune and vascular systems to restore tissue structure and function. However, injuries to the enthesis, a hypocellular and avascular tissue, often result in fibrotic scar formation and loss of mechanical properties, severely affecting musculoskeletal function and life quality. This raises questions about the healing capabilities of the enthesis. Herein, this study established an injury model to the Achilles entheses of neonatal mice to study the effectiveness of early-age enthesis healing. Histology and immunohistochemistry analyses revealed an atypical process that did not involve inflammation or angiogenesis. Instead, healing was mediated by secretion of collagen types I and II by resident cells, which formed a permanent hypocellular and avascular scar. Transmission electron microscopy showed that the cellular response to injury, including endoplasmic reticulum stress, autophagy, and cell death, varied between the tendon and cartilage ends of the enthesis. Single-molecule in situ hybridization, immunostaining, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assays verified these differences. Finally, gait analysis showed that these processes effectively restored function of the injured leg. These findings reveal a novel healing mechanism in neonatal entheses, whereby local extracellular matrix secretion by resident cells forms an acellular extracellular matrix deposit without inflammation, allowing gait restoration. These insights into the healing mechanism of a complex transitional tissue may lead to new therapeutic strategies for adult enthesis injuries.
伤口愈合通常会招募免疫和血管系统来恢复组织结构和功能。然而，在肌腱附着处（一种细胞稀少且无血管的组织）受伤时，通常会导致纤维组织疤痕形成和机械性能丧失，严重影响肌肉骨骼功能和生活质量。这就提出了关于肌腱附着处愈合能力的问题。在此，本研究建立了一种损伤新生小鼠跟腱附着处的模型，以研究早期肌腱附着处愈合的效果。组织学和免疫组织化学分析显示了一种非典型的过程，该过程不涉及炎症或血管生成。相反，愈合是由驻留细胞分泌 I 型和 II 型胶原介导的，形成永久性的细胞稀少且无血管的疤痕。透射电子显微镜显示，细胞对损伤的反应，包括内质网应激、自噬和细胞死亡，在肌腱和软骨末端的附着处之间存在差异。单分子原位杂交、免疫染色和末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记检测证实了这些差异。最后，步态分析表明，这些过程有效地恢复了受伤腿的功能。这些发现揭示了一种新生肌腱附着处的新型愈合机制，即驻留细胞局部细胞外基质的分泌形成无细胞的细胞外基质沉积物，而无炎症，从而允许步态恢复。这些对复杂过渡组织愈合机制的见解可能为成人肌腱附着处损伤提供新的治疗策略。
