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

因受伤或疾病而失去的骨骼再生是一个重大的健康挑战。骨再生方面的最大努力 中心集中在操纵来自骨干细胞利基的外源细胞，这不能提供足够的 细胞数量加上注射的细胞与宿主组织的功能、存活和整合能力差(引用自《RFA- De-20-006“)。在寻找内源性来源的过程中，我们研究了肌腱作为替代的潜在作用。 颅面骨生长和骨修复的谱系(超越其经典作用：连接肌肉和骨骼 用于关节运动)，因为头盖骨以下的大部分骨骼都覆盖在纤维层中。我们意想不到的 令人惊讶的发现是，肌腱附着的骨脊中的骨细胞是SCX+(一种高表达的基因 肌腱)；b.腱形成骨(TFB)(类似于牙槽骨)富含各种基质成分 (如肌腱、软骨和骨标记)，不同于传统的骨；c.TFB建立在 现有的骨骼，并不断膨胀，导致骨脊随着年龄的增长而更加突出；d.肌腱不 简单地与骨骼相连，但却生长到现有的骨骼中并与之融合，形成骨-肌腱界面 矿化的连续体，而不是简单的附着体；例如，TFB根据拉力的不同而变化 转分化为软骨细胞，而其他细胞直接进入纤维形成，然后成骨，如 以及对位置(如颧骨-颞缝)的影响；以及f.腱细胞快速而有力地重新编程 在创伤或炎症时转化为骨生成细胞，导致新的长时间大的TFB。作为对.的回应 这种RFA(需要另一种血统来促进颅面部的内源性愈合和再生 骨骼，避免注射外源细胞)我们建议肌腱细胞，一种自然但被忽视的 正常颅面骨生长的前体，是创伤或创伤后骨再生的强有力的替代谱系 发炎。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 目的：目的1：研究肌腱细胞在颅面骨发育过程中的可塑性。 下颌骨和颞骨作为测试模型；目标2：全面研究成人肌腱细胞，如 另一种血统，在创伤或创伤期间，将其自然肌腱计划切换为成骨计划 发炎。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地位。我们有 开发了强大且经过验证的细胞谱系跟踪技术，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。在完成建议的 工作中，我们希望填补我们在头面部肌腱成骨知识方面的一个明显空白，并 建立肌腱作为骨增强和骨替代谱系细胞来源的基础 创伤和疾病中的再生。

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.