From the Medical Research Council Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, United Kingdom.
Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.
J Biol Chem. 2018 Apr 20;293(16):5766-5780. doi: 10.1074/jbc.RA118.001987. Epub 2018 Mar 5.
Tendon is a dense connective tissue that transmits high mechanical forces from skeletal muscle to bone. The transcription factor scleraxis (Scx) is a highly specific marker of both precursor and mature tendon cells (tenocytes). Mice lacking exhibit a specific and virtually complete loss of tendons during development. However, the functional contribution of Scx to wound healing in adult tendon has not yet been fully characterized. Here, using -tracking and loss-of-function systems, we show in an adult mouse model of Achilles tendon injury that paratenon cells, representing a stem cell antigen-1 (Sca-1)-positive and Scx-negative progenitor subpopulation, display Scx induction, migrate to the wound site, and produce extracellular matrix (ECM) to bridge the defect, whereas resident tenocytes exhibit a delayed response. Scx induction in the progenitors is initiated by transforming growth factor β (TGF-β) signaling. -deficient mice had migration of Sca-1-positive progenitor cell to the lesion site but impaired ECM assembly to bridge the defect. Mechanistically, -null progenitors displayed higher chondrogenic potential with up-regulation of SRY-box 9 (Sox9) coactivator PPAR-γ coactivator-1α (PGC-1α) , and knock-in analysis revealed that forced expression of full-length significantly inhibited expression. Accordingly, -null wounds formed cartilage-like tissues that developed ectopic ossification. Our findings indicate a critical role of Scx in a progenitor-cell lineage in wound healing of adult mouse tendon. These progenitor cells could represent targets in strategies to facilitate tendon repair. We propose that this lineage-regulatory mechanism in tissue progenitors could apply to a broader set of tissues or biological systems in the body.
肌腱是一种致密的结缔组织，将高强度的机械力从骨骼肌传递到骨骼。转录因子 Scleraxis (Scx) 是前体细胞和成肌腱细胞（tenocytes）的高度特异性标志物。缺乏 的小鼠在发育过程中表现出特异性和几乎完全丧失肌腱。然而，Scx 对成年肌腱伤口愈合的功能贡献尚未得到充分表征。在这里，我们使用 追踪和功能丧失系统，在成年小鼠跟腱损伤模型中显示，腱旁细胞代表干细胞抗原-1 (Sca-1) 阳性和 Scx 阴性祖细胞亚群，表现出 Scx 诱导、迁移到伤口部位，并产生细胞外基质 (ECM) 来桥接缺陷，而驻留的 tenocytes 则表现出延迟反应。祖细胞中的 Scx 诱导是由转化生长因子 β (TGF-β) 信号启动的。 -/- 小鼠的 Sca-1 阳性祖细胞迁移到病变部位，但 ECM 组装受损，无法桥接缺陷。从机制上讲， -/- 祖细胞表现出更高的软骨形成潜能，上调 SRY 盒 9 (Sox9) 共激活因子过氧化物酶体增殖物激活受体-γ 共激活因子 1α (PGC-1α) ，敲入分析显示全长 的强制表达显著抑制 表达。因此， -/- 伤口形成软骨样组织，形成异位骨化。我们的研究结果表明，Scx 在成年小鼠肌腱伤口愈合中的祖细胞谱系中起着关键作用。这些祖细胞可能是促进肌腱修复策略的靶点。我们提出，这种组织祖细胞中的谱系调节机制可能适用于体内更广泛的组织或生物学系统。
