Periarticular Mesenchymal Progenitors Initiate and Contribute to Secondary Ossification Center Formation During Mouse Long Bone Development
Periarticular Mesenchymal Progenitors Initiate and Contribute to Secondary Ossification Center Formation During Mouse Long Bone Development
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关节周围间充质祖细胞在小鼠长骨发育过程中启动并促进次级骨化中心的形成
DOI：
10.1002/stem.2975
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发表时间：
2019-02
期刊：
影响因子：
5.2
通讯作者：
Qin Ling
中科院分区：
文献类型：
--
作者：
Tong Wei;Tower Robert J;Chen Chider;Wang Luqiang;Zhong Leilei;Wei Yulong;Sun Hao;Cao Gaoyuan;Jia Haoruo;Pacifici Maurizio;Koyama Eiki;Enomoto Iwamoto Motomi;Qin Ling
长骨发育包括早期骨干内初级骨化中心(POC)的胚胎形成，然后在每个骨痂处出生后形成次级骨化中心(SOC)。研究已经阐明了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-td Tomato(Col2/Tomato)报告小鼠，发现它们的关节周围区域包含大量番茄阳性的谱系细胞，其番茄荧光(称为Tomatoh)比下面的骨骺软骨细胞(称为TomatoL)高得多。随着时间的推移，在SOC内陷部位和软骨管中，TomatoHcell逐渐明显，在扩张的SOC中数量增多，并以间充质细胞的形式存在于软骨下骨中。这些数据在两个小鼠血统追踪模型Col2-Creer Rosa-td Tomato和Gli1-Creer Rosa-tdTomato中得到了验证。体外实验表明，COL2/TOMATOMICE的关节周围细胞含有具有多向分化能力的间充质祖细胞。在管腔起始过程中，细胞表达血管内皮生长因子(VEGF)，并先于单个或成群的内皮细胞迁移到骨骺软骨中，提示其在促进血管生成方面具有独特的作用。随后在SOC扩张过程中，骨骺软骨中的软骨细胞表达血管内皮生长因子，血管新生血管先于TomatoH细胞。显微解剖标本的基因表达分析显示，MMPs在内陷部位的关节周围细胞中表达上调，提示新的激酶和生长因子信号通路在调节SOC管起始中可能发挥作用。综上所述，我们的数据表明，骨骺软骨周围的关节周围区域含有启动SOC发育和形成软骨下骨的间充质前体细胞。StemCells2019；37：677-689意义陈述长骨发育包括在早期骨干中胚胎形成初级骨化中心，然后在每个骨痂处出生后形成次级骨化中心(SOC)。在目前的工作中，转基因荧光报告鼠被用来显示沿骨痂表面的一层高荧光细胞层，其中含有间充质干细胞，负责启动SOC的形成，招募周围的血管，并在这个骨室内建立所有的间充质系细胞。这一发现揭示了关节周围区域在骨骼发育过程中的重要作用，并强调了其作为治疗用多能祖细胞来源的潜在用途。
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 usedCol2-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 TomatoHcells 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-tdTomatoandGli1-CreER Rosa-tdTomato. In vitro tests showed that the periarticular TomatoHcells fromCol2/Tomatomice 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 TomatoHcells. 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. StemCells2019;37:677–689Significance StatementLong bone development involves the embryonic formation of a primary ossification center in the incipient diaphysis followed by postnatal development of secondary ossification centers (SOCs) at each epiphysis. In the present work, genetically modified fluorescent reporter mice were used to show a layer of highly fluorescent cells along the epiphyseal surface contain mesenchymal stem cells responsible for initiating SOC formation, recruiting surrounding vessels and establishing all mesenchymal lineage cells within this bone compartment. The finding reveals an important role of the periarticular region during skeletal development and highlights its potential use as a source of multipotent progenitor cells for therapeutic treatment.
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影响因子：
6.2
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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