Stem cell therapy for intervertebral disc degeneration: Clinical progress with exosomes and gene vectors

Abstract

Intervertebral disc degeneration is a leading cause of lower back pain and is characterized by pathological processes such as nucleus pulposus cell apoptosis, extracellular matrix imbalance, and annulus fibrosus rupture. These pathological changes result in disc height loss and functional decline, potentially leading to disc herniation. This comprehensive review aimed to address the current challenges in intervertebral disc degeneration treatment by evaluating the regenerative potential of stem cell-based therapies, with a particular focus on emerging technologies such as exosomes and gene vector systems. Through mechanisms such as differentiation, paracrine effects, and immunomodulation, stem cells facilitate extracellular matrix repair and reduce nucleus pulposus cell apoptosis. Despite recent advancements, clinical applications are hindered by challenges such as hypoxic disc environments and immune rejection. By analyzing recent preclinical and clinical findings, this review provided insights into optimizing stem cell therapy to overcome these obstacles and highlighted future directions in the field.

Key Words: Exosomes; Extracellular matrix repair; Gene vector system; Hypoxic environment; Intervertebral disc degeneration; Mesenchymal stem cells; Regenerative medicine; Stem cell therapy

Core Tip: The application of stem cell therapy in intervertebral disc degeneration has shown significant regenerative potential. Through differentiation, paracrine effects, and immunomodulation, stem cells can repair damaged extracellular matrix and slow the degenerative process. Emerging technologies such as exosomes and gene vector systems further enhance the therapeutic effects of stem cells, improving cell survival rates and regenerative capabilities. However, the long-term survival of stem cells in a hypoxic environment, the optimal injection dosage, and their long-term safety still requires further investigation. Future interdisciplinary collaboration will drive the clinical translation of stem cell therapy, making it a standard option for the treatment of intervertebral disc degeneration.

INTRODUCTION

Intervertebral disc degeneration (IVDD) is one of the primary causes of lower back pain, significantly contributing to disability and reducing the quality of life of millions of people worldwide. IVDD is characterized by the gradual loss of disc function with age and is driven primarily by the degeneration of nucleus pulposus cells (NPCs)[1,2]. NPCs play a crucial role in maintaining disc hydration and elasticity; however, over time, their number and functionality decline. Concurrently, the depletion of nucleus pulposus progenitor cells (ProNPs) exacerbates the reduction in extracellular matrix (ECM) synthesis, further diminishing disc hydration and elasticity[3-5]. Additionally, damage to the annulus fibrosus (AF) compromises the structural integrity of the disc, often leading to herniation[6,7]. This, in turn, can compress surrounding neural tissue, causing neuropathic pain and motor dysfunction[8]. These pathological changes result in significant impairment of daily activities, with severe cases progressing to disability.

Current treatment strategies for IVDD include conservative approaches such as medication and physical therapy as well as surgical interventions. Conservative treatments may provide symptomatic relief in the early stages but fail to halt disease progression. Surgical approaches, including discectomy and spinal fusion, address nerve compression but are invasive and unable to restore normal disc function[9]. Moreover, these methods only offer temporary relief and do not reverse the degenerative processes of the disc[10]. Given these limitations, there is a pressing need for innovative therapies capable of addressing the underlying mechanisms of IVDD, promoting tissue repair, and improving long-term outcomes.

Stem cell therapy has emerged as a promising regenerative approach for IVDD, offering the potential to repair damaged tissues, restore disc function, and slow disease progression. Stem cells can differentiate into NPCs and AF cells, and their paracrine effects promote ECM repair, inhibit inflammation, and reduce apoptosis[11-13]. This therapy provides a particularly viable option for patients who are unresponsive to traditional treatments or unable to tolerate surgery.

In recent years, advancements in technologies such as stem cell-derived exosomes and gene vector systems have further enhanced the potential of stem cell therapy. By introducing specific genes into stem cells, gene vector systems can increase cell survival in hypoxic environments, improve ECM repair, and increase anti-inflammatory capabilities[14-17]. Stem cell-derived exosomes, as nanoscale vesicles carrying therapeutic molecules, have demonstrated anti-inflammatory, antiapoptotic, and regenerative effects in IVDD models[12,16]. These developments collectively offer innovative strategies to optimize the therapeutic efficacy of stem cell-based treatments for IVDD.

This review aimed to synthesize the latest advancements in stem cell therapy for IVDD, focusing on the mechanisms underlying stem cell-mediated repair and the emerging roles of exosomes and gene vector systems. By addressing the challenges of clinical translation, including poor cell survival, limited ECM repair, and immune rejection, this work highlighted the potential of multidisciplinary approaches to bridge the gap between experimental findings and clinical applications.

MECHANISMS OF STEM CELL ACTION IN IVDD

Sources and types of stem cells

Stem cell therapy has promising applications in the treatment of IVDD. Stem cells from various sources offer distinct advantages in terms of their differentiation potential, anti-inflammatory properties, and clinical application prospects. Bone marrow-derived mesenchymal stem cells (BMSCs) are the most extensively studied stem cell type and possess significant self-renewal and multipotent differentiation abilities[18]. BMSCs regulate ECM production and reduce inflammation and apoptosis by secreting cytokines such as transforming growth factor beta (TGF-β), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF)[16,17]. In animal models, BMSC injections have demonstrated disc repair effects, with clinical studies also showing the potential of BMSCs to alleviate pain and promote NPC regeneration[3,16,19,20]. However, the hypoxic environment of the intervertebral disc presents a considerable challenge for BMSCs, and their long-term survival under hypoxic conditions requires further research[21,22].

