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Osteogenic programming of human mesenchymal stem cells with highly efficient intracellular delivery of RUNX2

Thiagarajan, Lalitha; Abu-Awwad, Hosam Al-Deen M.; Dixon, James E.

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Lalitha Thiagarajan

Hosam Al-Deen M. Abu-Awwad

Associate Professor


Mesenchymal stem cells (MSCs) are being exploited in regenerative medicine due to their tri-lineage differentiation and immunomodulation activity. Currently, there are two major challenges when directing the differentiation of MSCs for therapeutic applications. First, chemical and growth factor strategies to direct osteogenesis in vivo lack specificity for targeted delivery with desired effects. Second, MSC differentiation by gene therapy is difficult as transfection with existing approaches is clinically impractical (viral transfection) or have low efficacy (lipid-mediated transfection). These challenges can be avoided by directly delivering nonvirally derived recombinant protein transcription factors with the glycosaminoglycan-binding enhanced transduction (GET) delivery system (P21 and 8R peptides). We used the osteogenic master regulator, RUNX2 as a programming factor due to its stage-specific role in osteochondral differentiation pathways. Herein, we engineered GET-fusion proteins and compared sequential osteogenic changes in MSCs, induced by exposure to GET fusion proteins or conventional stimulation methods (dexamethasone and Bone morphogenetic protein 2). By assessing loss of stem cell-surface markers, upregulation of osteogenic genes and matrix mineralization, we demonstrate that GET-RUNX2 efficiently transduces MSCs and triggers osteogenesis by enhancing target gene expression directly. The high transduction efficiency of GET system holds great promise for stem cell therapies by allowing reproducible transcriptional control in stem cells, potentially bypassing problems observed with high-concentration growth-factor or pleiotropic steroid therapies.

Journal Article Type Article
Acceptance Date Sep 5, 2017
Online Publication Date Oct 31, 2017
Publication Date Nov 26, 2017
Deposit Date Nov 6, 2017
Publicly Available Date Nov 6, 2017
Journal Stem Cells Translational Medicine
Print ISSN 2157-6564
Electronic ISSN 2157-6580
Publisher Wiley Open Access
Peer Reviewed Peer Reviewed
Volume 6
Issue 12
Keywords Intracellular transduction; Glycosaminoglycan-binding enhanced transduction; Cell-penetrating peptide; Osteogenesis; RUNX2
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