rAAV-Mediated Overexpression of SOX9 and TGF-β via Carbon Dot-Guided Vector Delivery Enhances the Biological Activities in Human Bone Marrow-Derived Mesenchymal Stromal Cells
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rAAV-Mediated Overexpression of SOX9 and TGF-β via Carbon Dot-Guided Vector Delivery Enhances the Biological Activities in Human Bone Marrow-Derived Mesenchymal Stromal CellsAutor(es)
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2020-04-28Cita bibliográfica
Meng, W.; Rey-Rico, A.; Claudel, M.; Schmitt, G.; Speicher-Mentges, S.; Pons, F.; Lebeau, L.; Venkatesan, J.K.; Cucchiarini, M. rAAV-Mediated Overexpression of SOX9 and TGF-β via Carbon Dot-Guided Vector Delivery Enhances the Biological Activities in Human Bone Marrow-Derived Mesenchymal Stromal Cells. Nanomaterials 2020, 10, 855. https://doi.org/10.3390/nano10050855
Resumo
[Abstract]
Scaffold-assisted gene therapy is a highly promising tool to treat articular cartilage lesions
upon direct delivery of chondrogenic candidate sequences. The goal of this study was to examine
the feasibility and benefits of providing highly chondroreparative agents, the cartilage-specific
sex-determining region Y-type high-mobility group 9 (SOX9) transcription factor or the transforming
growth factor beta (TGF-β), to human bone marrow-derived mesenchymal stromal cells (hMSCs)
via clinically adapted, independent recombinant adeno-associated virus (rAAV) vectors formulated
with carbon dots (CDs), a novel class of carbon-dominated nanomaterials. Effective complexation
and release of a reporter rAAV-lacZ vector was achieved using four different CDs elaborated from
1-citric acid and pentaethylenehexamine (CD-1); 2-citric acid, poly(ethylene glycol) monomethyl ether
(MW 550 Da), and N,N-dimethylethylenediamine (CD-2); 3-citric acid, branched poly(ethylenimine)
(MW 600 Da), and poly(ethylene glycol) monomethyl ether (MW 2 kDa) (CD-3); and 4-citric acid
and branched poly(ethylenimine) (MW 600 Da) (CD-4), allowing for the genetic modification of
hMSCs. Among the nanoparticles, CD-2 showed an optimal ability for rAAV delivery (up to 2.2-fold
increase in lacZ expression relative to free vector treatment with 100% cell viability for at least 10 days,
the longest time point examined). Administration of therapeutic (SOX9, TGF-β) rAAV vectors in
hMSCs via CD-2 led to the effective overexpression of each independent transgene, promoting
enhanced cell proliferation (TGF-β) and cartilage matrix deposition (glycosaminoglycans, type-II
collagen) for at least 21 days relative to control treatments (CD-2 lacking rAAV or associated to
rAAV-lacZ), while advantageously restricting undesirable type-I and -X collagen deposition. These
results reveal the potential of CD-guided rAAV gene administration in hMSCs as safe, non-invasive
systems for translational strategies to enhance cartilage repair.
Palabras chave
Bone marrow-derived mesenchymal stromal cells
rAAV vectors
Carbon dots
SOX9
TGF-β
Cartilage repair
rAAV vectors
Carbon dots
SOX9
TGF-β
Cartilage repair
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Atribución 4.0 Internacional (CC BY 4.0)
ISSN
2079-4991