Introduction
The biogenesis if MSCs-derived exosomes
The mechanism of action of MSCs and derivative exosomes
Inhibition of inflammation
Improving angiogenesis in bone-associated diseases
Enhancing target cell proliferation and differentiation
Inhibition of matrix-degrading enzymes
MSCs-derived exosomes isolation, characterization, and its limits
Exosomes isolation
UF | DUC | |
---|---|---|
Isolation process | Based on particle size and molecular weight cut-off (MWCO) of the utilized filter membrane | Physical features of exosomes, the exerted centrifugal force, and the viscosity of the solvent |
Purity | Low | High |
Specificity | Low | Intermediate |
Time of isolation process | High | High |
Complexity | Low | Intermediate |
Sample volume | High | Intermediate |
Cost | Intermediate | Low |
Functionality of exosomes | Intermediate | Intermediate |
Exosomes yield | High | Intermediate |
Scalability | High | Intermediate |
Efficiency | Intermediate | Intermediate |
Characterizing
Improving exosomes’ yields
MSCs-exosomes in joint-associated musculoskeletal diseases
Osteoarthritis
Rheumatoid arthritis
Diseases | Cell source | Administration route | Model | Main results (ref) |
---|---|---|---|---|
OA | BM | – | In vitro (Chondrocyte) | Enhancement of the proliferation and suppression of the apoptosis of chondrocytes by targeting the lncRNA-KLF3-AS1/miR-206/GIT1 signaling pathway [81] |
RA | BM | Intravenous | DBA/1 mice | Down-regulation of the inflammation by suppression of T lymphocyte proliferation [206] |
OA | IPFP | Intra-articular | C57BL/6 J mice | Supporting the articular cartilage and alleviation of the gait dysfunctions by down-regulation of the mTOR [141] |
RA | BM | Intraperitoneal | DBA/1 mice | Attenuation of the joint deterioration by suppression of the synoviocyte hyperplasia and angiogenesis by exosomes derived from miR-150 overexpressing MSCs [207] |
OA | BM | Intra-articular | Mice | Reducing diseases severity by targeting the miR-124/NF-kB and miR-143/ROCK1/TLR9 axis [208] |
OA | BM | Intravenous | C57B/L10 mice | Improving the chondrogenesis and inhibition of the cartilage destruction through targeting WNT5A by exosomes derived from miR-92a-3p-overexpressing MSCs [209] |
RA | iPSCs SM | Intra-articular | C57B/L10 mice | The iPSCs-MSC-derived exosomes has a better therapeutic effect than the SM-MSC-derived exosomes [210] |
OA | BM | Intra-articular | C57BL/6 mice | Eliciting the chondroprotective and anti-inflammatory activities [99] |
OA | ESC | Intra-articular | C57BL/6 J mice | Reducing diseases severity by normalizing the synthesis and destruction of cartilage ECM [135] |
RA | BM | – | In vitro (FLS) | Suppression of the growth and motility of FLS and eliciting their apoptosis [211] |
RA | BM | Intra-articular | Rat | Amelioration of the joint damage and restoration of the trabecular bone volume fraction, trabecular number as well as connectivity density [212] |
OA | BM AT | Intra-articular | BALB/c mice | BM-MSCs-derived exosomes are a better therapeutic option than AT-MSCs-derived exosomes [213] |
RA | Gingival | Intravenous | DBA/1 J mice | Reducing IL-17A and increasing IL-10 levels in cartilage tissue in association with a drop in occurrences and bone erosion of arthritis [214] |
RA | BM | – | In vitro (FLS) | Down-regulation of the FLS activation through targeting the miR-143-3p/TNFAIP3/NF-κB pathway [215] |
RA | BM | Intravenous | C57BL/6 male mice | Inhibition of the diseases progress by exosomal miR-320a transfer [216] |
RA | BM | Intra-articular | SD rat | Improving the exosomes chondroprotective effect by kartogenin priming [217] |
OA | BM | Intra-articular | SD rat | Reducing diseases severity through inhibiting syndecan-1 by exosomal miR-9-5p [218] |
