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

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.

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.

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.

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.