Compared with BMSCs, adipose-derived mesenchymal stem cells (ADSCs) have similar multipotent differentiation potential but offer clinical advantages due to their wide availability and ease of acquisition[23,24]. ADSCs can promote NPC proliferation and enhance the production of essential ECM components, such as collagen and proteoglycans, thereby supporting disc structure and function[23,25,26]. Although ADSCs exhibit strong anti-inflammatory effects, their long-term survival in harsh, hypoxic disc environments remains challenging. Strategies to improve their therapeutic efficacy, such as genetic modification or combination with biomaterials such as hydrogels, are currently under exploration[26,27].

Owing to their low immunogenicity and high proliferative capacity, umbilical cord-derived mesenchymal stem cells (UC-MSCs) have become an attractive source for allogeneic transplantation[28]. By secreting anti-inflammatory and growth factors, including TGF-β, VEGF, and interleukin (IL)-10, UC-MSCs not only help mitigate inflammation but also promote ECM repair and regeneration[29-31]. While UC-MSCs have shown promising repair effects in vitro and in animal studies, their long-term efficacy and safety in clinical settings require further validation. Future research may focus on optimizing the application of UC-MSCs in disc repair through gene editing or exosome technology[32].

Additionally, nuclear ProNPs, as precursor cells with multipotent differentiation capability, play a critical role in disc repair by differentiating into mature NPCs[33-35]. Studies indicate that ProNPs can promote NPC regeneration and slow disc degeneration under hypoxic conditions by activating signaling pathways such as the Wnt and TGF-β pathways[5,36,37]. Future research will focus on the potential clinical application of these progenitor cells, particularly in gene regulation and exosome therapy[37].

The choice between autologous and allogeneic stem cells in clinical applications should be based on specific case requirements. With a lower risk of immune rejection, autologous stem cells are suitable for personalized treatment but are limited by complex harvesting processes and limited cell numbers[38-40]. In contrast, allogeneic stem cells, especially UC-MSCs, are easier to obtain and are suitable for large-scale treatments, although they carry a certain risk of immune rejection[41]. Although allogeneic stem cells may trigger immune responses during transplantation, technologies such as gene editing and immune modulation can mitigate this risk[39]. Future studies will aim to optimize the application of both cell types to improve efficacy and minimize side effects (Tables 1 and 2).

Table 1 Comparison of stem cell types.

Stem cell source	Harvesting method	Differentiation potential	Anti-inflammatory action	Applicable scenarios	Prospects for IVDD repair application
BMSCs	Bone marrow extraction, complex procedure	Multipotent differentiation potential, can differentiate into NPCs and AF cells	Secretes TGF-β, IGF-1, VEGF; regulates ECM metabolism, reduces NP cell apoptosis and inflammation	Suitable for severe disc damage	Demonstrates repair potential in in vivo and in vitro studies and early clinical research; long-term efficacy still requires validation
ADSCs	Fat extraction, relatively simple	Multipotent differentiation ability, promotes ECM production	Secretes anti-inflammatory factors, helps reduce NP cell apoptosis and inflammation	Minimally invasive treatment, suitable for wide application	Shows promising results in preclinical studies; combining with materials like hydrogels can enhance therapeutic effects
UC-MSCs	Extraction from umbilical cord tissue, easy to obtain	Multipotent differentiation potential, high proliferative capacity	Secretes TGF-β, VEGF, IL-10; exhibits significant anti-inflammatory and anti-apoptotic effects	Suitable for allogeneic transplantation and large-scale treatment, low immunogenicity	Shows good results in preclinical studies; can be further optimized with gene editing and exosome technologies
ProNPs	Extraction from the disc, relatively complex	Differentiates into mature NP cells	Promotes NP tissue regeneration through paracrine effects	Suitable for NP regeneration, high potential	Promotes ECM production by activating specific signaling pathways, high future application potential

BMSCs: Bone marrow-derived mesenchymal stem cells; ADSCs: Adipose-derived mesenchymal stem cells; UC-MSCs: Umbilical cord-derived mesenchymal stem cells; ProNPs: Nucleus pulposus progenitor cells; NPCs: Nucleus pulposus cells; AF: Annulus fibrosus; ECM: Extracellular matrix; TGF: Transforming growth factor; IGF: Insulin-like growth factor; VEGF: Vascular endothelial growth factor; IL: Interleukin; NP: Nucleus pulposus; IVDD: Intervertebral disc degeneration.

Table 2 Clinical and in vivo/in vitro experimental data.

