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 迫切需要新的方法来加速和增强骨骼再生。这是 通常取决于两个主要因素。第一，合适的骨祖细胞的募集和分化 细胞第二，上调协调细胞增殖和骨代谢的关键骨合成代谢途径， 成骨级联反应需要新的方法来增强这些因素中的一个或两个， 推进领域。2010年，人们发现颅面内的神经嵴衍生骨区域 骨骼有上级再生能力;这是真的，无论是骨骼的速度， 再生和骨形成的总量。2015年，进一步确定了这些地区 增强骨合成代谢信号传导和增加与增殖，自我更新， 干细胞生态位2021年，这些发现被证实适用于人类。但上游 驱动这一现象的机制仍然未知。此外，复制这种促进再生的能力 其他骨骼部位的计划尚未实现。这是知识上的一个关键差距。到 为了克服这一点，我们最近发现了一种独特的p75神经营养因子受体阳性（p75-NTR+）骨膜细胞 在神经再生区的表面上形成密集网络的群体。 嵴源骨这种网络即使在成年动物中也是持久的，并且在邻近区域中不存在， 中胚层起源的头盖骨。P75-NTR是一种427个氨基酸的跨膜受体， 与其他受体形成异聚体复合物，并与广泛的神经营养因子如神经生长因子结合， 因子，这也是已知的骨合成代谢。P75-NTR也被确定为神经嵴的标志物 衍生干细胞我们的中心假设是，这种强大的p75-NTR+细胞网络代表了 神经嵴衍生骨的上级促再生特性。本项目的工作将开始于 描述这种独特的细胞网络（目标1）。其次，我们将确定这是否是一个可移植的祖细胞 可用于促进其他骨骼部位的再生（目标2）。最后，我们将使用临床 p75-NTR调节剂作为增强局部骨合成代谢信号传导和骨形成的策略（目的3）。当 完成后，我们预计我们的结果将产生有价值的基本和翻译信息，将促进 生物启发的组织工程策略，以提高颅面和整形外科骨再生。