在小鼠长骨发育过程中，关节周围间充质祖细胞启动并促进次生骨化中心的形成,STEM CELLS

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在小鼠长骨发育过程中，关节周围间充质祖细胞启动并促进次生骨化中心的形成
STEM CELLS ( IF 4.0 ) Pub Date : 2019-02-06 , DOI: 10.1002/stem.2975
Wei Tong _{1,

2} , Robert J Tower ₁ , Chider Chen ₃ , Luqiang Wang ₁ , Leilei Zhong ₁ , Yulong Wei _{1,

2} , Hao Sun ₁ , Gaoyuan Cao ₄ , Haoruo Jia ₁ , Maurizio Pacifici ₅ , Eiki Koyama ₅ , Motomi Enomoto-Iwamoto ₆ , Ling Qin ₁

Affiliation

长骨发育涉及初始骨干中初级骨化中心 (POC) 的胚胎形成，然后是每个骨骺处的次级骨化中心 (SOC) 的出生后发育。研究阐明了 POC 发展的主要基本机制，但对 SOC 发展的了解相对较少。为了深入了解 SOC 的形成，我们使用了 Col2-Cre Rosa-tdTomato (Col2/Tomato) 报告小鼠，发现它们的关节周围区域包含许多番茄阳性谱系细胞，其表达的番茄荧光（称为 TomatoH）比下面的骨骺软骨细胞（称为番茄L）。随着时间的推移，TomatoH 细胞在 SOC 内陷部位和软骨管中变得明显，在扩张的 SOC 中数量增加，并作为软骨下骨中的间充质谱系细胞存在。这些数据在两个小鼠谱系追踪模型 Col2-CreER Rosa-tdTomato 和 Gli1-CreER Rosa-tdTomato 中得到验证。体外试验表明，来自 Col2/Tomato 小鼠的关节周围 TomatoH 细胞含有具有多分化能力的间充质祖细胞。在根管起始过程中，细胞表达血管内皮生长因子 (VEGF) 并先于单个或成簇的内皮细胞迁移到骨骺软骨中，表明在促进血管生成方面具有独特的作用。在 SOC 扩增后期，骺软骨中的软骨细胞表达 VEGF，血管生成血管先于 TomatoH 细胞。显微解剖样本的基因表达分析揭示了内陷部位关节周围细胞中 MMP 的上调，并表明了新型激酶和生长因子信号通路在调节 SOC 管启动中的潜在作用。总之，我们的数据表明骨骺软骨周围的关节周围区域包含启动 SOC 发育并形成软骨下骨的间充质祖细胞。干细胞 2019；37：677–689

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Periarticular mesenchymal progenitors initiate and contribute to secondary ossification center formation during mouse long bone development

Long bone development involves the embryonic formation of a primary ossification center (POC) in the incipient diaphysis followed by postnatal development of a secondary ossification center (SOC) at each epiphysis. Studies have elucidated major basic mechanisms of POC development, but relatively little is known about SOC development. To gain insights into SOC formation, we used Col2‐Cre Rosa‐tdTomato (Col2/Tomato) reporter mice and found that their periarticular region contained numerous Tomato‐positive lineage cells expressing much higher Tomato fluorescence (termed TomatoH) than underlying epiphyseal chondrocytes (termed TomatoL). With time, the TomatoH cells became evident at the SOC invagination site and cartilage canal, increased in number in the expanding SOC, and were present as mesenchymal lineage cells in the subchondral bone. These data were verified in two mouse lineage tracing models, Col2‐CreER Rosa‐tdTomato and Gli1‐CreER Rosa‐tdTomato. In vitro tests showed that the periarticular TomatoH cells from Col2/Tomato mice contained mesenchymal progenitors with multidifferentiation abilities. During canal initiation, the cells expressed vascular endothelial growth factor (VEGF) and migrated into epiphyseal cartilage ahead of individual or clusters of endothelial cells, suggesting a unique role in promoting vasculogenesis. Later during SOC expansion, chondrocytes in epiphyseal cartilage expressed VEGF, and angiogenic blood vessels preceded TomatoH cells. Gene expression analyses of microdissected samples revealed upregulation of MMPs in periarticular cells at the invagination site and suggested potential roles for novel kinase and growth factor signaling pathways in regulating SOC canal initiation. In summary, our data indicate that the periarticular region surrounding epiphyseal cartilage contains mesenchymal progenitors that initiate SOC development and form subchondral bone. Stem Cells 2019;37:677–689

更新日期：2019-02-06

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