Activation of the SOX-5, SOX-6, and SOX-9 trio of transcription factors using a gene-activated scaffold stimulates mesenchymal stromal cell chondrogenesis and inhibits endochondral ossification
Current treatments for articular cartilage defects relieve symptoms but often only delay cartilage degeneration. Mesenchymal stem cells (MSCs) have shown chondrogenic potential but tend to undergo endochondral ossification when implanted in vivo. Harnessing factors governing joint development to functionalize biomaterial scaffolds, termed developmental engineering, might allow to prime host MSCs to regenerate mature articular cartilage in situ without requiring cell isolation or ex vivo expansion. Therefore, the aim of this study is to develop a gene-activated scaffold capable of delivering developmental cues to host MSCs, thus priming MSCs for articular cartilage differentiation and inhibiting endochondral ossification. It is shown that delivery of the SOX-Trio induced MSCs to over-express COL2A1 and ACAN and deposit a sulfated and collagen type II rich extracellular matrix while hypertrophic gene expression and collagen type X deposition is inhibited. When cell-free SOX-Trio-activated scaffolds are implanted ectopically in vivo, they induced spontaneous chondrogenesis without evidence of hypertrophy. MSCs pre-cultured on SOX-Trio-activated scaffolds prior to implantation differentiate into phenotypically stable chondrocytes as evidenced by a lack of collagen X expression or vascular invasion. This SOX-trio-activated scaffold represents a potent, single treatment, developmentally inspired strategy to prime MSCs in situ for articular cartilage defect repair.
Science Foundation Ireland (SFI), Ireland, through the Advanced Materials and Bioengineering Research (AMBER) Centre (SFI/12/RC/2278)
European Research Council under the European Community’s Horizon 2020 research and innovation programme under ERC grant agreement n° 788753 (ReCaP)
CommentsThis is the peer reviewed version of the following article: Raftery RM, Gonzalez Vazquez AG, Chen G, O'Brien FJ. Activation of the SOX-5, SOX-6, and SOX-9 Trio of Transcription Factors Using a Gene-Activated Scaffold Stimulates Mesenchymal Stromal Cell Chondrogenesis and Inhibits Endochondral Ossification. Adv Healthc Mater. 2020;9(10):e1901827., which has been published in final form at https://doi.org/10.1002/adhm.201901827. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.
Published CitationRaftery RM, Gonzalez Vazquez AG, Chen G, O'Brien FJ. Activation of the SOX-5, SOX-6, and SOX-9 trio of transcription factors using a gene-activated scaffold stimulates mesenchymal stromal cell chondrogenesis and inhibits endochondral ossification. Adv Healthc Mater. 2020;9(10):e1901827.
Publication Date24 April 2020
- Tissue Engineering Research Group (TERG)
- Amber (Advanced Material & Bioengineering Research) Centre
- Anatomy and Regenerative Medicine
- Physiology and Medical Physics
- Chemistry and Pharmaceutical Sciences
- Biomaterials and Regenerative Medicine
- Immunity, Infection and Inflammation
- Accepted Version (Postprint)