Experiment type	Cell source	Main observed data	Comparative effects	Ref.
In vitro experiment	BMSCs, NPC	NP cell survival rate, ECM production	BMSCs and NPCs in coculture significantly increased NP cell survival and promoted the generation of type II collagen and proteoglycans. In a hypoxic environment, TGF-β and Notch pathways enhanced disc microenvironment repair	[16,67]
In vivo experiment	BMSCs, UC-MSCs	Disc height, NP cell count, NP cell apoptosis rate	Intradiscal injection of BMSCs and UC-MSCs significantly reduced NP cell apoptosis and restored disc height. Exosomes combined with hydrogels improved stem cell engraftment in the disc	[32,55]
Clinical trial	BMSCs	Pain relief, functional recovery, disc water content	Early clinical trials of BMSC injections showed significant pain reduction in patients, with increased NP water content at 12-month follow-up, confirming BMSC repair potential. Several studies showed significant pain relief postinjection with no severe side effects	[20]
In vitro test	ADSCs	Pain score, functional improvement, disc regeneration	ADSC injections demonstrated significant pain relief and functional improvement in patients with lower back pain, with substantial reductions in pain scores and no reported severe complications	[25]
Animal experiment	BMSC exosomes	ECM production, disc height, inflammation	BMSC exosomes significantly enhanced NP cell antiapoptotic capacity, promoted ECM synthesis, and restored disc structure and elasticity. Exosomes reduced inflammation in disc degeneration models by activating the PI3K/AKT pathway	[11]
In vitro test	BMSC and ADSC exosomes	Disc repair rate, inflammation modulation, cell survival	Stem cell-derived exosomes promoted disc repair by reducing inflammation and enhancing NP cell survival, showing significant therapeutic potential when combined with gene editing technology and biomaterials	[90,91]

BMSCs: Bone marrow-derived mesenchymal stem cells; ADSCs: Adipose-derived mesenchymal stem cells; UC-MSCs: Umbilical cord-derived mesenchymal stem cells; NP: Nucleus pulposus; ECM: Extracellular matrix; TGF: Transforming growth factor; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; NPC: Nucleus pulposus cells.

Mechanisms of stem cell-mediated repair in IVDD

Differentiation capacity: Under suitable microenvironmental conditions, stem cells can differentiate into NPCs, AF cells, or chondrocyte-like cells, thus contributing to disc tissue regeneration[42,43]. Studies have shown that the activation of signaling pathways such as the TGF-β and Wnt/β-catenin pathways enable stem cells to effectively differentiate into the cell types required for the restoration of disc structure and function[44,45]. The TGF-β pathway facilitates ECM production and the secretion of collagen and proteoglycans, which help NP cells maintain disc elasticity and hydration[45]. The Wnt/β-catenin pathway plays a critical role in cell differentiation and regeneration by regulating β-catenin accumulation and nuclear translocation, initiating the expression of relevant genes[44].

Paracrine effects: Another therapeutic mechanism of stem cells is their potent paracrine effects. By secreting various cytokines, such as TGF-β, IGF-1, and VEGF, stem cells can regulate local inflammatory responses, reduce NP cell apoptosis, and promote ECM synthesis[35,45]. These paracrine factors modulate inflammatory mediators, improving the disc microenvironment to delay degeneration and facilitating tissue regeneration. Additionally, studies have shown that stem cell-derived exosomes, which carry microRNAs (miRNAs) and proteins, play a key role in disc regeneration[4].

ECM repair: Stem cells participate directly in disc repair by secreting essential ECM components such as proteoglycans and collagen[46-48]. These ECM elements are crucial for maintaining the structural integrity and elasticity of the disc[46]. As disc degeneration progresses, ECM synthesis decreases, and NP cells gradually undergo apoptosis, leading to a decrease in disc height and elasticity[49,50]. Stem cell therapy effectively enhances ECM production and improves ECM quality, making the repaired disc tissue closer to a healthy state[51,52]. Research indicates that in addition to directly secreting ECM components stem cells promote repair through paracrine effects, releasing cytokines such as TGF-β and IGF-1 to further stimulate ECM synthesis[53,54]. Together, these mechanisms help slow NP cell attrition, prevent disc height loss, and delay disc degeneration. Furthermore, recent studies have shown that combining stem cells with biomaterials, such as hydrogels, improves stem cell engraftment and ECM repair in the disc, enhancing their clinical application potential[51,55,56]. This combined approach offers new possibilities for optimizing stem cell therapy.

MOLECULAR MECHANISMS OF STEM CELL REPAIR IN IVDD

In recent years, the molecular mechanisms by which stem cells repair IVDD have been extensively studied and have gained significant attention. These studies highlighted the importance of hypoxic conditions in stem cell differentiation and the critical roles of various signaling pathways in regulating stem cell regeneration. Under the hypoxic environment of the disc, stem cells activate a series of molecular signaling pathways to promote ECM synthesis and repair damaged tissue. Additionally, stem cell-derived exosomes and the application of gene vector systems play essential roles in intercellular communication, further enhancing repair efficacy (Figure 1 and Table 3).

Figure 1 Main biological mechanisms of stem cell-mediated repair in damaged intervertebral discs. Growth factors such as insulin-like growth factor 1 and vascular endothelial growth factor activate the phosphatidylinositol 3-kinase/protein kinase B pathway, which enhances protein synthesis through mechanistic target of rapamycin and promotes cell cycle progression via cyclin D1 and CDK4, facilitating stem cell proliferation. Transforming growth factor beta signaling, which is mediated by Smad2/3/4, promotes the expression of Sry-related HMG box 9, which is critical for chondrogenic differentiation, and the synthesis of key extracellular matrix components (COL2A1 and ACAN), which contribute to tissue repair. Notch signaling, which is activated by ligand binding (Jagged, Delta) to Notch receptors, leads to the formation of the Notch intracellular domain. The Notch intracellular domain downregulates Hes and Hey transcription factors, influencing stem cell differentiation. The Wnt/β-catenin pathway is pivotal for cell survival, regulating the balance between antiapoptotic (Bcl-2, Bcl-xL) and proapoptotic (Bax, Bak) factors to control apoptosis, thereby supporting the survival of stem cells in the damaged disc environment. These pathways work together to enhance tissue regeneration and restore intervertebral disc function. IGF: Insulin-like growth factor; VEGF: Vascular endothelial growth factor; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; mTOR: Mechanistic target of rapamycin; SOX9: Sry-related HMG box 9; TGF: Transforming growth factor; NICD: Notch intracellular domain.

