Characterization and function of a new p75-NTR+ cellular network in craniofacial bone

颅面骨中新型 p75-NTR 细胞网络的特征和功能

• 批准号: 10571278
• 负责人: Erica Lynn Scheller
• 金额: $ 42.76万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571278
• 关键词: Ablation; Acceleration; Adult; Affect; Agonist; Amino Acids; Automobile Driving; Binding; Bone Regeneration; Calvaria; Cell Culture Techniques; Cell Proliferation; Cells; Clinical; Clinical Treatment; Complex; Craniofacial Abnormalities; Defect; Economics; Gene Expression; Human; Knowledge; Ligands; Mediating; Membrane; Methods; Molecular; Myofibroblast; NGFR Protein; NGFR gene; Natural regeneration; Nerve Growth Factors; Nervous System; Neural Crest; Neurodegenerative Disorders; Orthopedics; Osteogenesis; PIK3CG gene; Pathway interactions; Patients; Periosteal Cell; Peripheral; Phase I/II Clinical Trial; Population; Procedures; Proliferating; Property; Regenerative capacity; Regenerative response; Role; Schwann Cells; Signal Transduction; Site; Skeleton; Speed; Surface; Testing; Tissue Engineering; Transgenic Mice; Transplantation; Up-Regulation; Wild Type Mouse; Work; beta catenin; bone; bone healing; cell motility; clinical translation; craniofacial; craniofacial bone; cranium; improved outcome; mature animal; migration; mouse model; neurotrophic factor; novel; osteogenic; osteoprogenitor cell; progenitor; programs; receptor; recruit; regeneration potential; regenerative; regenerative cell; repaired; single-cell RNA sequencing; skeletal; skeletal regeneration; social; stem cell niche; stem cell self renewal; stem cells

PROJECT SUMMARY There is a critical need for new methods to accelerate and enhance skeletal regeneration. This is generally dependent on two main factors. First, the recruitment and differentiation of suitable osteoprogenitor cells. Second, the upregulation of key osteoanabolic pathways that coordinate cell proliferation and the osteogenic cascade. Novel methods to enhance one or both of these factors are needed to significantly advance the field. In 2010, it was discovered that regions of neural crest-derived bone within the craniofacial skeleton have superior regenerative capacity; this is true in terms of both the speed of the skeletal regeneration and the total amount of bone formed. In 2015, it was further established that these regions have enhanced osteoanabolic signaling and increased expression of genes related to proliferation, self-renewal, and the stem cell niche. In 2021, it was confirmed that these findings extend to humans. However, the upstream mechanisms driving this remain as yet unknown. In addition, the ability to replicate this pro-regenerative program at other skeletal sites has not yet been achieved. This represents a key gap in knowledge. To overcome this, we recently identified a unique p75 neurotrophin receptor-positive (p75-NTR+) periosteal cell population that forms a dense network specifically over the surface of the pro-regenerative region of neural crest-derived bone. This network is persistent even in adult animals and is absent in neighboring regions and calvarial bones of mesodermal origin. P75-NTR is a 427-amino-acid transmembrane receptor that forms heteromeric complexes with other receptors and binds to a broad array of neurotrophins such as nerve growth factor, which is also known to be osteoanabolic. P75-NTR has also been identified as a marker of neural-crest derived stem cells. Our central hypothesis is that this robust p75-NTR+ cellular network represents the basis of the superior pro-regenerative properties of neural crest-derived bone. The work in this project will begin by characterizing this unique cell network (Aim 1). Second, we will determine if this is a transplantable progenitor population that can be used to promote regeneration at other skeletal sites (Aim 2). Last, we will use a clinical p75-NTR modulator as a strategy to enhance local osteoanabolic signaling and bone formation (Aim 3). When complete, we anticipate that our results will yield valuable basic and translational information that will promote biologically inspired tissue engineering strategies to enhance craniofacial and orthopedic bone regeneration.

项目摘要 迫切需要新方法加速和增强骨骼再生。这是 通常取决于两个主要因素。首先，募集和分化合适的骨基因生成剂 细胞。其次，关键骨代谢途径的上调，该途径是协调细胞增殖和 成骨级联。需要显着增强其中一个或两个因素的新方法 推进领域。在2010年，发现颅面内神经rest衍生的骨骼的区域 骨骼具有较高的再生能力；就骨骼的速度而言都是如此 再生和形成的骨骼总数。在2015年，进一步确定了这些地区 增强的骨代谢信号传导和与增殖，自我更新和相关基因的表达增加 干细胞生态位。在2021年，这些发现延伸到人类。但是，上游 驱动此驱动的机制仍然未知。另外，复制这种亲再生的能力 在其他骨骼部位的程序尚未实现。这代表了知识的关键差距。到 克服了这一点，我们最近确定了独特的P75神经营养蛋白受体阳性（p75-NTR+）骨膜细胞 在神经促再生区域的表面上形成密集网络的种群 波峰衍生的骨头。即使在成年动物中，该网络也持续存在，并且在邻近地区不存在 中胚层的颅骨。 P75-NTR是形成的427-氨基酸跨膜受体 与其他受体的杂体复合物，并与广泛的神经营养蛋白（如神经生长）结合 因素，也已知是骨代谢。 P75-NTR也被确定为神经沟的标记 衍生的干细胞。我们的中心假设是，这种强大的P75-NTR+蜂窝网络代表了 神经rest衍生的骨骼的优质促再生特性。该项目的工作将从 表征这个独特的单元网络（AIM 1）。其次，我们将确定这是否是可移植的祖细胞 可用于在其他骨骼部位促进再生的人群（AIM 2）。最后，我们将使用临床 p75-NTR调节剂是增强局部骨代谢信号传导和骨形成的策略（AIM 3）。什么时候 完整，我们预计我们的结果将产生有价值的基本和翻译信息，以促进 生物学启发的组织工程策略，以增强颅面和骨科骨再生。