Harnessing the Potential of Mesenchymal Stem Cells for IVD Regeneration.

Intervertebral disc (IVD) degeneration is one of the leading causes of low back pain, which affects a large proportion of the global population at a huge socioeconomic burden. Current treatments focus primarily on symptomatic pain relief or surgery, but offer relatively poor long-term efficacy as they fail to address the pathogenesis of the underlying IVD degeneration. In order to offer improved clinical outcomes, a number of biological and regenerative therapies are currently being developed which target the disease at a molecular and cellular level and aim to restore IVD function. This review focusses on the considerations for development of cell-based therapies for IVD regeneration. In particular it focusses on the identification of novel progenitor cell populations within the IVD and the application of mesenchymal stem cells (MSCs) in IVD tissue engineering, which are being increasingly studied as they offer huge potential for tissue regeneration. Additionally it highlights how the growing understanding of the molecular phenotype of IVD cells is allowing tailored differentiation strategies to be developed and how MSC source and choice of growth factor influences cell phenotype and appropriate tissue formation. Finally, it reviews the range of functional biomaterials being developed to aid MSC delivery and differentiation, and discusses the potential impact the degenerate IVD microenvironmental niche may have on MSC behaviour following implantation.

Growth differentiation factor 6 and transforming growth factor-beta differentially mediate mesenchymal stem cell differentiation, composition, and micromechanical properties of nucleus pulposus constructs.

INTRODUCTION: Currently, there is huge research focus on the development of novel cell-based regeneration and tissue-engineering therapies for the treatment of intervertebral disc degeneration and the associated back pain. Both bone marrow-derived (BM) mesenchymal stem cells (MSCs) and adipose-derived MSCs (AD-MSCs) are proposed as suitable cells for such therapies. However, currently no consensus exists as to the optimum growth factor needed to drive differentiation to a nucleus pulposus (NP)-like phenotype. The aim of this study was to investigate the effect of growth differentiation factor-6 (GDF6), compared with other transforming growth factor (TGF) superfamily members, on discogenic differentiation of MSCs, the matrix composition, and micromechanics of engineered NP tissue constructs. METHODS: Patient-matched human AD-MSCs and BM-MSCs were seeded into type I collagen hydrogels and cultured in differentiating media supplemented with TGF-ß3, GDF5, or GDF6. After 14 days, quantitative polymerase chain reaction analysis of chondrogenic and novel NP marker genes and sulfated glycosaminoglycan (sGAG) content of the construct and media components were measured. Additionally, construct micromechanics were analyzed by using scanning acoustic microscopy (SAM). RESULTS: GDF6 stimulation of BM-MSCs and AD-MSCs resulted in a significant increase in expression of novel NP marker genes, a higher aggrecan-to-type II collagen gene expression ratio, and higher sGAG production compared with TGF-ß or GDF5 stimulation. These effects were greater in AD-MSCs than in BM-MSCs. Furthermore, the acoustic-wave speed measured by using SAM, and therefore tissue stiffness, was lowest in GDF6-stiumlated AD-MSC constructs. CONCLUSIONS: The data suggest that GDF6 stimulation of AD-MSCs induces differentiation to an NP-like phenotype and results in a more proteoglycan-rich matrix. Micromechanical analysis shows that the GDF6-treated AD-MSCs have a less-stiff matrix composition, suggesting that the growth factor is inducing a matrix that is more akin to the native NP-like tissue. Thus, this cell and growth-factor combination may be the ideal choice for cell-based intervertebral disc (IVD)-regeneration therapies.