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Title: 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
Author(s): Meng, Weikun
Rey-Rico, Ana
Claudel, Mickaël
Schmitt, Gertrud
Speciher-Mentges, Susanne
Pons, Françoise
Lebeau, Luc
Venkatesan, Jagadeesh K.
Madry, Magali
Language: English
Title: Nanomaterials
Volume: 10
Issue: 5
Publisher/Platform: MDPI
Year of Publication: 2020
Free key words: bone marrow-derived mesenchymal stromal cells
rAAV vectors
carbon dots
SOX9
TGF-β
cartilage repair
DDC notations: 610 Medicine and health
Publikation type: Journal Article
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.
DOI of the first publication: 10.3390/nano10050855
Link to this record: urn:nbn:de:bsz:291--ds-310515
hdl:20.500.11880/29235
ISSN: 2079-4991
Date of registration: 9-Jun-2020
Faculty: M - Medizinische Fakultät
Department: M - Orthopädie
Professorship: M - Prof. Dr. Henning Madry
Collections:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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