To define the novel roles of endochondrogenesis in mandible formation and trauma repair

项目摘要/摘要 创伤和癌症引起的组织损伤在下颌骨中很常见。与电流相关的严重故障 移植治疗，如骨坏死，是由于当地恶劣的条件和有限的 移植物和宿主组织。最近的研究表明，软骨移植产生了良好的血管化和整合。 骨再生类似于同种异体移植，表明软骨细胞可以形成骨。作为一种机制，细胞 已经证实了软骨细胞向骨细胞的转分化。然而，膜性成骨 目前被认为是下颌骨体形成和修复的唯一机制，尽管有两种类型的 软骨(Meckel‘s软骨，MC；和喙突，RP)存在于下颌骨生长发育过程中。类似于 在小鼠模型中，在人类胎儿和婴儿中发现了一种RP-MC样结构。为了解决是否 软骨内生有助于下颌骨体的生长和修复，一系列研究使用 已经采取了补充办法。主要发现如下：1)下颌骨体由 2)MC和RP中肥大的软骨细胞直接反式转化成软骨细胞。 向骨细胞分化，而不是直接进入细胞凋亡；3)rp-mc是一个连续的软骨；4)一个新的 发现了浓缩间充质祖细胞带，为RP和MC提供了新的细胞来源 5)内软骨生成在下颌骨修复中起着关键作用。 创伤修复程序(软骨内骨)的默认程序(膜骨)，其中 软骨生成(需要有限的血管生成)首先发生，其次是软骨细胞反式生长。 分化成骨骼。基于这些发现，中心假设是下颌体是由 软骨内和膜骨都是如此，内软骨形成在下颌骨修复中起着关键作用。 为了验证这一中心假设，提出了三个高度相关但又独立的具体目标：1)确定 MC和RP如何通过软骨细胞的转分化促进下颌骨的形成；2)描绘 RP由cMP派生而来的机制，cMP-rp是一种类似生长板的结构，收敛于 在细胞和分子水平上延长下颌骨生长过程中MC的两端；3)确定 内生性软骨形成如何通过默认发育的转换机制促进下颌骨修复 通过干细胞的改变，将(膜骨)程序转化为创伤修复程序(软骨内骨) 命运。这个项目的完成将1)证明CMP-RP-MC复合体有助于下颌骨的生长 通过将RP-MC软骨细胞转化为骨细胞；以及2)确定一些关键因素，这些因素包括 负责通过干细胞的改变从膜性成骨转变为内软骨生成 命运在修复的过程中。这些结果可能会修正目前的概念，为这方面提供新的知识 很大程度上未知但至关重要的领域，并为开发新方法奠定基础，这最终将 加快未来下颌骨创伤修复的进程。

Project Summary/Abstract Trauma- and cancer-induced tissue damage is common in the mandible. Critical failures associated with current grafting treatments, like osteonecrosis, occur due to poor local conditions and limited integration between the graft and the host tissue. Recent studies show that cartilage grafts produce well-vascularized and integrated bone regeneration similar to an isograft, indicating that chondrocytes can form bones. As a mechanism, cell trans-differentiation from chondrocytes into bone cells has been demonstrated. Yet, membranous osteogenesis is currently considered the sole mechanism in the formation and repair of mandible body, despite two types of cartilage (Meckel’s cartilage, MC; and Rostral Process, RP) present during mandible growth. Similar to the mouse model, a RP-MC-like structure is identified in human fetuses and infants. To address whether endochondrogenesis contributes to the growth and repair of mandible body, a series of studies using complementary approaches has been performed. The key findings are: 1) the mandible body is composed of both membranous and endochondral bones; 2) hypertrophic chondrocytes in MC and RP directly trans- differentiate to bone cells instead of directly entering apoptosis; 3) RP-MC is one continuous cartilage; 4) a new Condensed Mesenchymal Progenitor (CMP) zone is identified, which provides new cell sources for RP and MC expansion; and 5) endochondrogenesis plays a key function in the mandible repair via a switch mechanism from the default program (membranous bone) to a trauma repair program (endochondral bone), where chondrogenesis (with limited requirement of angiogenesis) occurs first, followed by chondrocyte trans- differentiation into bone. Based on these findings, the central hypothesis is that the mandible body is composed of both endochondral and membranous bones, and that endochondrogenesis plays a key role in mandible repair. To test this central hypothesis, three highly related, yet independent Specific Aims are proposed: 1) To determine how MC and RP contribute to mandible formation via chondrocyte trans-differentiation; 2) To delineate the mechanism by which RP is derived from the CMP, and the CMP-RP, a growth-plate like structure, converges and elongates the two ends of MCs during mandible growth at cellular and molecular levels; 3) To determine how endochondrogenesis contributes to mandible repair via a switch mechanism from the default development program (membranous bone) to a trauma repair program (endochondral bone) through a change in the stem cell fate. Completion of this project will 1) demonstrate that the CMP-RP-MC complex contributes to mandible growth via the trans-differentiation of RP-MC chondrocytes into bone cells; and 2) identify some of key factors that are responsible for the switch from membranous osteogenesis to endochondrogenesis via a change of the stem cell fate in the repair process. These results will likely revise the current concept, provide new knowledge in this largely unknown but vital area, and create a foundation for developing novel approaches, which will ultimately accelerate future mandible trauma repair processes.