Regenerative potential of embryonic notochordal nucleus pulposus progenitors

胚胎脊索髓核祖细胞的再生潜力

• 批准号: 9225462
• 负责人: Neil Malhotra
• 金额: $ 21.94万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-03 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9225462
• 关键词: Address; Alleles; Biological; Biological Response Modifier Therapy; Cell Differentiation process; Cell Separation; Cells; Deposition; Development; Disease; Embryo; Embryonic Development; Exhibits; Extracellular Matrix; Growth Factor; Health; Hydrostatic Pressure; Image; Impairment; Injectable; Intervertebral disc structure; Low Back Pain; Maps; Mechanics; Mediating; Modeling; Molecular Profiling; Mus; Natural regeneration; Operative Surgical Procedures; Pain; Pattern; Population; Positioning Attribute; Property; Proteoglycan; Role; Signal Pathway; Signal Transduction; Source; Stem cells; Structure; Symptoms; Therapeutic; Time; Tissues; Transgenic Mice; Work; base; cell growth; cell motility; disc regeneration; effective therapy; experience; improved; in vivo; in vivo Model; interest; intervertebral disk degeneration; migration; mouse model; notochord; novel; novel therapeutics; nucleus pulposus; postnatal; progenitor; reduce symptoms; regenerative; spine bone structure; targeted treatment; tool; transcriptome sequencing; treatment strategy

Abstract Lumbar intervertebral disc degeneration is a cascade of cellular, structural and mechanical changes that is strongly implicated as a cause of low back pain. The central nucleus pulposus (NP) is implicated in the initiation of this degenerative cascade, where decreasing proteoglycan content and an associated reduction in hydrostatic pressure impair the ability of the NP to effectively engage the surrounding annulus fibrosus and to evenly distribute and transfer compressive loads between the vertebrae. There is a critical need for therapies for disc degeneration that restore disc structure and mechanical function by directly addressing the underlying biological causes. A key challenge to developing effective biological treatments for disc degeneration is the need to recapitulate the structural complexity and specialized extracellular matrix of the component tissues, which comprise cells of multiple developmental lineages. Here we propose to address this challenge by directly applying developmental paradigms to establish an optimized biological disc regeneration strategy. Embryonic and postnatal disc formation is regulated by cells derived from the notochord. These cells secrete an array of growth factors that regulate cell migration, proliferation, differentiation and extracellular matrix deposition, and ultimately, directly give rise to the NP itself. There is therefore intense interest in identifying notochordal cell-secreted factors and applying them to develop improved therapeutic strategies for disc regeneration. The ideal stage to investigate the regenerative potential of notochordal cells is when they are most actively contributing to embryonic and early postnatal disc development. Therefore the overall objective of this proposal is to establish the regenerative potential of embryonic, notochord-derived nucleus pulposus progenitor cells (NDCs). Specifically, we will define the growth factor expression profile of NDCs at key stages of embryonic and postnatal disc development using whole transcriptome sequencing (RNA-Seq), and directly establish the regenerative potential of NDCs as a function of developmental stage using an in vivo mouse model of disc degeneration. The results of this work will provide a roadmap for optimizing cell and growth factor-based therapeutics for disc regeneration.

抽象的 腰椎间盘退变是一系列细胞、结构和机械变化 这与腰痛的原因密切相关。中央髓核（NP）参与 这种退行性级联的启动，其中蛋白聚糖含量减少以及相关的减少 静水压力会损害 NP 有效接合周围纤维环的能力并影响 在椎骨之间均匀分布和转移压缩载荷。迫切需要治疗 针对椎间盘退变，通过直接解决底层问题来恢复椎间盘结构和机械功能 生物学原因。开发有效的生物治疗方法来治疗椎间盘退变的一个关键挑战是 需要概括组成组织的结构复杂性和专门的细胞外基质， 其中包含多个发育谱系的细胞。在这里，我们建议通过以下方式应对这一挑战： 直接应用发育范例建立优化的生物椎间盘再生 战略。胚胎和出生后椎间盘的形成受到脊索来源的细胞的调节。这些细胞 分泌一系列调节细胞迁移、增殖、分化和细胞外生长的生长因子 基质沉积，最终直接产生纳米粒子本身。因此人们对 识别脊索细胞分泌因子并应用它们来开发改进的治疗策略 椎间盘再生。研究脊索细胞再生潜力的理想阶段是当它们 对胚胎和产后早期椎间盘发育做出了最积极的贡献。因此总体 该提案的目的是确定胚胎、脊索来源的再生潜力 髓核祖细胞（NDC）。具体来说，我们将定义生长因子表达谱 使用全转录组测序研究胚胎和出生后椎间盘发育关键阶段的 NDC (RNA-Seq)，并直接建立 NDC 的再生潜力作为发育阶段的函数 使用椎间盘退变的体内小鼠模型。这项工作的结果将为 优化基于细胞和生长因子的椎间盘再生疗法。