Exosomes derived from stem cells as an emerging therapeutic strategy for intervertebral disc degeneration

Table 1 Characteristics of three main types of extracellular vesicles

Types of vesicles	Diameter	Markers	Cargos	Density (g/mL)	Origin	Ref.
Exosomes	30-150 nm	CD63, CD81, CD9, HSP70, Flotillin, TSG101, etc.	mRNA, microRNA, lncRNA, circRNA, DNA lipid, protein, etc.	1.13-1.18	Endosomes pathway	[51,74-77]
Microvesicles	50-1000 nm	Integrins, selectins, CD40 ligand	mRNA, microRNA, other non-coding RNA, protein, etc.	1.16-1.19	Plasma membrane; outward budding	[51,75]
Apoptotic bodies	500-2000 nm	Phosphatidylserine, genomic DNA	Nuclear fractions, cell organelles, etc.	1.16-1.28	Plasma membrane	[47,51,78]

Table 2 Studies on exosomes for intervertebral disc degeneration

Ref.	Experimental objective	Cargo analysis	Animal model	In vitro appraisement	In vivo appraisement	Inhibition test	Research type
HBMSCs; Lu et al[26]	To detect the role of exosomes derived from BM-MSCs in NPCs	Not mentioned	None	(1) Promoted proliferation; and (2) Increased synthesis of extracellular matrix and decrease in degradation	None	None	Cell experimentation
HBMSC; Cheng et al[28]	To explore the protective effect of MSC-exosomes on NPCs in a cell and rat model	Highly enrichment in miR-21	SD rat model of IVD degeneration by needle puncture	(1) Decreased apoptosis rate; and (2) Decreased cleaved caspase-3	(1) IVD degeneration score lower; (2) Decreased apoptosis rate; and (3) Lower histologic score	MiR-21 antagonist enhanced cell apoptosis	Cell and animal experimentation
Rat nucleus pulposus; Moen et al[79]	To study the role of extracellular miRNA in lumbar radicular pain	Increased miR-223	Lewis rat IVD herniation	None	MiR-223 increased after disc herniation	None	Animal experimentation
Porcine notochordal cells; Bach et al[80]	To explore the biologic effect of the NCCM-derived EVs on canine and human CLCs from degenerated IVDs in vitro	None	None	Increased glycosaminoglycan (GAG) deposition	None	None	Cell experimentation
HBMSCs; Liao et al[27]	To prove that the delivery of MSC-exos could modulate ER stress and inhibit excessive NP cell apoptosis during IDD	None	SD rat model of IVD degeneration by needle puncture	(1) Western blot and TUNEL assays indicated decreased apoptosis rate; and (2) Western blot and qPCR data indicated decreased reticulum stress	(1) Higher DHI; (2) Lower Pfirrmann grade; (3) Lower histological grades; and (4) Decreased apoptosis rate	Akt inhibitor LY294002; ERK inhibitor PD98059	Cell and animal experimentation
C57BL/6 mice BMSCs; Xia et al[69]	To investigate the therapeutic effect of exosomes for use as IVDD therapeutics	None	Rabbit model of IVD degeneration by needle puncture	(1) Decreased apoptosis rate; (2) Western blot and qPCR data indicated recovery of matrix homeostasis; (3) Decreased inflammatory marker expression; (4) Suppressed inflammasome; and (5) Recovery of mitochondrial-related proteins and attenuated mitochondrial dysfunction	(1) Higher DHI; (2) Lower Pfirrmann MRI grade; (3) Lower histological grades; and (4) Decreased apoptosis rate	None	Cell and animal experimentation

BMSC: Bone marrow stromal cells; IVDD: Intervertebral disc degeneration; MRI: Magnetic resonance imaging; IVD: Intervertebral disc; IDD: Intervertebral disc degeneration; MSC: Mesenchymal stem cell; HBMSC: Human bone marrow stromal cells; CLC: Cardiomyoblast-like cells; NPC: Nucleus pulposus cells.