Mesenchymal Stem Cell-Derived Extracellular Vesicles: Seeking into Cell-Free Therapies for Bone-Affected Lysosomal Storage Disorders
Abstract
1. Introduction
LSD | Enzyme Deficiency | Accumulated Substrate | Symptoms | Ref. |
---|---|---|---|---|
GD I/III | GBA | GlcCer | osteopenia, sclerotic lesions, osteonecrosis, decrease mineralization. | [30] |
ML II/III | GlcNAc-1-fosfo. | Mucolipids | dystosis multiplex, osteopenia, osteodystrophy, kyphosis, coarse facies. | [31] |
MPS I | IDUA | DS/HS | dysostosis multiplex, kyphosis, coarse facies, short stature, hip dysplasia, pectus excavatum | [32] |
MPS II | IDS | DS/HS | dysostosis multiplex, coarse facies, claw hands, kyphosis/gibbus, scoliosis, short stature, foot deformity. | [33] |
MPS IIIA | SGSH | HS | Joint stiffness, contractures, dysostosis multiplex, scoliosis and hip dysplasia. | [34] |
MPS IVA | GALNS | KS/C6S | dysostosis multiplex, pectus carinatum, gibbus, kyphosis, scoliosis, genu valgum, short stature, hypermobile joints, coarse facies | [35] |
MPS VI | ARSB | DS | dysostosis multiplex, genu valgum, coarse facies, short stature | [36] |
MPS VII | GUSB | HS, DS, and CS | dysostosis multiplex, coarse facies, joint contractures, genu valgum, short stature. | [37] |
NPD-B | ASMase | Sphingo. | delayed skeletal maturation, osteopenia, osteoporosis. | [38] |
Mann. | α-Mannosidase | MCO | dysostosis multiple, coarse facies. | [39,40] |
Galacto. | Cathepsin A | Sial-Oligo | dysostosis multiple, coarse facial features. | [41] |
Sial-II | Neuraminidase | Sial-Oligo | coarse facies, dysostosis multiplex, kyphoscoliosis. | [42] |
Aspartyl. | AGA | GlcNAc-Asn | osteoporosis, hypermobile joints, delayed skeletal maturation. | [43,44] |
2. The Bone: Structure and Microenvironment
3. MSCs and MSC-EVs
3.1. MSC Secretome
3.1.1. Exosomes
3.1.2. Microvesicles
3.1.3. Apoptotic Bodies
4. MSC-EVs and Bone-Affected LSDs
4.1. MSC-EVs and ERT
4.2. MSC-EVs and GT
5. MSC-EVs: A Perspective from Bone-Affected Non-LSDs
5.1. MSC-EVs’ Engineering—Therapeutic Molecules
5.2. MSC-EVs’ Engineering—Targeting Bone/Cartilage
6. Future Perspectives
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
AD-MSC | Adipose-derived mesenchymal stem cells |
BM | Bone marrow |
BM-MSCs | Bone marrow-derived mesenchymal stem cells |
DP-MSCs | Dental pup-derived mesenchymal stem cells |
ERT | Enzyme replacement therapy |
GT | Gene therapy |
MSCs | Mesenchymal stem cells |
P-MSCs | Placenta-derived mesenchymal stem cells |
SM-MSCs | Skeletal muscle-derived mesenchymal stem cells |
UC-MSCs | Umbilical cord-derived mesenchymal stem cells |
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Trial ID | Status | Dis. | Source | Phase | DM | Dose Par/Dose | Outcomes Measured | Main Findings |
---|---|---|---|---|---|---|---|---|
NCT06713902 | Recruiting | OA/KJ | AD | Obs. | NA | NA | Encapsulation of AD-MSCs into PRP-derived fibrin gel | NP |
NCT05060107 | Completed | OA/KJ | NA | I | IA | Single 3–5 × 1011 | Safety, pain, and disability reduction | MSC-EVs were safe and reduced pain while improving function |
NCT06431152 | Recruiting | OA/KJ | UC | I | IA | Single L: 2 × 109 M: 6 × 109 H: 2 × 1010 | Safety, pain, and disability reduction | NP |
NCT06466850 | Recruiting | OA/KJ | NA | I | IA | * Double | Safety, pain, and disability reduction | NP |
NCT06463132 | Not yet recruiting | OA/KJ | PL | I | IA | ** Single | Safety, clinical improvements after 12 months | NP |
NCT06713902 | Recruiting | OA/KJ | AD | Obs. | NA | NA | Encapsulation of AD-MSCs into PRP-derived fibrin gel | NP |
NCT06688318 | Active, not recruiting | OA/KJ | UC | I/II | IA | ** Single | Safety, pain reduction. | NP |
NCT04998058 | Not yet recruiting | EM | AD | I/II | MSL | ** Single | Bone density and quantity | NP |
NCT05261360 | Unknown | DMI | SF | II | IA | *** 1 × 106 | Safety, pain reduction, cytokine profile | NP |
Drawback | Description | Ref. |
---|---|---|
Cargo heterogeneity | Cargo is greatly influenced by MSCs’ source, passage, and culture conditions. | [103,151] |
Limited cargo loading | Low loading efficiency is often observed, mainly when passive (incubation/shaking) methods are used. | [152] |
Non-standardized isolation protocols | Ultracentrifugation, density gradient centrifugation, size-exclusion chromatography, ultrafiltration, precipitation, and immunocapture yield different purities. Characterization procedures upon isolation are inconsistent, thereby limiting biochemical composition identification. | [153,154] |
Leak of biodistribution assays | Although some studies use fluorescence-based MSC-EVs, this is not the case for all studies. It is also unclear how MSC-EVs are cleared. | [155,156] |
Potential immunogenicity | Engineered MSC-EVs can increase the risk of immune response activation, thus exacerbating disease pathology. | [57,157] |
Scalability | Large-scale production is still limited. | [158] |
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Leal, A.F.; Pachajoa, H.; Tomatsu, S. Mesenchymal Stem Cell-Derived Extracellular Vesicles: Seeking into Cell-Free Therapies for Bone-Affected Lysosomal Storage Disorders. Int. J. Mol. Sci. 2025, 26, 6448. https://doi.org/10.3390/ijms26136448
Leal AF, Pachajoa H, Tomatsu S. Mesenchymal Stem Cell-Derived Extracellular Vesicles: Seeking into Cell-Free Therapies for Bone-Affected Lysosomal Storage Disorders. International Journal of Molecular Sciences. 2025; 26(13):6448. https://doi.org/10.3390/ijms26136448
Chicago/Turabian StyleLeal, Andrés Felipe, Harry Pachajoa, and Shunji Tomatsu. 2025. "Mesenchymal Stem Cell-Derived Extracellular Vesicles: Seeking into Cell-Free Therapies for Bone-Affected Lysosomal Storage Disorders" International Journal of Molecular Sciences 26, no. 13: 6448. https://doi.org/10.3390/ijms26136448
APA StyleLeal, A. F., Pachajoa, H., & Tomatsu, S. (2025). Mesenchymal Stem Cell-Derived Extracellular Vesicles: Seeking into Cell-Free Therapies for Bone-Affected Lysosomal Storage Disorders. International Journal of Molecular Sciences, 26(13), 6448. https://doi.org/10.3390/ijms26136448