Enhancing Intervertebral Disc Regeneration with BMSCs and Hydrogels

Introduction to Intervertebral Disc Degeneration and Challenges

Intervertebral disc degeneration (IVDD) represents a significant medical challenge affecting a substantial portion of the population, with estimates indicating that over 80% of individuals may experience lower back pain at some point in their lives (Fu et al., 2025). IVDD is characterized by a gradual deterioration of the intervertebral discs, leading to a cascade of deleterious effects, including reduced disc height, changes in extracellular matrix (ECM) composition, and eventual rupture of the annulus fibrosus (AF) (Zhao et al., 2023). The complexity of IVDD is compounded by the intricate structure of the disc, which consists of the nucleus pulposus (NP), the AF, and the cartilage endplates, all of which play critical roles in maintaining disc integrity (Miao et al., 2023). Current treatment options, which range from conservative management to surgical interventions, often fail to address the underlying degenerative processes, necessitating innovative therapeutic strategies.

The primary challenge in treating IVDD lies in the limited regenerative capacity of the disc tissues, particularly due to the avascular nature of the NP and AF, which restricts nutrient and oxygen delivery (Zhu et al., 2022). The emergence of regenerative medicine approaches, including the use of stem cells and hydrogels, has provided new avenues for enhancing disc repair (Hu et al., 2023). Among these, bone mesenchymal stem cells (BMSCs) have garnered attention due to their multipotent differentiation potential and ability to modulate the local microenvironment (Yang et al., 2021). This article reviews the role of BMSCs in intervertebral disc regeneration, particularly when utilized in combination with matrix hydrogels, to overcome the challenges posed by IVDD.

Role of BMSCs in Alleviating Intervertebral Disc Degeneration

BMSCs are a type of adult stem cell that can differentiate into various cell types, including chondrocytes and osteoblasts, making them a prime candidate for tissue engineering applications (Smith et al., 2023). The regenerative capacities of BMSCs extend beyond their potential for differentiation; they also secrete bioactive factors that promote cellular repair, reduce inflammation, and enhance ECM synthesis (Fan et al., 2023). In the context of IVDD, BMSCs can potentially restore the NP’s function by modulating the degenerative process and promoting the regeneration of the disc structure.

In experimental models, BMSCs have demonstrated the ability to improve disc height and restore ECM integrity when delivered to degenerated discs (Huang et al., 2023). Recent studies have indicated that BMSCs can inhibit oxidative stress-induced ferroptosis in annulus fibrosus cells (AFCs), a form of regulated cell death associated with IVDD (Fu et al., 2025). By protecting AFCs from ferroptosis, BMSCs not only preserve cellular viability but also potentially enhance the regenerative capacity of the disc.

Matrix Hydrogels as Effective Carriers for Stem Cell Therapy

Matrix hydrogels have emerged as a promising vehicle for stem cell delivery, facilitating the localized application of BMSCs while providing a supportive microenvironment for cell survival and function (Xu et al., 2025). These hydrogels can be engineered to mimic the ECM, providing structural support and biochemical cues that guide cell behavior (Zhou et al., 2022). Importantly, hydrogels can also be designed to release bioactive factors in a controlled manner, further enhancing the therapeutic potential of BMSCs.

In the context of IVDD, the injectable nature of hydrogels allows for minimally invasive delivery directly into the disc space, overcoming the challenges posed by traditional surgical approaches (Luo et al., 2024). Recent studies have shown that hydrogels containing BMSCs can significantly improve disc hydration and reduce pathological changes associated with degeneration (Han et al., 2024). The combination of hydrogels and BMSCs not only provides structural integrity but also facilitates the sustained release of growth factors that promote disc health.

Mechanisms of Ferroptosis in Annulus Fibrosus Cells

Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation, and recent findings have implicated it in the pathogenesis of IVDD (Zhu et al., 2023). In AFCs, oxidative stress leads to ferroptosis, exacerbating cellular dysfunction and contributing to disc degeneration. The underlying mechanisms involve the depletion of glutathione and the accumulation of reactive oxygen species (ROS), resulting in cellular damage and death (Yang et al., 2021).

BMSCs have been shown to mitigate ferroptosis in AFCs by upregulating protective mechanisms, such as enhancing antioxidant defenses and modulating iron metabolism (Fu et al., 2025). The ability of BMSCs to regulate the JAK2/STAT3 signaling pathway is particularly relevant, as activation of this pathway has been linked to ferroptosis and cellular apoptosis (Zhao et al., 2023). By inhibiting the activation of STAT3, BMSCs can effectively reduce oxidative stress-induced ferroptosis in AFCs, thereby promoting disc health and mitigating degeneration.

Impact of STAT3 Signaling Pathway on Intervertebral Disc Health

The STAT3 signaling pathway plays a critical role in cellular responses to various stressors, including oxidative stress and inflammation (Bai et al., 2023). In IVDD, activated STAT3 has been associated with the promotion of degenerative processes, including ECM degradation and apoptosis of disc cells (Xu et al., 2023). Inhibition of the STAT3 pathway has been proposed as a therapeutic strategy to mitigate these effects and promote disc regeneration.

