Table 4.

The effect of exosomes isolated from the distinct MSC sources on the prevention/modification of OA

Source of cells	In vitro	In vivo	Ref
SM-MSC (Human)	Exosomes derived from overexpressing miR-140-5p SM-MSC and WT SM-MSC have increased migration and proliferation. The presence of miR-140-5p reduced the degradation of ECM caused by WNT5a/b carried in SMSC exosomes	Rat; 12 weeks; No adverse effect was observed. The progression of OA was significantly delayed in the group treated with exosomes derived from SMSC overexpressing miR-140-5p vs exosomes derived from non-modified cells	[177]
BM-MSC (Mouse)	Exosomal miR-3960 has led to decreased degradation of ECM and inflammation of OA chondrocytes through regulation of the PHLDA2/SDC1/Wnt/β-catenin axis	Mice; 7 weeks; No adverse effect was observed. The delayed progression of OA and decrease of proinflammatory markers were highly reduced after exposure to MSC-EVs-miR-3960	[191]
BM-MSC (Human)	hBMMSC-EXOs have increased the viability, migration, proliferation and mitochondrial function in chondrocytes	Rabbit; 5 weeks; No adverse effect was observed. The osteochondral defect was partially repaired	[192]
BM-MSC (Human)	The exosomes derived from BMSC have an impact on macrophages polarisation from M1 to M2 and neutralise their effect on chondrocytes hypertrophy after co-culture	Rat; 4 weeks; No adverse effect was observed. The BMSC exosomes decreased hypertrophic markers and reduced the formation of osteophytes in the damaged joint area. Additionally, the infiltration of synovial macrophages was weakened	[178]
UC-MSC (Human)	UC-MSC exosomes increase the proliferation and migration of chondrocytes. They protect chondrocytes from IL-1β induced apoptosis and maintain their phenotype	Rat; 4 weeks; No adverse effect was observed. The injected exosomes isolated from UC-MSC prevented damaged cartilage from developing OA and promoted the expression of anti-inflammatory factors. They caused the enrichment of the M2 macrophages population	[193]
MSC (Human)	Exosomes derived from MSC overexpressing lncRNA malat-1, inhibited the apoptosis and inflammatory markers related to OA in treated chondrocytes better than exosomes from non-modified MSC. They also increased the proliferation and migration of chondrocytes	Rat; 6 weeks; No adverse effect was observed. The malat-1 exosomes had better protective properties and less degraded ECM in OA-induced damages of the rat knee compared to exosomes from non-modified MSC	[194]
BM-MSC (Rat)	Exosomes enriched with miRNA-127-3p were responsible for diminished damage and apoptosis of chondrocytes exposed to IL-1β by targeting the Wnt/β-catenin pathway through downregulation of CDH11	N.D	[195]
BM-MSC (Human)	Exosomal miR-125a-5p significantly impacts chondrocytes migration, proliferation and ECM production through regulation of E2F2 in the traumatic OA	N.D	[184]
MSC (Human)	Exosomes containing lncRNA-KLF3-AS1 have been responsible for regulating GIT1 expression by binding to miR-206. Consequently, its presence led to increased proliferation, maintaining of chondrogenic phenotype and inhibited apoptosis induced by IL-1β	N.D	[182]
SM-MSC (Human)	Isolated exosomes from overexpressing miR-31 SM-MSCs promoted the proliferation and migration of chondrocytes through reduced expression of KDMA2	Mice; 8 weeks; No adverse effect was observed. The exosomes enriched with miR-31 and non-modified one has shown similar protection against OA with mildly reduced inflammation markers	[196]
SM-MSC (Human)	The SMSC containing WNT5a/b and circRNA3503 has promoted migration and proliferation of chondrocytes without loss of ECM proteins. They have shown alone and slowly released in PDLLA-PEG-PDDLA hydrogel the chondroprotective properties against IL-1β induced OA	Rat; 12 weeks; No adverse effect was noticed. The combination of hydrogel with modified exosomes has shown the best protective effect against OA	[188]
UC-MSC (Human)	Mechanical stimulation of UC-MSC enriched exosomal cargo with lncRNA H19, positively affecting chondrocytes viability, proliferation, migration and increased production of ECM	Rat; 4 and 8 weeks; No side effects were notified. The exosomes derived from mechanically stimulated cells had improved the regeneration of damaged cartilage better than the control groups and exosomes with reduced expression of lncRNA H19	[197]
BM-MSC (Human)	miR-92a-3p transported in exosomes promoted proliferation, enhanced expression of matrix-related genes downregulating WNT5a. That miR also enhanced the chondrogenic differentiation of MSC	Mice; 4 weeks; Lack of adverse effect was observed The damage of cartilage was partially inhibited with maintained ECM in the group of exosomes isolated from MSC overexpressing miR-92a-3p	[198]
UC-MSC (Human)	miR-1208 transported in UC-MSC exosomes is responsible for chondrocytes enhanced proliferation, migration and inhibition of apoptosis through downregulation of METTL3. The degradation of ECM was inhibited by the modification of macrophages' inflammation response by modification of NLRP3 activity	Mice; 6 weeks; No adverse effect was observed. The injection of exosomes containing miR-1208 prevented the degradation of ECM and delayed the progression of OA	[187]
BM-MSC (Human)	Exosomes had a stimulatory effect on viability, proliferation, migration and maintenance of the stable chondrogenic phenotype after IL-1β OA induction. Their caused decreased phosphorylation of proinflammatory pathways Erk1/2, PI3K/Akt p38, TAK1 and NF-κB	N.D	[199]
BM-MSC (Human)	After exposure to IL-1β, BM-MSC has secreted exosomes significantly enriched with miR-147b compared to non-treated cells. Consequently, the inflammation of synovial cells was more efficiently diminished by modified EXO. The mechanism involved inhibition of NF-κB pathway	N.D	[181]
UC-MSC (Human)	Exosomes are responsible for M2 macrophage polarisation, enabling them to protect chondrocytes from their apoptosis and decreasing the severity of IL-β induced OA. Their immunomodulatory effect was better after stimuli with exosomes vs PRP. The enriched population of several miRNA in UC-MSC exosomes was notified (miR-122-5p, miR-486-5p, miR-let-7a-5p and miR-100-5p)	Rat; 4 and 8 weeks; No adverse effect was observed. Exosomes from UC-MSC have improved knee cartilage restoration and protection better than PRP injections. Polarised and infiltrated M2 macrophages caused the diminished progression of OA	[200]
AD-MSC (Mouse)	Exosomes isolated from AD-MSC overexpressing miR-338-3p, which targets the RUNX2 gene, has promoted the increased proliferation, viability and reduced degradation of ECM of chondrocytes in IL-1β induced OA in comparison with non-modified exosomes	N.D	[180]
BM-MSC (Human)	Exosomes enriched with miR-136-5p have limited the degradation of ECM specific for hyaline chondrocytes and promoted their migration by targeting ELF3, a transcript factor elevated in traumatic OA	Mice; 1 h; No adverse effect was observed. The injection of modified exosomes protected cartilage from severe damage caused by trauma-induced OA	[201]
AD-MSC (Human)	Exosomes positively impacted chondrocytes and synoviocytes exposed to IL-1β by diminishing proteins regulating the NF-κB signalling pathway. As a result, the expression of the proinflammatory and catabolic enzymes was downregulated	N.D	[202]
SMSC (Human)	EVs isolated from SMSC pretreated with LPS has shown better protective properties in chondrocytes exposed to IL-β. They increased migration, motility, proliferation and viability. The exosomal let-7b was responsible for that outcome by targeting ADAMTS5	Mice; 6 weeks; No adverse effect was observed. The EVs from LPS-treated SMSCs protected cartilage from ECM degradation better than EVs isolated from non-modified cells	[203]
UD-MSC (Human)	EVs isolated from hypoxic UD-MSC increased the migration and proliferation of chondrocytes. Their effect was provided by upregulated miR-26a-5p, which modified the expression of PTEN	N.D	[204]
BM-MSC (Human)	Exosomes protected the chondrocytes from TNF-α induced inflammation by inhibition of NF-κB signalling pathway. They enhanced chondrocyte proliferation and production of ECM	N.D	[205]
BM-MSC (Human)	Isolated exosomes have shown the protective effect against IL-1β induced OA by inhibiting apoptosis through regulation of lncRNA LYRM4-AS1/GRPR/miR-6515-5p axis	N.D	[206]
ESC-MSC (Human)	Exosomes isolated from differentiated hESC into MSC has shown their involvement in the protection of chondrocytes exposed to IL-1β by promoting ECM production and reducing catabolic activity	Mice; 8 weeks. No adverse effect was observed. The injected exosomes have shown to decelerate the progression of OA and promote ECM production	[207]
MSC (Human)	EVs containing circRNA HIPK3 are responsible for increased proliferation, migration, expression of chondrogenic markers and viability of chondrocytes. They protect them from OA progression after IL-1β exposure. The mechanism of EVs is related to the regulatory network between circRNA HIPK3/miR-124-3p/MYH9	Mice; N.D.; The injected EVs isolated from circHIPK3 overexpressing and non-modified MSCs have shown protective properties against the OA development with maintenance expression markers characteristic of hyaline cartilage	[185]

