Mechanical load modulates chondrogenesis of human mesenchymal stem cells through the TGF‐β pathway

Abstract

This study investigated the effect of mechanical load on human mesenchymal stem cell (hMSC) differentiation under different exogenous transforming growth factor-β1 (TGF-β1) concentrations (0, 1 or 10 ng/ml).The role of the TGF-β signalling pathway in this process was also studied. Human MSCs were seeded into fibrin-biodegradable polyurethane scaffolds at a cell density of 5 × 106 cells per scaffold and stimulated using our bioreactor. One hour of surface motion superimposed on cyclic compression was applied once a day over seven consecutive days. Scaffolds were analysed for gene expression, DNA content and glycosaminoglycan amount. Addition of TGF-β1 in the culture medium was sufficient to induce chondrogenesis of hMSCs. Depending on the TGF-β1 concentration of the culture medium, mechanical load stimulated chondrogenesis of hMSCs compared to the unloaded scaffolds, with a much stronger effect on gene expression at lower TGF-β1 concentrations. With TGF-β1 absent in the culture medium, mechanical load stimulated gene transcripts and protein synthesis of TGF-β1 and TGF-β3. TGF-β type I receptor inhibitor LY364947 blocked the up-regulation on TGF-β1 and TGF-β3 production stimulated by mechanical load, and also blocked the chondrogenesis of hMSCs. Taken together, these findings suggest that mechanical load promotes chondrogenesis of hMSCs through TGF-β pathway by up-regulating TGF-β gene expression and protein synthesis.

Expansion in the presence of FGF-2 enhances the functional development of cartilaginous tissues engineered using infrapatellar fat pad derived MSCs

“…Therefore identifying expansion and differentiation conditions that promote a more chondrogenic phenotype is critical to enhancing their utility for cartilage tissue engineering applications. Differentiation conditions that have been shown to promote the chondrogenic potential of MSCs include a low oxygen (5%) microenvironment (Khan et al 2007;Buckley et al 2010a;Meyer et al 2010), various combinations of growth factors (Mastrogiacomo et al 2001;Sakimura et al 2006;Hennig et al 2007;Diekman et al 2010;Buxton et al 2011) and mechanical signals (Huang et al 2005;Mauck et al 2007;Huang et al 2010a;Huang et al 2010b;Kelly and Jacobs 2010;Li et al 2010; Thorpe et al 2010;Haugh et al 2011). …”

Ultrasound Effect on Gene Expression of Sex Determining Region Y-box 9 (SOX9) and Transforming Growth Factor β Isoforms in Adipose Stem Cells

“…The results of pervious study showed that compressive loading increased in TGF-β1 gene expression [12]. In the culture medium without TGF-β1, mechanical loading stimulated gene and protein expression of TGF-β1 and TGF-β3 [22]. TGF-β signaling may magnify the sensitivity of cells to mechanical forces by increasing of transcriptional factors such as SOX9 as a master gene of chondrgenesis.…”

Roles of type VI collagen and decorin in human mesenchymal stem cell biophysics during chondrogenic differentiation

“…ColVI trimer formation occurs intracellularly before being secreted into the PCM for microfibrillar networking via BGN or DCN (Bruns et al, 1986;Engvall et al, 1986;Wiberg et al, 2003;DiMicco et al, 2007) and is maintained at low levels of transcription (DiMicco et al, 2007;Vigfusdottir et al, 2010). DCN is a ubiquitous proteoglycan, consisting of a core protein with a single chondroitin sulphate (Li et al, 2010) or dermatan sulphate (Knudson et al, 1996) side chain. It interacts with multiple collagens to create functional bridges between the PCM and surrounding ECM, and is involved in controlling fibrillogenesis and growth factor bioavailability (Chen et al, 2009;Lewis et al, 2010;Zhang et al, 2011).…”

“…These growth factors cause PCM accumulation during chondrogenesis in a concentration dependent manner (Mehlhorn et al, 2006;Lee et al, 2010;Li et al, 2010). Sequestration of growth factors immediately surrounding the cell allows for specifically stimulated responses, being released mechanically or enzymatically from their associated PG for presentation to the cell membrane.…”