Therapeutic strategies for intervertebral disc degeneration: Extracellular vesicles and microRNAs derived from mesenchymal stem cells

Table 1 Effectiveness of mesenchymal stem cell biological therapy in various studies

Biological therapies	Effects	Ref.
TGF-β1	MSC differentiation toward NP/chondrogenic phenotype and upregulation of ERK1/2 activity	[38,51]
TGF-β3	MSC differentiation to NPC and AFC in combination with BMP-2 and IGF-1	[31,32,34,35,52,53]
BMP2	Differentiation into NPCs with TGF-β3 and PRP	[32,34,44,54]
BMP7	MSC differentiation into NP-like cells via the Smad pathway	[55]
IGF1	MSC differentiation into NPC-like cells	[48,49,56]
FGF2	MSC differentiation into NPC-like cells	[48,50,57]

TGF: Transforming growth factor; MSC: Mesenchymal stem cell; NP: Nucleus pulposus; ERK: Extracellular signal-regulated kinase; NPC: Nucleus pulposus cell; AFC: Annulus fibrosus cell; BMP: Bone morphogenetic protein; PRP: Platelet-rich plasma; IGF: Insulin-like growth factor; FGF: Fibroblast growth factor.

Table 2 Effectiveness of mesenchymal stem cells-derived extracellular vesicles in biological therapy across various studies

Biological therapies	Effects	Ref.
NLRP3	Exosomes play an anti-inflammatory role in pathological NPCs by suppressing inflammatory mediators and NLRP3 inflammasome activation	[78]
MLK3	Bone marrow MSCs-derived exosomes-packaged miR-142-3p alleviates NPCs injury through suppressing MAPK signaling by targeting MLK3	[72]
RASSF5	MSCs may suppress TNF-α-induced apoptosis, ECM degradation, and fibrosis deposition in NPCs through the delivery of miR-532-5p via targeting RASSF5	[73]
Notch1	Inhibition of the Notch1 pathway facilitates NPC exosome-induced differentiation of MSCs into NP-like cells in vitro	[74]
PI3K and AKT	Exosomal miR-21 restrains PTEN and thus activates PI3K/AKT pathway in apoptotic NPCs	[80]
AKT and ERK	MSC-exosomes could attenuate ER stress-induced apoptosis by activating AKT and ERK signaling	[81]
ZNF121	Exo-antagomiR-4450 retarded damage of NPCs in vitro, alleviated IDD damage, and ameliorated gait abnormality in vivo	[82]
ATF6	MSC-exosomes reduced apoptosis and calcification of EPCs via regulation of the miR-31-5p/ATF6/ER stress pathway	[83]

NLRP3: Nod-like receptor protein 3; MLK3: Mixed-lineage kinase 3; MSC: Mesenchymal stem cell; NPC: Nucleus pulposus cell; MAPK: Mitogen-activated protein kinases; RASSF5: Ras association domain family member 5; TNF: Tumor necrosis factor; ECM: Extracellular matrix; PI3K: Phosphatidylinositol-3-kinase; AKT: Protein kinase B; PTEN: Phosphatase and tensin homolog; ERK: Extracellular signal-regulated kinase; Exo: Exosomes; IDD: Intervertebral disc degeneration; ZNF121: Zinc finger protein-121; EPC: Epithelioma papulosum cyprini; ATF6: Activating transcription factor 6; ER: Endoplasmic reticulum.