Coordinated resident macrophage-tenocyte signaling in tendon formation

肌腱形成过程中协调的常驻巨噬细胞-肌腱细胞信号传导

• 批准号: 10742461
• 负责人: Nathaniel A. Dyment
• 金额: $ 18.7万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10742461
• 关键词: Ablation; Address; Adult; Affect; Age; Biology; CSF1 gene; Cell Differentiation process; Cell Lineage; Cells; Cellular biology; Clinical; Coculture Techniques; Collagen; Communication; Data; Development; Embryo; Endothelial Cells; Extracellular Matrix; Fascicle; Fibroblasts; Flow Cytometry; Future; Growth; Growth Factor; Growth and Development function; Homeostasis; Impairment; In Situ; Knowledge; Label; Ligands; Macrophage; Macrophage Colony-Stimulating Factor; Macrophage Colony-Stimulating Factor Receptor; Maintenance; Mechanics; Messenger RNA; Mus; Neurons; Osteoblasts; Outcome; PTPNS1 gene; Pattern; Phenotype; Play; Population; Positioning Attribute; Proliferating; Qualifying; Receptor Signaling; Reporting; Role; Signal Transduction; Source; Spatial Distribution; Stains; Structure; Tendon structure; Testing; Time; Tissues; Yolk Sac; cell type; improved; insight; novel; postnatal; regenerative approach; repaired; single-cell RNA sequencing; spatiotemporal; tendon development

Summary Despite the vast knowledge of the structure and mechanical function of mature tendons, the understanding of tenogenic cell differentiation during development and how cell types from non-tenogenic origins, such as macrophages, influence tenogenesis is limited. Tissue resident macrophages play key roles in the development of several tissues and colony stimulating factor 1 receptor (CSF1R) signaling is essential for their differentiation and survival. The source of ligands that act on CSF1R (CSF1 being the most common) often originate from adjacent resident cells. In addition to CSF1R signaling acting on the macrophages, macrophages often produce trophic factors that act on the adjacent resident cells to regulate aspects of tissue development. In exciting new data, we demonstrate that CSF1R-expressing resident macrophages are situated adjacent to CSF1-expressing tenocytes within linear arrays in the tendon fascicle from initial formation (E15.5) into adulthood, these resident macrophages rapidly accumulate to nearly 10% of the total cell population within tendons during early postnatal growth, and CSF1 produced by tenogenic cells is required for their survival. Additionally, these macrophages internalize collagen in situ, which may indicate a potential role in matrix remodeling during growth and development. Despite their relative abundance and presumed communication with adjacent tenocytes, our limited understanding of the role of resident macrophages in tendon growth and development and potential trophic signaling to tenocytes are significant gaps in knowledge. As macrophages are critical to the development and repair of numerous tissues, defining their role in tendon development will provide insight into signaling mechanisms that could be leveraged in future therapies to improve repair outcomes, which is an unmet clinical need. To address these gaps in knowledge, this proposal will define the ontogeny, distribution, and phenotypic profile of resident macrophages and establish their cross-talk with tenocytes to regulate tendon formation during growth and development. Our central hypothesis is that stable macrophage-tenocyte cross-talk exists and this communication is necessary for tendon formation. Aim 1 will define the ontogeny, abundance, and distribution of resident macrophages with respect to Csf1-expressing tenocytes and the phenotypic profile of these cells at multiple stages of growth and development. Aim 2 will then establish the cross-talk between macrophages and adjacent tenocytes and its role in tendon formation and growth. In this proposal, we will elucidate the importance of stable macrophage-tenocyte cross-talk in promoting cell differentiation and tendon formation in growth and development, thus providing new and critical insight to tendon cell biology that will inform future regenerative strategies.

概括 尽管对成熟肌腱的结构和机械功能有广泛的了解，但对 发育过程中的替代细胞分化以及细胞类型如何来自非养生的起源，例如 巨噬细胞，影响肾脏的作用是有限的。组织居民巨噬细胞在开发中起关键作用 在几个组织和菌落刺激因子1受体（CSF1R）信号中，信号对于它们的分化至关重要 和生存。对CSF1R作用的配体的来源（CSF1最常见）通常来自 相邻的居民细胞。除了作用于巨噬细胞的CSF1R信号传导外，巨噬细胞还经常产生 对相邻居民细胞作用的营养因子来调节组织发育的各个方面。令人兴奋的新 数据，我们证明了表达CSF1R的居民巨噬细胞位于CSF1表达 从初始地层（E15.5）到成年的线性阵列内的弯曲细胞，这些居民 巨噬细胞迅速积累到产后早期肌腱内肌腱中总细胞群的近10％ 生长和田纳西细胞产生的CSF1的生存需要其生存。另外，这些巨噬细胞 原位内化胶原蛋白，这可能表明在生长过程中矩阵重塑和 发展。尽管它们相对丰富，并且假定与相邻的侧侧进行了交流，但我们的 对居民巨噬细胞在肌腱生长和发育中的作用的了解有限 对养殖细胞的营养信号在知识上是显着的差距。因为巨噬细胞对发展至关重要 并修复众多组织，定义其在肌腱发育中的作用将提供有关信号传导的洞察力 可以在未来疗法中利用的机制来改善修复结果，这是一种未经满足的临床 需要。为了解决这些知识的差距，该建议将定义本体发育，分布和表型 驻留巨噬细胞的剖面，并与tenocyttes建立串扰，以调节肌腱形成 增长与发展。我们的中心假设是，稳定的巨噬细胞串扰存在，这 沟通对于肌腱形成是必要的。 AIM 1将定义个体发育，丰度和分布 相对于表达CSF1的Tenocytes和这些细胞在 增长和发展的多个阶段。 AIM 2将建立巨噬细胞之间的串扰，并 邻近的弯曲细胞及其在肌腱形成和生长中的作用。在此提案中，我们将阐明重要性 在促进生长和 开发，从而为肌腱细胞生物学提供了新的和关键的见解，这些见解将为未来的再生提供信息 策略。