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Neuronal Regulation of Skeletal Development and Repair

骨骼发育和修复的神经元调节

基本信息

批准号：
10378304
负责人：
Thomas L Clemens
金额：
$ 48.42万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-07 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10378304
关键词：
Acute Afferent Neurons Area Axon Blood Vessels Bone Diseases Bone Regeneration Calvaria Cell Differentiation process Cell Lineage Cell Proliferation Cells Cephalic Coculture Techniques Collaborations Data Dermal Femur Fiber Follistatin Funding Genes Genetic Transcription Genomics Growth Histologic Home Homeostasis Human Impairment In Vitro Joint structure of suture of skull Knock-in Mouse Location Maps Mediating Mesenchymal Mesenchymal Stem Cells Methods Microfluidics Modeling Molecular Monitor Morphogenesis Mus Natural regeneration Nerve Nerve Fibers Nerve Growth Factors Neurons Nociception Osteogenesis Pattern Peripheral Phenocopy Phenotype Phosphotransferases Play Proliferating Recombinants Regulation Reporter Reporting Role Scaphycephaly Sensory Signal Induction Signal Pathway Signal Transduction Skeletal Development Surgical sutures Techniques Time Transgenic Organisms Tropomyosin Undifferentiated Up-Regulation Vascularization adenovirus mediated delivery afferent nerve angiogenesis bone cell behavior cranium genetic signature inhibitor/antagonist insight limb regeneration mechanical load nerve supply neurotropic osteogenic osteoprogenitor cell premature preservation programs receptor relating to nervous system repaired response skeletal skeletal stem cell spatiotemporal stem cell expansion stem cell proliferation stem cells time interval tool transcriptomics

项目摘要

ABSTRACT This is a renewal application of a program investigating the role of sensory nerves in bone. Our studies during the first funding period demonstrate that NGF-dependent TrkA signaling by sensory nerves is the primary driver of angiogenesis and osteogenesis in the developing femur and skull. In these avascular settings, acute up-regulation of NGF in mesenchymal lineage cell domains is followed by nociceptive fiber ingrowth, which subsequently home to locations of proliferating mesenchymal cells. Blockade of sensory nerve ingrowth, either by inhibition of TrkA signaling or disruption of NGF, retards vascularization and disrupts femoral and calvarial bone formation. Histological data in the calvaria model revealed that loss of sensory nerve fibers is associated with reduced numbers of proliferating mesenchymal progenitor cells (MPCs) in the sutures and premature suture closure. These observations suggest a paradigm in which sensory nerves function in developing bone to maintain MPC plasticity, a concept well established in models of limb regeneration and supported by recent studies in developing mouse femur. Our preliminary findings directly examining the interaction of sensory nerve axons with MPCs in microfluidic chambers suggest that infiltrating DRG nerve fibers induce MPC proliferation, but limit differentiation in a non-contact dependent fashion. These effects appear to be mediated by neural derived FSTL1, which induces MPC proliferation and impairs BMP-induced osteogenic differentiation. Together, this data support the premise that TrkA+ sensory nerves function in developing bone to maintain stem cells in a proliferative, undifferentiated state by delivering soluble factors that activate mitogenic and anti-differentiation signaling pathways. This conceptual model will be explored in studies divided into two Specific Aims. Specific Aim 1 will define the spatiotemporal patterning of TrkA+ skeletal sensory nerves in the developing cranium, determine their influence on MPC proliferation and cellular fate, and further elucidate signaling pathways associated with impaired innervation. Specific Aim 2 will identify sensory axon-derived factors that regulate MPC proliferation and cell fate decisions, and definitively identifying FSTL1 as a neural-derived factor which impacts MPC cellular behavior. Our results should provide new insights into the fundamental roles sensory nerves play in skeletal morphogenesis, homeostasis and repair, and provide critical insight into the neuropathological manifestations associated with bone disorders in humans.

摘要