Table 3 Comparison of signaling pathways and effects.

Signaling pathway	Key factors	Regulatory mechanism	Functional effects
TGF-β signaling pathway	TGF-β, Smad2/3	Promotes ECM production and reduces cell apoptosis by activating the Smad pathway	Enhances the survival of NPCs, promotes type II collagen and proteoglycan production, maintains disc elasticity
Wnt/β-catenin pathway	β-catenin	Activates the translocation of β-catenin into the nucleus, regulating the expression of cartilage-related genes	Promotes differentiation of NPCs and chondrocyte-like cells, enhances ECM production, maintains disc structural integrity
PI3K/AKT pathway	PI3K, AKT, mTOR, Bcl-2	Enhances stem cell survival and reduces apoptosis of nucleus pulposus cells by activating mTOR and Bcl-2	Increases stem cell survival rate under hypoxic conditions, enhances regenerative ability, reduces inflammatory response
NF-κB signaling pathway	NF-κB, TNF-α, IL-6	Inhibits the expression of inflammation-related molecules like TNF-α, IL-6, and IL-1β associated with NF-κB, delays tissue damage, and reduces apoptosis of NPCs	Improves the survival rate of NPCs through anti-inflammatory and antiapoptotic effects, promoting tissue regeneration
Notch signaling pathway	Notch1, Notch2, CSL, NICD	Activates the CSL transcription factor through ligand binding, promoting stem cell proliferation and differentiation	Enhances the formation of NPCs and annulus fibrosus cells, increases the regenerative potential of disc tissue
HIF-1α signaling pathway	HIF-1α, IGF-1	Regulates the metabolism of NPCs and ECM synthesis, enhancing cell survival in a hypoxic microenvironment	Maintains disc tissue elasticity, reduces cell apoptosis, delays disc degeneration

TGF: Transforming growth factor; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; NF-κB: Nuclear factor-kappaB; mTOR: Mechanistic target of rapamycin; TNF: Tumor necrosis factor; IL: Interleukin; NICD: Notch intracellular domain; HIF: Hypoxia-inducible factor; IGF-1: Insulin-like growth factor 1; ECM: Extracellular matrix; NPC: Nucleus pulposus cells.

Regulation of NPC survival and function by hypoxia-inducible factor-1α in hypoxic environments

The intervertebral disc, especially the NP, is one of the few avascular tissues in the body and remains in a hypoxic environment over time. Hypoxia-inducible factor-1α (HIF-1α) plays a critical role in this environment, serving as an essential regulator of NP cell survival and function[57]. In response to local oxygen partial pressure changes, HIF-1α regulates cellular metabolism and matrix production, helping stem cells differentiate into NP-like cells and promoting the synthesis of ECM components, such as collagen and proteoglycans[58,59].

During disc degeneration, HIF-1α not only supports NP cell survival but also promotes metabolic activity and inhibits apoptosis through downstream gene regulation[60]. The cooperative interaction between HIF-1α and the Notch signaling pathway helps slow the degenerative process by activating growth factors such as IGF-1 and TGF-β, thereby enhancing the regenerative capacity of NPCs[59]. Furthermore, studies have shown that activation of the HIF-1α pathway in stem cell therapy can significantly increase ECM production, improve disc elasticity and function, and delay tissue degeneration[4,60]. Future research may explore the application of HIF-1α as a potential therapeutic target, utilizing gene editing or pharmacological modulation to increase its activity in degenerated discs.

Signaling pathways involved in stem cell-mediated repair

Stem cells utilize multiple signaling pathways to exert reparative effects on disc degeneration. These pathways regulate stem cell survival, proliferation, and differentiation and influence the inflammatory response and ECM production. The Notch signaling pathway plays a crucial role in regulating stem cell self-renewal and differentiation[61]. When the Notch receptor binds with its corresponding ligand, it releases the intracellular domain, which enters the nucleus and initiates the transcription of genes that promote NPC generation[62,63]. Studies have shown that upon ligand binding, Notch releases Notch intracellular domain into the nucleus, activating the Sry-related HMG box 9 (Sox9) gene to stimulate the synthesis of type II collagen and proteoglycans, thereby restoring disc structure[64,65]. Proper activation of this pathway is essential for maintaining cellular balance, as overactivation may lead to fibrosis and other adverse effects[66,67].

The Wnt/β-catenin signaling pathway improves stem cell survival in adverse environments by enhancing antiapoptotic abilities and promoting NPC differentiation. When Wnt binds to the Frizzled receptor on the cell surface, β-catenin is released and enters the nucleus, activating antiapoptotic genes such as Bcl-2 and survivin[68-71]. This pathway also works in conjunction with HIF-1α to adapt to the hypoxic environment of the disc, supporting cellular energy metabolism[72,73]. The Wnt pathway is essential for stem cell differentiation into NPC and chondrocyte-like cells, promoting ECM synthesis and restoring disc elasticity.

