Intervertebral disc (IVD) degeneration is a major cause of low back pain (LBP) worldwide which is expected to affect 80% of the world’s population. IVD degeneration (IDD) is a key player in the degenerative cascade associated with LBP. Pro-inflammatory cytokines and mediators, such as nitric oxide, have been shown to be triggers and mediators of IDD. Due to the avascular nature of the adult IVD, the disc is unable to heal or regenerate when damaged. The multi-components of the IVD, namely glycosaminoglycan (GAG)-rich nucleus pulposus (NP), a concentric collagen dense annulus fibrosis (AF), and cartilage endplates (CEPs), further complicate possible regenerative solutions. Cell therapies show promise.
This is supported by studies that demonstrate the use of mesenchymal stem cells (MSCs) in animal models showing potential in mitigating inflammatory signaling as well as recovering proteoglycan content. Despite these promising findings, several gaps in knowledge remain. While the biochemical and mechanical properties of an injured disc (via physical or chemical stimulation) have been characterized, the resulting inflammatory signaling cascades remain undefined. A growing body of evidence suggests that TLR4 is involved in the pathogenesis of the IVD. However, it is unknown how TLR4 mediates injury responses of the IVD. Second, it is unknown how mechanical loading of IVDs can influence the transcriptome or secretome of the IVD. The IVD is normally exposed to multimodal loading (e.g., compression, tension, shear, hydrostatic pressure, and osmotic pressure). Both frequency and magnitude regulate whether loading is beneficial or detrimental to disc integrity, which will be explored. Furthermore, the secretome of the IVD, especially during loading, may be essential to creating therapies targeted for regeneration of the IVD. There may be key, distinct paracrine factors that are released in IVD conditioned loading media which can influence the regenerative and anti-inflammatory capabilities of cell-based therapies.
To address these gaps, this thesis describes a series of experiments employing novel ex vivo organ culture model to study the response of the IVD to various injury modalities (inflammatory stimulation, puncture injury, compressive loading), and resulting changes in inflammatory, biomechanical, and biochemical responses. Through methods such as RNA sequencing and proteomics, we now have expanded the characterization to beyond candidate genes or proteins, and are more informed on (1) the IVD response to injury, (2) the role of TLR4 signaling in this ex vivo organ culture model, in addition to (3) the downstream effects of loading and how paracrine factors can be used to improve and develop potential cell and molecular therapies. Sex-based differences, in male and female rat caudal IVDs, were also identified and are analyzed in the context of response to injury.
| Identifer | oai:union.ndltd.org:columbia.edu/oai:academiccommons.columbia.edu:10.7916/ad55-9p06 |
| Date | January 2024 |
| Creators | Kenawy, Hagar Mohamed |
| Source Sets | Columbia University |
| Language | English |
| Detected Language | English |
| Type | Theses |
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