RA | BM | Intra-articular | Lewis rats | Inhibition of the proliferation, migration, and inflammatory response prompted by FLS by exosomal circFBXW7 [219] |
OA | BM | Intra-articular | SD rat | Increasing the cartilage repair and chondrocyte proliferation by exosomal KLF3-AS1 [20] |
OA | BM | Intra-articular | C57BL/6 mice | Eliciting the chondrocyte migration in vitro and attenuating the cartilage degeneration in vivo by exosomal miR-136-5p [220] |
OA | BM | – | Wistar rats | Reducing diseases severity by targeting PTGS2 [221] |
MSCs-exosomes in bone-associated musculoskeletal diseases
Osteoporosis
Osteonecrosis
Traumatic fractures
Diseases | Cell source | Administration route | Model | Main results (Ref) |
---|---|---|---|---|
Bone fracture | UC | Near the fracture | Mice | Stimulation of the bone fracture healing by the transmission of miR-126 released from hypoxic MSCs-derived exosomes [23] |
Bone fracture | BM | Into the fracture | C57BL/6 mice | Acceleration of fracture healing [222] |
Osteoporosis | BM | – | In vitro (hFOB 1.19 cells) | Stimulating the osteoblast proliferation by activating the MAPK pathway [22] |
ONFH | BM | – | Rabbit | Induction of the proliferation of osteoblasts by miR-122-5p-enriched BM-MSC-derived exosomes [189] |
Radiation-induced bone loss | BM | Intravenous | SD rat | Alleviation of the radiation-induced bone loss [223] |
Osteoporosis | iPSCs | Intra-articular | SD rat | Promotion of the bone regeneration by triggering angiogenesis and osteogenesis [181] |
ONFH | iPSCs | Intravenous | SD rat | Amelioration of the glucocorticoid-induced ONFH by miR-135b-enriched exosomes [224] |
Osteoporosis | AT | Intra-articular | SD rat | Inhibition of the NLRP3 inflammasome induction in osteoclasts and thereby attenuation of the bone loss [171] |
Osteoporosis | BM | Intravenous | SD rat | Improving the new bone formation [225] |
Bone fracture | BM | Into the fracture | C57BL/6 mice | Up-regulation of the Wnt/β-catenin pathway in fracture mice as well as osteoblasts [226] |
Bone fracture | BM | Near the fracture | SD rat | Inducing the osteogenesis and bone fracture healing by regulation of the Smad5 [227] |
ONFH | BM | Intravenous | SD rat | Promoting angiogenesis by hypoxic MSCs-derived exosomes [228] |
Osteoporosis | BM | – | In vitro (hFOB 1.19 cells) | Amelioration of the osteoporosis by induction of the osteoblast proliferation and abrogating cell apoptosis [21] |
ONFH | UC | Intravenous | SD rat | Promoting the osteogenesis by the activating miR-365a-5p/Hippo signaling axis [229] |
Bone fracture | BM | Near the fracture | C57BL/6 J mice | Induction of the fracture healing by miR-25-enriched BM-MSC-exosomes [230] |
Osteoporosis | AT | – | SD rat | Eliciting the anti-inflammation effect on osteoclasts by miR-146a-enriched AT-MSCs-derived exosomes [172] |
Conclusion and future directions
Condition | Dose | Route | Participant number | Phase | Location | Status | NCT number |
---|---|---|---|---|---|---|---|
COVID-19 | – | Intravenous | 60 | 2/3 | Indonesia | Recruiting | NCT05216562 |
Osteoarthritis | 3–5 × 1011 particles/dose | Intra-articular | 10 | 1 | Chile | Not yet recruiting | NCT05060107 |
Macular Holes | 20–50 μg | Intravitreal | 44 | Early1 | China | Active, not recruiting | NCT03437759 |
AD | 5–20 μg | Intranasal | 9 | 1/2 | China | Recruiting | NCT04388982 |
Cutaneous Ulcer | – | Local | 30 | NA | Spain | Not yet recruiting | NCT05243368 |
DEB | – | Local | 10 | 1/2 | – | Not yet recruiting | NCT04173650 |
COVID-19 | 2–8 × 109 particles/dose | Intravenous | 55 | 1/2 | USA | Not yet recruiting | NCT04798716 |
COVID-19 | 0.5–2 × 1010 particles/dose | Inhalation | 90 | 2 | Russian | Enrolling by invitation | NCT04602442 |
COVID-19 | 0.5–2 × 1010 particles/dose | Inhalation | 30 | 1/2 | Russian | Completed | NCT04491240 |