Timing of mesenchymal stem cell delivery impacts the fate and therapeutic potential in intervertebral disc repair.

Cell-based therapies offer a promising approach to treat intervertebral disc (IVD) degeneration. The impact of the injury microenvironment on treatment efficacy has not been established. This study used a rat disc stab injury model with administration of mesenchymal stromal cells (MSCs) at 3, 14, or 30 days post injury (DPI) to evaluate the impact of interventional timing on IVD biochemistry and biomechanics. We also evaluated cellular localization within the disc with near infrared imaging to track the time and spatial profile of cellular migration after in vivo delivery. Results showed that upon injection into a healthy disc, MSCs began to gradually migrate outwards over the course of 14 days, as indicated by decreased signal intensity from the disc space and increased signal within the adjacent vertebrae. Cells administered 14 or 30 DPI also tended to migrate out 14 days after injection but cells injected 3 DPI were retained at a significantly higher amount versus the other groups (p < 0.05). Correspondingly the 3 DPI group, but not 14 or 30 DPI groups, had a higher GAG content in the MSC injected discs (p = 0.06). Enrichment of MSCs and increased GAG content in 3 DPI group did not lead to increased compressive biomechanical properties. Findings suggest that cell therapies administered at an early stage of injury/disease progression may have greater chances of mitigating matrix loss, possibly through promotion of MSC activity by the inflammatory microenvironment associated with injury. Future studies will evaluate the mode and driving factors that regulate cellular migration out of the disc. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:32-40, 2017.

Emerging trends in biological therapy for intervertebral disc degeneration.

Intervertebral disc disease is characterized by a series of deleterious changes in cellularity that lead to loss of extracellular matrix structure, altered biomechanical loading, and symptomatic pain. At present the "gold standard" of therapy is discectomy -- surgical removal of the diseased disc followed by fusion of the adjacent vertebral bodies. The procedure alleviates pain, but fusion limits range of motion and alters the mechanical loading at other spinal levels, hastening disease at previously unaffected sites. Biological therapeutics have the potential to repair damaged tissue by several means: (1) altering cell phenotype to regenerate matrix components, (2) augmenting tissue with reparative cells, (3) delivering bioactive materials to reestablish disc biomechanics and serve as a template for cell-based regeneration. Although research into biological treatments for disc degeneration has been ongoing for over a decade, few treatments have progressed to clinical testing and none are currently commercially available, primarily due to a limited understanding of disease etiology. Further work is needed to identify targets and interventional time points as disc degeneration progresses from early to later stages. This review focuses on emerging trends in biological treatments and identifies key obstacles to their clinical translation.