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The tendon cell is a robust alternative lineage for bone repair upon trauma or inflammation

肌腱细胞是一种强大的替代谱系，用于创伤或炎症时的骨修复

基本信息

批准号：
10347376
负责人：
JIAN Q. FENG
金额：
--
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2022-05-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10347376
关键词：
Adult Aging Area Bone Diseases Bone Growth Bone Regeneration Calvaria Cartilage Cell Count Cell Lineage Cells Chondrocytes Chondrogenesis Development Disease Foundations Future Generations Genes Glare Health IL6 gene Image Immune Inflammation Injections Injury Interleukin-4 Knowledge Location Mandible Methods Minerals Modeling Mus Muscle Natural regeneration Osteogenesis Periosteum Positioning Attribute Production Research Proposals Role Site Source Surgical sutures Techniques Temporal bone structure Tendon structure Testing Tissues Trauma Work alveolar bone bone bone cell bone repair craniofacial craniofacial bone cranium fibrogenesis healing injury and repair intramembranous bone joint mobilization mechanical force novel novel strategies osteogenic postnatal programs repaired response scaffold single-cell RNA sequencing stem cells substantia spongiosa

项目摘要

Regeneration of bone lost to injury or disease is a major health challenge. Most efforts toward bone regeneration center around the manipulation of exogenous cells from bone stem cell niches, which cannot provide sufficient cell numbers plus poor function, survival and integration of the injected cells with host tissues (cited from “RFA- DE-20-006”). In search for endogenous sources, we have studied potential roles of tendon as an alternative lineage for craniofacial bone growth and bone repairs (beyond its classic role: connecting muscles and bones for joint movement) as most bones of the skull below the calvaria are sheathed in the fibrous. Our unexpected and striking findings are a. The bone cell in bone ridges attached by tendon are Scx+ (a gene highly expressed in tendon); b. Tendon-formed bone (TFB) (similar to alveolar bone) is rich with a mixture of matrix components (such as tendon, cartilage and bone markers) that is distinct from conventional bone; c. TFB is built on the existing bone, and continuously expands, leading to more prominent bone ridges with aging; d. Tendon is not simply connected to bone but rather grows into and merges with the existing bone, making bone-tendon interface a mineralized continuum rather than a simple attachment; e. TFB varies depending on tensile forces with some transdifferentiating into chondrocytes while others directly entering into fibrogenesis and then osteogenesis, as well as on the location (such as zygomatic-temporal suture); and f. Tendon cells rapidly and robustly reprogram into bone-generating cells upon trauma or inflammation, leading to new long lasting large TFB. In response to this RFA (that requests an alternative lineage to promote endogenous healing and regeneration of craniofacial bones, and avoid injection of exogenous cells) we propose that the tendon cell, a natural but overlooked precursor for normal craniofacial bone growth, is a robust alternative lineage for bone regeneration in trauma or inflammation. We will achieve our objective by pursuing the following two highly related but independent specific aims: Aim 1: To define the plasticity of tendon cells in formation of craniofacial bone during development using mandible and temporal bones as testing models; Aim 2: To comprehensively study how an adult tendon cell, as an alternative lineage, switches its natural tendon program to an osteogenic program during trauma or inflammation. By virtue of our exciting discoveries, we are uniquely well positioned for this study. We have developed powerful and proven cell lineage tracing techniques with state of the art imaging and single cell RNA- seq methods to analyze cell plasticity in health and reprogramming in trauma. Upon completion of the proposed work, we expect to fill a glaring gap in our knowledge of craniofacial osteogenesis derived from tendon, and lay the foundation for establish tendon as an alternative lineage cell source for bone augmentation and bone regeneration in trauma and diseases.

因受伤或疾病而失去的骨骼再生是一个重大的健康挑战。为骨再生所做的最大努力以操纵来自骨干细胞生态位的外源细胞为中心，这些细胞不能提供足够的细胞数量加上注射细胞的功能、存活和与宿主组织的整合较差（引自“RFA- DE-20-006”）。在寻找内源性来源时，我们研究了肌腱作为替代品的潜在作用颅面骨生长和骨骼修复的谱系（超越其经典作用：连接肌肉和骨骼用于关节运动），因为颅骨下方的大部分颅骨都包裹在纤维中。我们意想不到的惊人的发现是：肌腱附着的骨嵴中的骨细胞是Scx+（一种高表达基因）在肌腱中）； b.腱形成骨 (TFB)（类似于牙槽骨）富含基质成分的混合物与传统骨骼不同的（例如肌腱、软骨和骨骼标记）； c. TFB 是建立在现有的骨骼，并不断扩展，导致随着年龄的增长，骨嵴更加突出； d.肌腱不是只是与骨骼连接，而是生长并与现有骨骼融合，形成骨-肌腱界面矿化的连续体而不是简单的附着物； e. TFB 随拉力变化，有些情况下转分化为软骨细胞，而其他细胞则直接进入纤维形成，然后进入骨形成，如以及位置（例如颧颞缝）；和f。肌腱细胞快速而稳健地重新编程在创伤或炎症时进入骨生成细胞，产生新的持久的大 TFB。作为回应这个 RFA（要求替代谱系来促进颅面的内源性愈合和再生）骨骼，并避免注射外源细胞）我们提出肌腱细胞，一种天然但被忽视的细胞正常颅面骨生长的前体，是创伤或骨再生的强大替代谱系炎。我们将通过追求以下两个高度相关但独立的具体目标来实现我们的目标：目标：目标 1：使用以下方法定义发育过程中肌腱细胞在颅面骨形成中的可塑性：下颌骨和颞骨作为测试模型；目标2：全面研究成体肌腱细胞如何作为另一种谱系，在创伤或创伤期间将其天然肌腱程序切换为成骨程序炎。凭借我们令人兴奋的发现，我们在这项研究中处于独特的有利位置。我们有开发了强大且经过验证的细胞谱系追踪技术，具有最先进的成像和单细胞 RNA- seq 方法分析健康中的细胞可塑性和创伤中的重编程。完成提议后工作中，我们期望填补我们对肌腱衍生的颅面成骨知识的明显空白，并奠定为建立肌腱作为骨增强和骨替代谱系细胞来源奠定基础创伤和疾病的再生。