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway plays a central role in stem cell survival, proliferation, and differentiation[74]. PI3K activation generates PIP3, which activates downstream AKT, initiating signaling pathways related to antiapoptotic effects and cell proliferation[75,76]. AKT enhances cell survival in hypoxic environments by inhibiting proapoptotic factors such as Bad and Bax and activating antiapoptotic proteins such as Bcl-2 and Bcl-xL[77]. Additionally, the PI3K/AKT pathway regulates cell cycle-related proteins, such as cyclin D1 and CDK4, promoting cell proliferation to provide a sufficient cell source for disc repair[75,76]. This pathway also regulates the Sox9 gene, promoting the differentiation of stem cells into NP-like or chondrocyte-like cells, thus accelerating disc repair[66].

The TGF-β signaling pathway is a key regulator of ECM production and differentiation in stem cells[78,79]. Through both Smad-dependent and non-Smad-dependent pathways, TGF-β promotes the regeneration of NP and AF cells, particularly through regulation of the Sox9 gene, which governs the synthesis of type II collagen and proteoglycans, thereby restoring disc mechanical strength[80,81]. Moreover, TGF-β reduces inflammatory responses by inhibiting the nuclear factor-kappaB (NF-κB) pathway, improving the local microenvironment and further enhancing stem cell-mediated repair capacity[82].

The regulation of the mechanistic target of rapamycin (mTOR) and NF-κB signaling pathways is particularly crucial for stem cell survival in adverse environments[83,84]. mTOR promotes protein synthesis and cellular metabolism, enhances cell growth and antiapoptotic functions, while simultaneously suppressing the proinflammatory effects of NF-κB and reducing the release of inflammatory mediators[85-87]. By activating these pathways, stem cells can effectively respond to the hypoxic and inflammatory microenvironment of the disc, maintaining cellular function.

RESEARCH PROGRESS ON THE DEGENERATION OF STEM CELLS IN INTERVERTEBRAL DISC

The role of stem cells in the repair of IVDD has been extensively validated through in vitro experiments, animal models, and clinical studies. These studies revealed the regenerative potential of stem cells in disc tissues as well as the mechanisms of repair under various conditions and environments (Table 4).

Table 4 Comparison of stem cell therapy and traditional treatments.

Treatment method	Advantages	Indications	Limitations	Clinical application cases
Conservative treatment	High safety, suitable for early-stage patients, usually includes medication and physical therapy, low risk	Suitable for patients with early mild symptoms	Cannot reverse disc degeneration, limited effectiveness, can only temporarily relieve symptoms	Commonly used for early IVDD patients but cannot fundamentally stop disease progression
Minimally invasive surgery	Minimal surgical trauma, shorter recovery time, low risk	Applicable to patients with moderate IVDD	The effect may not be as good as traditional surgery, and symptoms may recur in some patients	Shows good short-term effects in some patients, suitable for those unwilling to undergo invasive surgery
Open surgery	Relieves nerve compression symptoms caused by disc herniation; spinal fusion can restore spinal stability	Suitable for severe degenerative disc disease and neurological symptoms	High trauma, long recovery time, high surgical risks, possible postoperative complications, and inability to restore normal disc function	Surgical treatment can effectively relieve pain and neurological symptoms, but recovery is slow, and there is a risk of recurrence
Stem cell therapy	Minimally invasive, with regenerative potential, capable of repairing disc tissue through differentiation and paracrine mechanisms; has immunomodulatory effects, reduces inflammation, and inhibits apoptosis	Applicable to early IVDD patients who do not respond to traditional treatments	The long-term survival rate and safety of stem cells in the disc require further research, with potential risks of immune rejection and tumor formation	Clinical trials indicate that BMSC injections can significantly reduce patient pain, with follow-up showing increased hydration of the nucleus pulposus
Stem cell + exosome therapy	Stem cell exosomes help enhance stem cell survival rate, and exosomes act as carriers of signaling molecules, promoting tissue repair	Suitable for patients who are not candidates for surgery	Long-term efficacy needs further validation, and the isolation and preparation techniques for exosomes still need improvement	Combining gene editing technology and biomaterials has enhanced its regenerative effects, with preclinical studies demonstrating significant regenerative potential

IVDD: Intervertebral disc degeneration; BMSCs: Bone marrow-derived mesenchymal stem cells.

In vitro studies

In in vitro experiments, coculturing stem cells with NPCs has shown that stem cells significantly increase NPC survival and stimulate the secretion of more ECM components, such as collagen and proteoglycans[88]. Studies indicate that stem cells under hypoxic conditions in vitro contribute to the restoration of the disc microenvironment[36,57]. Stem cell-derived exosomes, which carry various bioactive molecules, further increase NPC survival and differentiation, improve the inflammatory environment, and increase the disc repair capacity[89-91].

