The regulation of human mesenchymal stem cell chondrogenesis through multiaxial load

Abstract

The repair of damaged articular cartilage remains a clinical problem despite the development of numerous surgical approaches for cartilage regeneration. As result new options for therapeutic approaches are being sought. One of the candidate cell types for cartilage repair are mesenchymal stem cells (MSCs). These cells can be isolated from a number of different tissues and have the ability to differentiate down several different mesenchymal lineages. This thesis focused on the use of MSCs for repairing damaged articular cartilage. Specifically I investigated the effect of producing regenerative medicine type constructs containing different populations of MSCs on the induction of chondrogenesis in response to mechanical load, compared the induction of chondrogenesis in MSCs through the application of exogenous TGF-β1 and multiaxial mechanical load and identified potentially novel markers of MSC chondrogenesis. The results presented in this thesis show that the induction of chondrogenesis in MSCs can be manipulated by producing constructs that contain separate populations of MSCs. The work demonstrated that seeding a layer of MSCs on the loaded surface of a fibrin-poly(ester-urethane) scaffold could increase the deposition of histologically detectable matrix. However, it was not possible to determine the mechanism responsible for this. Comparison of the secretomes of MSCs stimulated with TGF-β1 and mechanical load showed that these two forms of chondrogenic stimulation are not analogous and that a number of markers, including GRO and MMP13 may be useful for monitoring the progression of MSCs through chondrogenesis and hypertrophy. These data provide further insights into the effect of joint-like load on MSCs within tissue engineering/regenerative medicine style constructs, and the chondrogenic response of MSCs to this stimulation, which may prove to be useful for the development of constructs for cartilage repair