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

定义软骨内形成在下颌骨形成和创伤修复中的新作用

• 批准号: 10523056
• 负责人: Yan Jing
• 金额: $ 11.79万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-07 至 2025-12-06
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10523056
• 关键词: Acceleration; Address; Adolescent; Allografting; Animal Model; Anterior; Apoptosis; Area; Biology; Bone Regeneration; Bone necrosis; Cartilage; Cells; Cellular biology; Child; Chondrocytes; Chondrogenesis; Classification; Clinical Skills; Complex; Data; Developmental Biology; Embryo; Epiphysial cartilage; Failure; Fetus; Foundations; Future; Goals; Growth; Human; Infant; Isogenic transplantation; Knowledge; Laboratories; Learning; Mandible; Meckel' s cartilage; Mentors; Mesenchymal Stem Cells; Molecular; Molecular Biology; Mus; Newborn Infant; Orthodontic; Osteogenesis; Play; Process; Productivity; Program Development; Publications; Reagent; Recording of previous events; Reporting; Research; Research Proposals; Role; Scientist; Series; Solid; Source; Structure; Technical Expertise; Testing; Tissues; Training; Trauma; Vascularization; Work; angiogenesis; bone; bone cell; carcinogenesis; career; cartilage transplantation; craniofacial; healing; medical specialties; mouse model; novel; novel strategies; novel therapeutic intervention; postnatal; progenitor; programs; repaired; scaffold; skeletal; stem cell biology; stem cell fate; tissue regeneration; transdifferentiation

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.

项目概要/摘要 外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）的发生是由于当地条件较差以及骨组织之间的整合有限。 移植物和宿主组织。最近的研究表明，软骨移植物可产生血管化良好且完整的软骨 骨再生类似于同种移植物，表明软骨细胞可以形成骨骼。作为一种机制，细胞 已证实从软骨细胞转分化为骨细胞。然而，膜成骨 目前被认为是下颌体形成和修复的唯一机制，尽管有两种类型 软骨（梅克尔软骨，MC；和喙突，RP）存在于下颌骨生长过程中。类似于 在小鼠模型中，在人类胎儿和婴儿中发现了类似 RP-MC 的结构。解决是否 软骨内发生有助于下颌体的生长和修复，一系列研究使用 已采取补充方法。主要发现是：1）下颌体由以下部分组成： 膜骨和软骨内骨； 2) MC和RP中的肥大软骨细胞直接反式 分化为骨细胞而不是直接进入细胞凋亡； 3）RP-MC是一块连续软骨； 4）一个新的 鉴定出浓缩间充质祖细胞（CMP）区，为 RP 和 MC 提供新的细胞来源 扩张; 5）软骨内生成通过开关机制在下颌骨修复中发挥关键作用 默认程序（膜骨）到创伤修复程序（软骨内骨），其中 首先发生软骨生成（对血管生成的要求有限），然后是软骨细胞转移 分化为骨。基于这些发现，中心假设是下颌体是由 软骨内和膜骨的形成，软骨内发生在下颌骨修复中起着关键作用。 为了检验这一中心假设，提出了三个高度相关但独立的具体目标： 1) 确定 MC 和 RP 如何通过软骨细胞转分化促进下颌骨形成； 2) 划定 RP源自CMP的机制，并且CMP-RP（一种生长板状结构）会聚 并在下颌骨生长过程中在细胞和分子水平上拉长MC的两端； 3）确定 软骨内生成如何通过默认发育的开关机制促进下颌骨修复 通过干细胞的变化将程序（膜骨）转变为创伤修复程序（软骨内骨） 命运。该项目的完成将 1) 证明 CMP-RP-MC 复合体有助于下颌骨生长 通过 RP-MC 软骨细胞转分化为骨细胞； 2）确定一些关键因素 负责通过干细胞的变化从膜成骨转变为软骨内形成 修复过程中的命运。这些结果可能会修正当前的概念，提供这方面的新知识 很大程度上未知但至关重要的领域，并为开发新方法奠定了基础，最终将 加速未来下颌骨创伤修复过程。