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

因损伤或疾病而丢失的骨再生是一项重大的健康挑战。大多数对骨再生的努力 中心围绕操纵来自骨干细胞龛的外源性细胞，这不能提供足够的 细胞数量以及注射细胞与宿主组织的不良功能、存活和整合（引自“RFA- DE-20-006”）。为了寻找内源性来源，我们研究了肌腱作为替代品的潜在作用 用于颅面骨生长和骨修复（超越其经典作用：连接肌肉和骨骼 用于关节运动），因为颅骨的大部分骨头在颅骨下方被纤维包裹。我们意想不到的 令人震惊的发现是。肌腱附着的骨嵴中的骨细胞是Scx+（一种高表达的基因 在腱中）; B.腱形成骨（TFB）（类似于牙槽骨）富含基质成分的混合物 (such作为肌腱、软骨和骨标记物），其不同于常规骨; c. TFB建立在 现有骨，并不断膨胀，导致随着年龄的增长骨脊更突出; d.肌腱不是 简单地连接到骨，而是生长到现有骨中并与现有骨合并，使骨-肌腱界面 矿化连续体而不是简单的附着; e. TFB根据张力而变化， 转分化为软骨细胞，而其他直接进入纤维化，然后成骨，如 以及在该位置上（诸如颞肌-颞肌缝）;以及f.肌腱细胞快速而稳健地重编程 在创伤或炎症时转化为骨生成细胞，导致新的持久的大TFB。响应于 这种RFA（需要替代谱系来促进颅面的内源性愈合和再生） 骨，避免注射外源性细胞），我们建议，肌腱细胞，一个自然的，但被忽视的 正常颅面骨生长的前体，是创伤或 炎症我们将通过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：明确肌腱细胞在颅面骨发育过程中的可塑性， 目的2：全面研究成年肌腱细胞，如下颌骨和颞骨， 另一种谱系，在创伤期间将其天然肌腱程序转换为成骨程序， 炎症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 开发了强大的和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方法来分析健康中的细胞可塑性和创伤中的重编程。在完成拟议的 工作，我们希望填补一个明显的差距，我们的知识颅面成骨来源于肌腱，奠定 建立肌腱作为骨增量和骨替代谱系细胞来源的基础 创伤和疾病的再生。

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.