Animal model studies

In animal models, stem cell injections have been shown to restore disc height, repair NP tissue, and significantly alleviate symptoms caused by degenerative changes. Research has demonstrated that injecting BMSCs or ADSCs into IVDD models effectively increases the number of NPCs, promotes ECM production, and thereby restores disc elasticity and function[92]. Additionally, the survival, migration, and differentiation of stem cells after injection into the disc are key indicators for evaluating therapeutic efficacy. In animal studies[93], stem cells significantly delay disc degeneration by activating hypoxic signaling pathways, increasing cell survival, and promoting the secretion of growth factors. Animal research has also explored the impact of various injection methods on stem cell survival and differentiation. For example, studies have shown that stem cells injected with exosomes or combined with biomaterials such as hydrogels are more likely to engraft in disc tissue, significantly enhancing their regenerative effects[93].

Clinical studies

In clinical studies, stem cell injections have shown efficacy in improving clinical symptoms and functional recovery in patients with IVDD. Multiple clinical trials have reported that intradiscal injection of BMSCs, ADSCs, and UC-MSCs can significantly reduce patient pain, restore disc function, and slow further disease progression[20]. Different sources of stem cells offer unique advantages. For example, BMSCs are widely studied and exhibit strong regenerative abilities, whereas UC-MSCs, owing to their low immunogenicity, have significant potential in clinical applications[92]. However, while clinical studies indicate the potential of stem cell therapy, optimizing injection methods, cell dosages, and long-term safety remains a research priority. Studies also suggest that future exploration of exosome and gene-editing technologies in conjunction with stem cell therapy may further enhance therapeutic effects[94]. In summary, experimental and clinical research on stem cells in IVDD has demonstrated their substantial promise in regenerative medicine. However, further large-scale clinical trials and long-term follow-up studies are essential to confirm the safety and efficacy of stem cell therapy.

APPLICATION OF STEM CELL EXOSOMES IN THE REPAIR OF IVDD

In recent years, stem cell-derived exosomes, as essential mediators of intercellular communication, have shown great potential in repairing IVDD. Exosomes are small membrane-bound vesicles with diameters ranging from 30 to 150 nm that carry various bioactive substances, including mRNAs, miRNAs, proteins, and lipids, that regulate target cell function and participate in multiple biological processes[95,96]. Owing to their low immunogenicity, ease of acquisition, and stability, stem cell-derived exosomes are gaining attention in regenerative medicine[97].

Mechanisms of stem cell-derived exosomes in disc repair

Stem cell-derived exosomes have significant biological advantages in the inflammatory and degenerative environment of the intervertebral disc, particularly in suppressing inflammation and promoting cell survival[49]. As small vesicles secreted by cells, exosomes contain abundant proteins, nucleic acids, and lipids that enable signal transmission between cells and regulate key signaling pathways, such as the TGF-β, PI3K/AKT, and NF-κB pathways[98]. In the inflammatory microenvironment of IVDD, stem cell-derived exosomes modulate the release of the proinflammatory factors tumor necrosis factor-alpha and IL-6, effectively suppressing inflammation[98,99]. These proinflammatory factors not only accelerate apoptosis but also degrade the ECM. Stem cell-derived exosomes improve the disc microenvironment by carrying anti-inflammatory miRNAs and proteins, inhibiting NF-κB pathway activation and reducing proinflammatory factor secretion[100,101].

Additionally, stem cell-derived exosomes help NP cells resist the apoptosis induced by proinflammatory factors and oxidative stress by regulating antiapoptotic pathways such as the PI3K/AKT and mTOR pathways[4]. By activating AKT, stem cell-derived exosomes promote the expression of antiapoptotic proteins and inhibit proapoptotic factors, significantly reducing NP cell apoptosis[68,102]. Moreover, stem cell-derived exosomes carry TGF-β or regulate its signaling pathway, promoting ECM synthesis and suppressing local inflammation[84]. TGF-β signaling not only regulates cell differentiation and ECM production in NPCs but also modulates macrophage polarization, reducing inflammation intensity and creating a microenvironment conducive to disc repair[103].

By regulating the Wnt/β-catenin and TGF-β signaling pathways, stem cell-derived exosomes increase the differentiation efficiency of NP and chondrocyte-like cells, promote ECM synthesis, and restore disc elasticity and structural integrity[104]. Additionally, the immunomodulatory properties of stem cell-derived exosomes can reduce immune responses within the disc by regulating T cell and macrophage activity, further inhibiting disease progression and promoting regeneration[105,106].

Applications of exosomes in experimental studies

The effects of exosomes have been validated in various in vitro and in vivo studies. Research has shown that stem cell-derived exosomes significantly improve the NPC microenvironment, reduce inflammatory responses, and increase antiapoptotic capacity through the activation of survival pathways such as the PI3K/AKT pathway[11,107]. Furthermore, exosomes can facilitate stem cell differentiation into NP-like cells, accelerating the disc repair process[108]. Experimental studies have also revealed that exosomes can serve as efficient drug delivery systems for the targeted transport of anti-inflammatory drugs or growth factors to degenerated disc sites[109]. This delivery system enables drugs to act more directly on diseased tissues, enhancing therapeutic efficacy while reducing systemic side effects. For example, in animal models of disc degeneration, stem cell-derived exosomes significantly mitigate disc height loss and restore disc function by improving ECM synthesis[55,110]. Studies have also shown that combining exosomes with other biomaterials, such as hydrogels, further improves exosome engraftment and persistence within the disc, significantly delaying degenerative progression[55,56]. In summary, stem cell-derived exosomes have broad application potential in regulating NPC function and inhibiting disc degeneration. With further preclinical research, exosomes are expected to become novel biotherapies for early intervention and long-term management of IVDD.

