Regenerative potential of embryonic notochordal nucleus pulposus progenitors

点击翻译按钮获取中文摘要

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.