Utilization of Mesenchymal Stem Cells for Treatment of Disc Degeneration by Modulation of the WNT Signaling Pathway
Background: Intervertebral disc degeneration is a leading cause of back pain worldwide2. Its underlying molecular mechanisms consists of a myriad of pathways, one of the main ones being degeneration of the nucleus pulposus and it’s extracellular matrix2. The nucleus pulposus (NP) consists of type II collagen and proteoglycans, and it is these proteoglycans that allow for the retention of water and subsequently act as a shock absorber2. When the integrity of the NP is compromised, patients may show a loss of disc height and present with debilitating back pain1. Physicians often quickly resort to therapeutic medications or surgical intervention, but this treatment has the potential to fail and cause worsening back pain. Not to mention, there is always risk of drug abuse with schedule II drugs that tend to be the mainstay for chronic pain management. As a result, researchers have approached a more conservative approach to regenerating the NP by examining the effects of exogenous and endogenous mesenchymal stem cells (MSCs), which are multipotent stem cells that have the ability to self-renew and differentiate into cartilage, bone, muscle and fat3. There has been some controversy surrounding the Wnt signaling pathway and its implications with regards to IVD degeneration, but the majority of research shows that stimulating this pathway will lead to NPC apoptosis and therefore, disc degeneration3.
Objective: In this review, we explored the effects that Wnt signaling inhibition had on NPC regeneration in the context of exogenous MSCs administration and by stimulating endogenous MSCs.
Search Methods: An online search through the PubMed database was conducted and extensively explored from the years 2019-2023. Key words “disc degeneration,” “Wnt signaling pathway,” and “mesenchymal stem cells” were used.
Results: In this study, NPCs that were subjected to compression were found to have undergone less apoptosis when treated with DKK-1, a WNT/β catenin signaling inhibitor, than NPCs that were cultured alone and pre-treated with compression. Specifically, the Wnt/β catenin pathway was downregulated by aquaporin 3, a protein channel that regulates NPC apoptosis and ECM breakdown. It was found that when the Wnt signaling pathway was activated this promoted cell senescence as well as activation of TNF-alpha, which further promotes an inflammatory response. When NPCs were treated with Wharton’s Jelly (WJ) derived – MSCs, the Wnt signaling pathway was shown to markedly decrease. NPCs cultured alone with DKK-1 were found to have a slightly lower apoptosis rate than NPCs cultured with WJ-MSC and DKK-1, which indicates that endogenous MSCs, aka NPCs, may act as progenitors of the IVD.
Conclusions: Multiple studies have shown that inhibition of the Wnt signaling pathway will attenuate apoptosis of NPCs in disc degeneration. MSCs, both exogenous and endogenous, can be inhibitors of the Wnt signaling pathway, but for this particular study, stimulating our body’s own NPCs will help regenerate the disc. Supplementing degenerated intervertebral discs with exogenous MSCs has shown promising effects; however, therapeutic efficacy has not been optimized as it has been found to lose its desired outcome over time due to the acidic and hypoxic nature of a degenerated disc. This is something to consider moving forward.
- Deshmukh V, Ibanez M, Hu H, et al. A small-molecule inhibitor of the Wnt pathway, lorecivivint (SM04690), as a potential disease-modifying agent for the treatment of degenerative disc disease.Spine J. 2020;20(9):1492-1502. doi:10.1016/j.spinee.2020.04.024.
- Kirnaz, S., Capadona, C., Wong, T., Goldberg, J. L., Medary, B., Sommer, F., McGrath, L. B., Jr, & Härtl, R. (2022). Fundamentals of Intervertebral Disc Degeneration.World neurosurgery, 157, 264–273. https://doi-org.srv-proxy1.library.tamu.edu/10.1016/j.wneu.2021.09.066.
- Zhao YT, Qin Y, Yang JS, et al. Wharton’s Jelly-derived mesenchymal stem cells suppress apoptosis of nucleus pulposus cells in intervertebral disc degeneration via Wnt pathway.Eur Rev Med Pharmacol Sci. 2020;24(19):9807-9814. doi:10.26355/eurrev_202010_23190