APPLICATION OF GENE VECTOR SYSTEMS IN THE TREATMENT OF IVDD

Gene vector classification in IVDD therapy

Gene therapy holds significant promise for the treatment of IVDD because it allows precise modulation of gene expression in disc cells. A central element of this strategy involves selecting suitable vectors to deliver therapeutic genes, which can be broadly categorized as viral, nonviral, or nanomaterial-based[111]. Viral vectors, such as lentiviruses, adenoviruses, and adeno-associated viruses, provide robust transfection efficiencies but can pose immunogenicity and safety concerns. Nonviral vectors, including plasmid DNA, liposomes, and polyplex micelles, generally offer safer profiles owing to their lower immunogenicity, although at the expense of reduced transfection efficiency. Nanomaterial-based vectors, including nanoparticles, graphene oxide, and nanofibers, present advantages such as enhanced stability, targeted delivery, and improved cellular uptake[112]. Each vector type has distinct strengths and limitations, and the choice of vector depends on therapeutic objectives, target cell types, the desired duration of gene expression, and safety considerations. Current research efforts focus on optimizing these vectors to further improve both their efficacy and safety, thereby advancing the potential of gene therapy in IVDD treatment.

Enhancing stem cell efficacy in disc repair through gene vector systems

A gene vector system is a technique used to deliver specific genes to target cells or tissues. In stem cell therapy, gene vector systems can enhance stem cell repair abilities by introducing specific genes[14,15]. In the treatment of IVDD, gene vector systems help stem cells better adapt to the disc microenvironment, enhancing their differentiation, proliferation, and antiapoptotic capacities and thereby promoting disc regeneration (Figure 2 and Table 5).

Figure 2 Gene vector-based stem cell therapy for intervertebral disc degeneration. A gene vector containing a target gene is introduced into various types of stem cells, including bone marrow-derived mesenchymal stem cells, adipose-derived mesenchymal stem cells, umbilical cord-derived mesenchymal stem cells, and progenitor nucleus pulposus cells. These genetically modified stem cells secrete exosomes, which are rich in biologically active contents such as RNA, proteins, and cytokines. These components contribute to the repair and regeneration of degenerated intervertebral discs by promoting cellular communication, reducing inflammation, and supporting tissue regeneration. Therapy aims to restore disc function and alleviate degenerative symptoms. BMSCs: Bone marrow-derived mesenchymal stem cells; ADSCs: Adipose-derived mesenchymal stem cells; US-MSCs: Umbilical cord-derived mesenchymal stem cells; ProNPs: Progenitor nucleus pulposus cells.

Table 5 Applications of combining gene editing with biomaterials in stem cell therapy.

Technology/material type	Target gene/material	Main mechanism of action	Application scenario	Experimental results	Ref.
CRISPR-Cas9	Parkin	CRISPR-dCas9-KRAB system used to silence the expression of Parkin	Targeting Parkin provides a new approach for IVDD repair	Inhibition of Parkin significantly reduces mitophagy and accelerates apoptosis of NPCs	[128]
siRNA	Bcl-2	Reduces apoptosis by inhibiting the expression of apoptosis-related gene Bcl-2	Inhibition of NPC apoptosis	Decreases the apoptosis rate of NPCs, promoting disc tissue repair	[113,114]
Gene editing + hydrogel	HIF-1α	Enhances HIF-1α expression in hypoxic environments, improving stem cell survival	Disc regeneration and cell protection under hypoxic conditions	Significantly improves stem cell colonization and survival, promoting regeneration of nucleus pulposus tissue	[26,27]
Gene editing + chitosan	IGF-1	Enhances IGF-1 expression, promoting cell proliferation and differentiation	NP tissue repair and regeneration	Increases the proliferation rate of NPCs, enhances type II collagen and proteoglycan production	[123]
Nanofiber scaffold	No gene editing	Provides 3D structural support, enhancing stem cell colonization efficiency	Tissue regeneration and structural repair	Nanofiber scaffold provides ideal mechanical support, significantly improving tissue structure restoration	[112]
CRISPR + exosome	miRNA	Increases miRNA content in exosomes, regulates inflammation, and promotes tissue repair	Inflammation control and disc regeneration	Significantly reduces inflammation, promotes ECM production, and enhances cell repair capacity	[30]
Gene editing + nanoparticles	VEGF	Overexpression of the VEGF gene increases angiogenesis, improving blood supply to the disc	Disc vascularization and regeneration	Promotes angiogenesis in disc tissue, enhancing regeneration capacity	[30,128]

siRNA: Small interfering RNA; HIF: Hypoxia-inducible factor; IGF-1: Insulin-like growth factor 1; miRNA: MicroRNA; VEGF: Vascular endothelial growth factor; ECM: Extracellular matrix; NPC: Nucleus pulposus cells; NP: Nucleus pulposus; 3D: Three-dimensional; IVDD: Intervertebral disc degeneration.

