Current Status of the Instructional Cues Provided by Notochordal Cells in Novel Disc Repair Strategies.

Ajay Matta,William Mark Erwin

doi:10.3390/ijms23010427

Abstract

Numerous publications over the past 22 years, beginning with a seminal paper by Aguiar et al., have demonstrated the ability of notochordal cell-secreted factors to confer anabolic effects upon intervertebral disc (IVD) cells. Since this seminal paper, other scientific publications have demonstrated that notochordal cells secrete soluble factors that can induce anti-inflammatory, pro-anabolic and anti-cell death effects upon IVD nucleus pulposus (NP) cells in vitro and in vivo, direct human bone marrow-derived mesenchymal stem cells toward an IVD NP-like phenotype and repel neurite ingrowth. More recently these factors have been characterized, identified, and used therapeutically to induce repair upon injured IVDs in small and large pre-clinical animal models. Further, notochordal cell-rich IVD NPs maintain a stable, healthy extracellular matrix whereas notochordal cell-deficient IVDs result in a biomechanically and extracellular matrix defective phenotype. Collectively this accumulating body of evidence indicates that the notochordal cell, the cellular originator of the intervertebral disc holds vital instructional cues to establish, maintain and possibly regenerate the intervertebral disc.

Highlights

A host of biological factors have been postulated to offer restorative effects upon degenerative intervertebral disc (IVD) including growth factors as well as anti-catabolic factors such as inhibitors of nuclear transcription factors such as Nuclear Factor kappa-light-chain-enhancer of activated B cells (Nfκβ), and Wntβ-catenin
It has been confirmed by several groups that conditioned media obtained from notochordal cell tissue culture confers anabolic, anti-apoptotic, and anti-catabolic effects on cells derived from the IVD nucleus pulposus (NP) validating that such factors confer instructive cues to the heterogenous cell population within the IVD [1,3,4,5,6,7,8,9]
Others have suggested that the extracellular matrix of the notochordal cell rich IVD NP itself may provide instructional cues that could aid in disc repair [10]

Summary

Introduction

A host of biological factors have been postulated to offer restorative effects upon degenerative intervertebral disc (IVD) including growth factors (including a variety of members of the transforming growth factor family—such as bone morphogenic proteins ‘BMPs’) as well as anti-catabolic factors such as inhibitors of nuclear transcription factors such as Nuclear Factor kappa-light-chain-enhancer of activated B cells (Nfκβ), and Wntβ-catenin. In mice leads to reductions in downstream TGF-β Smad-related signaling and accelerated degenerative disc changes including reduced cartilage endplate tissue, increases in MMP-13 expression and related ECM degradation [24] These findings are important and highly relevant to the question of TGF-β and Smads with respect to notochordal cells since the developing IVD NP is highly notochordal in content- in rodents. It is interesting to note that some reports have shown an increase in TGF-β1 expression in degenerative discs whereas others have shown this growth factor to be of low or undetectable amounts in surgical samples [7,29] These observations when taken together provide evidence for an incompletely understood pleiotropic mechanism involving growth factors, cytokines and complex cell-extracellular matrix regulation within the IVD [7,26]

Notochordal Cell Associated Extracellular Matrix Interaction

Notochordal Cell Secreted Proteins

Influence of Notochordal Cells upon Mesenchymal Stem Cells

Notochordal Cell-Rich Extracellular Matrix Instructional Cues

Dichotomy of IVD NP Cell Secreted Growth Factors upon IVD Health and Disease

Conclusions