Intervertebral disc (IVD) degeneration is a primary or secondary cause of low back pain with associatedmedical costs ranging from at least $20 to $100 billion annually, yet surgical treatment options do not focuson preventing degeneration or repairing discs. The high prevalence of disc degeneration in humans andrarity of disc degeneration in animal species that retain notochordal (NC) cells into maturity supports theconcept that NC cells are integral to preventing degeneration and/or promoting repair. There are few studiesinvestigating interactions between NC cells with mature IVD cells, even fewer exploring the mechanisms forthese interactions, and no scientific literature on interactions between NC cells with bone mesenchymalstem cells (MSCs).The first hypothesis is that NC cells orchestrate the biology of IVDs, functioning by interacting with andinfluencing the functions of nucleus pulposus (NP) and annulus fibrosus (AF) cells in a dose-dependentmanner that is mediated via soluble factors. The second hypothesis is that NC cells promotedifferentiation of MSCs towards a young NP phenotype, via the action of soluble factors. The proposedSpecific Aims will test the functional relevance and mechanisms of interaction between soluble factors fromNC cells with NP and AF cells (Aim 1) and with MSCs (Aim 2). The assay system will consist of 3-dimensional cell pellet cultures to maintain cell morphology, isolate soluble factor effects, and elucidatemechanisms for action. The parameters to be analyzed include cell biosynthesis and phenotypicdifferentiation based on IVD matrix gene expression and protein synthesis, as well as cell proliferation andapoptosis. NC, NP and AF cells are harvested from immature porcine and mature bovine IVDs as theselarge animal models provide a consistent source of sufficient numbers of cells required in the proposedstudies. Human MSCs will be used in view of their clinical relevance.This study fills an important gap in the literature. Preliminary results are limited but compelling anddemonstrate significant interactions of NC cells with mature IVD cells and evidence that NC cell solublefactors strongly increase glycosaminoglycan production in MSCs and specifically differentiate these cellstowards a young NP phenotype. The exploration of a young NP phenotype along with evaluation of specificmechanisms for action in the proposed study is consistent with the exploratory/high impact objectives of theR21 mechanism. Clinical relevance involves determination of target molecules for pharmaceutical use onmature disc cells and on MSCs to prevent degenerative changes and promote cell therapy repairtechniques.
Intervertebral disc degeneration is commonly implicated in low back pain with a very high prevalence in humans and very low prevelance in animal species that retain notochordal cells into maturity. Basic science information on notochordal cells is very limited, and the overall hypothesis is that notochordal cells orchestrate the biology of the intervertebral disc and may be used to prevent disc degeneration and to promote disc repair. The purpose of the proposed studies is to investigate the functional relevance and mechanisms of interaction between notochordal cells with nucleus pulposus and anulus fibrosus cells and also with bone mesenchymal stem cells.