Application of gene vector systems in disc degeneration

In stem cell therapy for disc degeneration, gene vector systems improve stem cell survival rates in the hypoxic, nutrient-poor disc environment by introducing specific genes. For example, antiapoptotic genes (e.g., Bcl-2) or prodifferentiation genes (e.g., TGF-β, IGF-1) can be delivered into stem cells via viral or nonviral vectors, promoting their directed differentiation into NP or AF cells within the disc[16]. This genetic modification not only enhances cell survival but also increases ECM production, thereby improving disc elasticity and function. Additionally, gene vector systems can suppress inflammation associated with disc degeneration. Through the introduction of anti-inflammatory genes (e.g., IL-10 and tumor necrosis factor-alpha inhibitors) or the use of gene silencing techniques (e.g., small interfering RNA), inflammation within the disc can be significantly reduced, slowing disease progression[4,113,114]. This combination of gene editing with stem cell therapy addresses limitations in traditional stem cell therapies related to inflammation control, thereby increasing overall treatment efficacy.

Combination of stem cell-derived exosomes and gene vector systems

In recent years, researchers have explored the use of gene vector systems to modulate exosomes secreted by stem cells to enhance therapeutic effects. Stem cell-derived exosomes, as extracellular vesicles, carry repair-related genes, proteins, and miRNAs and facilitate intercellular communication[115,116]. By introducing specific genes into stem cells via gene vectors, the content of regenerative factors in their exosomes, such as antiapoptotic miRNAs or growth-promoting factors, can be increased, thereby improving the efficiency of disc regeneration[117-119].

ADVANTAGES AND LIMITATIONS OF STEM CELL THERAPY

Stem cell therapy has several advantages in the treatment of IVDD, particularly in terms of tissue regeneration, minimally invasive treatment, and immune modulation[120]. By differentiating into NP and AF cells, stem cells can directly repair disc tissue and secrete growth factors and anti-inflammatory factors, promoting ECM production, suppressing inflammation, and slowing the progression of disc degeneration[4,10]. Compared with traditional surgical treatments, stem cell therapy is less invasive, offers faster recovery, and presents a lower risk of complications. Clinical studies have shown that stem cell therapy can effectively relieve pain and promote disc regeneration.

However, stem cell therapy also faces certain limitations, especially concerning cell survival rates in hypoxic environments and uncertain long-term efficacy[57,121]. The complex structure of the AF limits the repair capacity of stem cells, particularly in cases of extensive damage[122,123]. Additionally, allogeneic stem cells may carry the risk of immune rejection, and their long-term safety remains to be further verified, especially regarding potential risks of tumor formation and ectopic differentiation, which requires more clinical data support. Therefore, although stem cell therapy shows great promise, future research must focus on optimizing its efficacy and safety[124,125].

CURRENT RESEARCH FOCUS AND FUTURE OUTLOOK

In recent years, research on stem cell therapy for IVDD has focused primarily on combining stem cells with biomaterials, gene editing technology, and optimized injection methods[57,126,127]. Combining stem cells with biomaterials such as hydrogels provides mechanical support, enhances cell engraftment and differentiation within the disc, and mimics the physical properties of the NP to promote tissue regeneration. Gene editing techniques (e.g., CRISPR-Cas9) further increase the reparative potential of stem cells by regulating specific genes to improve their differentiation and antiapoptotic abilities, while hypoxic preconditioning aids stem cells in adapting to the hypoxic environment of the disc[57,127,128]. Additionally, optimizing the injection dosage and methods is crucial; studies indicate that multiple small-dose injections are more effective in enhancing cell survival and efficacy than single large-dose injections[129].

Although stem cell therapy shows significant promise, gene vector systems are also receiving attention for their potential to increase therapeutic efficacy. However, challenges remain in the application of gene vectors. Viral vectors offer high gene delivery efficiency but may pose risks of immune rejection and tumor formation, whereas nonviral vectors such as plasmids and liposomes are safer but have lower gene delivery efficiency, limiting their clinical application. Future research should aim to optimize gene vector design to minimize side effects and improve transfection efficiency while promoting personalized gene therapies tailored to individual patient needs.

Future research directions should continue to explore the molecular mechanisms of stem cell regeneration, accumulate more clinical data, and refine personalized treatment strategies. Combining new technologies, such as exosome delivery and gene vectors, can further improve therapeutic precision and efficiency, expanding the clinical potential of stem cell therapy in the treatment of IVDD[130].

CONCLUSION

In recent years, stem cell therapy for IVDD has shown immense promise because of its inherent regenerative capacity. Stem cells can differentiate into key disc cell types, stimulating ECM production. Moreover, they exert paracrine effects, modulating inflammation and reducing cell death. Stem cell-derived exosomes amplify this regenerative response by delivering signaling molecules to target cells within the degenerated disc. However, challenges exist. The harsh disc environment hinders stem cell survival. Regenerating the complex AF structure presents difficulties. Additionally, the use of allogeneic stem cells necessitates addressing the risk of immune rejection.

To realize the clinical potential of stem cell therapy, future research must prioritize enhancing stem cell survival through strategies such as biomaterial support and gene editing. Addressing AF regeneration will require innovative approaches, including bioengineered scaffolds and manipulation of stem cell differentiation. Minimizing immune rejection will necessitate strategies such as immunosuppression, immunomodulation, and the use of patient-specific stem cells. Finally, rigorous clinical trials are crucial for evaluating safety and efficacy and refining treatment protocols. Through continued research, stem cell therapy has the potential to revolutionize IVDD treatment, offering patients a more effective and durable solution.