Research has demonstrated that BMSCs can effectively inhibit the activation of the STAT3 pathway in AFCs subjected to oxidative stress, thereby reducing the incidence of ferroptosis and promoting cell survival (Fu et al., 2025). By modulating the STAT3 pathway, BMSCs enhance the regenerative potential of the disc and provide a rationale for their use in combination with hydrogels for IVDD treatment. The interplay between BMSCs, hydrogels, and the STAT3 signaling pathway highlights a novel therapeutic approach to combating IVDD.

Conclusion: Future Directions in Intervertebral Disc Regeneration

The integration of BMSCs and matrix hydrogels represents a promising strategy for enhancing intervertebral disc regeneration. By addressing the limitations of conventional treatments, this approach harnesses the regenerative properties of stem cells and the supportive characteristics of hydrogels to promote disc health. Future research should focus on optimizing the delivery methods of BMSCs and hydrogels, elucidating their interactions within the disc microenvironment, and exploring the potential of combination therapies that target multiple pathways involved in IVDD.

Furthermore, understanding the mechanistic underpinnings of ferroptosis and the role of the STAT3 signaling pathway in IVDD will provide valuable insights into novel therapeutic targets. As the field of regenerative medicine continues to evolve, the development of innovative biomaterials and cell therapy strategies will pave the way for effective interventions that restore disc function and alleviate the burden of IVDD.

References

1. Fu, S., Lv, R., Wang, L. Q., Wang, Z., Wang, F., Gao, H., Zhao, W., Huang, X. & Li, X. (2025). Bone mesenchymal stem cells based on matric hydrogels attenuate intervertebral disc degeneration by suppressing oxidative stress-induced ferroptosis. Scientific Reports. https://doi.org/10.1038/s41598-025-00278-x

2. Zhou, L. P., et al. (2022). Ferroptosis: A potential target for the intervention of intervertebral disc degeneration. Frontiers in Endocrinology. https://doi.org/10.3389/fendo.2022.1042060

3. Zhao, Y., et al. (2023). Chlorogenic acid alleviates chronic stress-induced duodenal ferroptosis via the inhibition of the Il-6/Jak2/Stat3 signaling pathway in rats. Journal of Agricultural and Food Chemistry

4. Miao, D., et al. (2023). Leptin modulates the expression of catabolic genes in rat nucleus pulposus cells through the Mitogen-Activated protein kinase and Janus kinase 2/signal transducer and activator of transcription 3 pathways. Molecular Medicine Reports

5. Huang, S., et al. (2023). Stem cell-based approaches for intervertebral disc regeneration. Current Stem Cell Research & Therapy

6. Yang, R. Z., et al. (2021). Involvement of oxidative stress-induced annulus fibrosus cell and nucleus pulposus cell ferroptosis in intervertebral disc degeneration pathogenesis. Journal of Cell Physiology

7. Bai, X., et al. (2023). Cyanidin attenuates the apoptosis of rat nucleus pulposus cells and the degeneration of intervertebral disc via the Jak2/Stat3 signal pathway in vitro and in vivo. Pharmaceutical Biology

8. Xu, H. W., et al. (2023). Alpha-Ketoglutaric acid ameliorates intervertebral disk degeneration by blocking the Il-6/Jak2/Stat3 pathway. American Journal of Physiology - Cell Physiology

9. Zhu, J., et al. (2022). The deubiquitinase Usp11 ameliorates intervertebral disc degeneration by regulating oxidative stress-induced ferroptosis via deubiquitinating and stabilizing Sirt3. Redox Biology

10. Smith, L. J., et al. (2023). In vitro characterization of a Stem-Cell-Seeded Triple-Interpenetrating-Network hydrogel for functional regeneration of the nucleus pulposus. Tissue Engineering Part A

FAQs

What is intervertebral disc degeneration (IVDD)?
IVDD is a degenerative condition of the intervertebral discs that can lead to chronic pain and reduced mobility. It involves changes in disc structure, hydration, and cellular function.

How do bone mesenchymal stem cells (BMSCs) help in treating IVDD?
BMSCs can differentiate into disc-like cells, secrete growth factors, and modulate the local environment, helping to regenerate the damaged disc tissue and inhibit cell death.

What role do hydrogels play in stem cell therapy for IVDD?
Hydrogels serve as scaffolds for delivering BMSCs to the site of degeneration, providing support and a favorable environment for cell survival and function.

What is ferroptosis, and how is it related to IVDD?
Ferroptosis is a form of regulated cell death associated with oxidative stress. It has been implicated in the degeneration of disc cells, making it a target for therapeutic intervention.

How does the STAT3 signaling pathway influence IVDD?
The STAT3 pathway regulates various cellular processes, including inflammation and cell survival. Inhibition of STAT3 activation can protect disc cells from degeneration and promote regeneration.