Cytomegalovirus induces abnormal chondrogenesis and osteogenesis during embryonic mandibular development.
Cytomegalovirus induces abnormal chondrogenesis and osteogenesis during embryonic mandibular development.
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巨细胞病毒在胚胎下颌发育过程中诱导异常软骨生成和骨生成。
DOI：
10.1186/1471-213x-8-33
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发表时间：
2008-03-27
影响因子：
--
通讯作者：
Melnick, Michael
中科院分区：
文献类型：
--
作者：
Jaskoll, Tina;Abichaker, George;Sedghizadeh, Parish P.;Bringas, Pablo, Jr.;Melnick, Michael
人类临床研究和小鼠模型清楚地表明，巨细胞病毒（CMV）破坏正常器官和组织发育。虽然CMV是人类主要出生缺陷的最常见原因之一，但目前对CMV诱导的先天性畸形的潜在机制知之甚少。我们以前的研究表明，CMV感染的第一鳃弓衍生物（唾液腺和牙齿）诱导严重异常的表型和CMV有一个特定的嗜性神经嵴衍生的间充质（NCM）。由于早期胚胎对CMV感染几乎不敏感，并且现存的证据表明，胚胎组织对病毒感染和病毒诱导的病理学敏感的分化程序需要进行得很好，因此本研究的目的是确定第一鳃弓NCM细胞在分化NCM衍生物之前是否对mCMV感染敏感。E11小鼠下颌突（MAN）在体外用小鼠CMV（mCMV）感染长达16天。未分化的胚胎小鼠MAN的mCMV感染诱导小颌畸形，从而减少Meckel软骨软骨形成和下颌骨形成。具体而言，mCMV感染导致异常的基质细胞结构，较小的畸形Meckel软骨，下颌骨和髁状突畸形。病毒分布分析表明，mCMV主要感染NCM细胞和衍生物。初步定位研究表明，mCMV感染改变了FN，NF-κB2，RelA，RelB，Shh和Smad 7蛋白的细胞特异性表达。我们的研究结果表明，mCMV的主要NCM细胞及其衍生物的关键信号通路的失调严重破坏下颌骨形态和骨骼发生。发病机制似乎围绕着经典和非经典NF-κB途径，异常基质细胞和周围基质存在不寻常的并列。此外，由于在发育过程中信号分子在适当的细胞群中表达是至关重要的，因此相关信号通路的组分的异常定位可能揭示下颌骨畸形的致病机制。
Human clinical studies and mouse models clearly demonstrate that cytomegalovirus (CMV) disrupts normal organ and tissue development. Although CMV is one of the most common causes of major birth defects in humans, little is presently known about the mechanism(s) underlying CMV-induced congenital malformations. Our prior studies have demonstrated that CMV infection of first branchial arch derivatives (salivary glands and teeth) induced severely abnormal phenotypes and that CMV has a particular tropism for neural crest-derived mesenchyme (NCM). Since early embryos are barely susceptible to CMV infection, and the extant evidence suggests that the differentiation program needs to be well underway for embryonic tissues to be susceptible to viral infection and viral-induced pathology, the aim of this study was to determine if first branchial arch NCM cells are susceptible to mCMV infection prior to differentiation of NCM derivatives. E11 mouse mandibular processes (MANs) were infected with mouse CMV (mCMV) for up to 16 days in vitro. mCMV infection of undifferentiated embryonic mouse MANs induced micrognathia consequent to decreased Meckel's cartilage chondrogenesis and mandibular osteogenesis. Specifically, mCMV infection resulted in aberrant stromal cellularity, a smaller, misshapen Meckel's cartilage, and mandibular bone and condylar dysmorphogenesis. Analysis of viral distribution indicates that mCMV primarily infects NCM cells and derivatives. Initial localization studies indicate that mCMV infection changed the cell-specific expression of FN, NF-κB2, RelA, RelB, and Shh and Smad7 proteins. Our results indicate that mCMV dysregulation of key signaling pathways in primarily NCM cells and their derivatives severely disrupts mandibular morphogenesis and skeletogenesis. The pathogenesis appears to be centered around the canonical and noncanonical NF-κB pathways, and there is unusual juxtaposition of abnormal stromal cells and surrounding matrix. Moreover, since it is critically important that signaling molecules are expressed in appropriate cell populations during development, the aberrant localization of components of relevant signaling pathways may reveal the pathogenic mechanism underlying mandibular malformations.