Enthesis fibrocartilage cells originate from a population of Hedgehog-responsive cells modulated by the loading environment
Enthesis fibrocartilage cells originate from a population of Hedgehog-responsive cells modulated by the loading environment
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DOI：
10.1242/dev.112714
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发表时间：
2015-01-01
期刊：
影响因子：
4.6
通讯作者：
Thomopoulos, Stavros
中科院分区：
文献类型：
--
作者：
Schwartz, Andrea G.;Long, Fanxin;Thomopoulos, Stavros
肌腱通过一种特殊的组织附着在骨骼上，这种组织被称为末端。这种组织调节肌腱和骨骼两种材料之间的肌力传递，这两种材料的机械性能截然不同。许多肌腱的末端由矿化的分级纤维软骨组成，该软骨在出生后发育，并伴随着骨骺的矿化。尽管功能成熟度的矿化和发育需要肌肉负荷，但调节末端发育的生物学因素却知之甚少。通过对Hedgehog(HH)信号反应中表达Gli1的细胞进行遗传学划分，我们发现在发育中的小鼠胚胎中有一组独特的HH反应细胞，它们不同于肌腱成纤维细胞和骨骺软骨细胞。谱系追踪实验表明，起源于子宫的Gli1谱系细胞最终填充在整个成熟的末端。肌肉麻痹增加了末端HH反应细胞的数量，表明对HH的反应部分是由肌肉负荷调节的。在出生后发育的第一周切除HH反应细胞导致矿化纤维软骨的丢失，在细胞切除后5周几乎没有组织重塑。从发育中的肌腱和末端有条件地缺失对IHH反应所必需的Smobled分子改变了末端前体细胞的分化，导致纤维软骨矿化显著减少，生物力学功能降低。综上所述，这些结果表明，发育中的末端纤维软骨细胞内的HH信号是末端形成所必需的。
Tendon attaches to bone across a specialized tissue called the enthesis. This tissue modulates the transfer of muscle forces between two materials, i.e. tendon and bone, with vastly different mechanical properties. The enthesis for many tendons consists of a mineralized graded fibrocartilage that develops postnatally, concurrent with epiphyseal mineralization. Although it is well described that the mineralization and development of functional maturity requires muscle loading, the biological factors that modulate enthesis development are poorly understood. By genetically demarcating cells expressing Gli1 in response to Hedgehog(Hh) signaling, we discovered a unique population of Hh-responsive cells in the developing murine enthesis that were distinct from tendon fibroblasts and epiphyseal chondrocytes. Lineage-tracing experiments revealed that the Gli1 lineage cells that originate in utero eventually populate the entire mature enthesis. Muscle paralysis increased the number of Hh-responsive cells in the enthesis, demonstrating that responsiveness to Hh is modulated in part by muscle loading. Ablation of the Hh-responsive cells during the first week of postnatal development resulted in a loss of mineralized fibrocartilage, with very little tissue remodeling 5 weeks after cell ablation. Conditional deletion of smoothened, a molecule necessary for responsiveness to Ihh, from the developing tendon and enthesis altered the differentiation of enthesis progenitor cells, resulting in significantly reduced fibrocartilage mineralization and decreased biomechanical function. Taken together, these results demonstrate that Hh signaling within developing enthesis fibrocartilage cells is required for enthesis formation.