Schulze-Tanzil Gundula G, Delgado-Calcares Manuel, Stange Richard, Wildemann Britt, Docheva Denitsa
Institute of Anatomy and Cell Biology, Paracelsus Medical University, Nuremberg, Germany.
Experimental Trauma Surgery, Department of Trauma Surgery, University Regensburg Medical Centre, Regensburg, Germany.
Bone Joint Res. 2022 Aug;11(8):561-574. doi: 10.1302/2046-3758.118.BJR-2021-0576.R1.
Tendon is a bradytrophic and hypovascular tissue, hence, healing remains a major challenge. The molecular key events involved in successful repair have to be unravelled to develop novel strategies that reduce the risk of unfavourable outcomes such as non-healing, adhesion formation, and scarring. This review will consider the diverse pathophysiological features of tendon-derived cells that lead to failed healing, including misrouted differentiation (e.g. de- or transdifferentiation) and premature cell senescence, as well as the loss of functional progenitors. Many of these features can be attributed to disturbed cell-extracellular matrix (ECM) or unbalanced soluble mediators involving not only resident tendon cells, but also the cross-talk with immigrating immune cell populations. Unrestrained post-traumatic inflammation could hinder successful healing. Pro-angiogenic mediators trigger hypervascularization and lead to persistence of an immature repair tissue, which does not provide sufficient mechano-competence. Tendon repair tissue needs to achieve an ECM composition, structure, strength, and stiffness that resembles the undamaged highly hierarchically ordered tendon ECM. Adequate mechano-sensation and -transduction by tendon cells orchestrate ECM synthesis, stabilization by cross-linking, and remodelling as a prerequisite for the adaptation to the increased mechanical challenges during healing. Lastly, this review will discuss, from the cell biological point of view, possible optimization strategies for augmenting Achilles tendon (AT) healing outcomes, including adapted mechanostimulation and novel approaches by restraining neoangiogenesis, modifying stem cell niche parameters, tissue engineering, the modulation of the inflammatory cells, and the application of stimulatory factors.Cite this article: 2022;11(8):561-574.
肌腱是一种生长缓慢且血管分布较少的组织，因此，其愈合仍然是一项重大挑战。必须阐明成功修复所涉及的分子关键事件，以开发新策略来降低诸如不愈合、粘连形成和瘢痕形成等不良后果的风险。本综述将探讨导致愈合失败的肌腱来源细胞的多种病理生理特征，包括分化错误（如去分化或转分化）和细胞过早衰老，以及功能性祖细胞的丧失。这些特征中的许多都可归因于细胞与细胞外基质（ECM）的紊乱或可溶性介质的失衡，这不仅涉及驻留的肌腱细胞，还涉及与迁移免疫细胞群体的相互作用。创伤后不受控制的炎症可能会阻碍成功愈合。促血管生成介质引发血管过度增生，并导致不成熟修复组织的持续存在，这种组织无法提供足够的机械能力。肌腱修复组织需要实现与未受损的高度分层有序的肌腱ECM相似的ECM组成、结构、强度和刚度。肌腱细胞充分的机械传感和转导协调ECM的合成、交联稳定和重塑，这是适应愈合过程中增加的机械挑战的先决条件。最后，本综述将从细胞生物学角度讨论增强跟腱（AT）愈合结果的可能优化策略，包括适应性机械刺激以及通过抑制新生血管生成、修改干细胞微环境参数、组织工程、调节炎症细胞和应用刺激因子的新方法。引用本文：2022;11(8):561-574。