AD-MSCs adipose tissue-derived MSCs, BM-MSCs bone marrow MSCs, CDH11 Cadherin 11, circRNA circular RNA, E2F2 E2F transcription factor 2, ECM extracellular matrix, ELF3 E74 Like ETS Transcription Factor 3, ERK1/2 extracellular signal‑regulated protein kinase, GIT1, ARF GTPase-Activating Protein, GRPR Gastrin Releasing Peptide Receptor, HIPK3 homeodomain interacting protein kinase 3, IL-1β interleukin 1β, KDMA2 Lysine Demethylase 2A, lncKLF3-AS1 KLF Transcription Factor 3 Antisense RNA 1, lncRNA long-non coding RNA, LYRM4 LYR Motif-Containing Protein 4, METTL3 Methyltransferase 3, miRNA micro RNA, MSC mesenchymal stromal cell, MYH9 myosin heavy chain 9, N.D. No data, NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells, NLRP3 NLR family pyrin domain containing 3, OA osteoarthritis, PDDLA-PEG-PDDLA Poly(D,L-lactide)-block-poly(ethylene glycol)-block-poly(D,L-lactide), PHLDA pleckstrin homology‐like domain family 2, PI3K/Akt phosphatidylinositol 3-kinase/Protein Kinase B, PRP platelet-rich plasma, PTEN phosphatase and tensin homolog deleted on chromosome ten, RUNX2 RUNX family transcription factor 2, SDC1 Syndecan 1, SM-MSCs synovial membrane MSCs, TAK1 Transforming Growth Factor-Beta-Activated Kinase 1, TNFα tumour necrosis factor α, UC-MSCs umbilical cord MSCs, WNT/β-catenin Wingless and Int-1/Beta-catenin signalling pathway, WNT5a/b Wnt Family Member 5A/5B