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Table 1 Pro-tenogenic growth factors

From: Boosting tendon repair: interplay of cells, growth factors and scaffold-free and gel-based carriers

Growth factor Cell source Cell proliferation and differentiation Gene expression ECM production Study type and animal model Reference
TGF-β1 (5 ng/ml) & TNF-α (0.0025 ng/ml) Rat TSPCs TGF- β1 or TNF-α alone did not enhance the proliferation and differentiation of TSPCs, but in combination or upon sequential application of these two signalling molecules facilitated their proliferation and differentiation. Furthermore the combined application of TGF-β1 in addition to TNF-α could resque the growth inhibition induced by TNF-a. TGF-β signalling pathway significantly activated the expression levels of certain members of Smad family. In addition, the expression of tenogenic/osteogenic markers was also significantly increased under the combined treatment of TGF-β1 and TNF-α Not studied In vitro Han et al. 2017
TGF-β3 (20 ng/ml) Equine embryo-derived SCs (ESCs) TGF- β3 can promote tenocyte differentiation of ESCs in 2D monolayer cultures. The ESCs did not develop areas of cartilage or bone tissue, and it was concluded that the differentiation response is specific to tenogenic lineage. Express tendon-associated genes were detected. The presence of TGF-β3 induced the expression of late-onset tenogenic markers, namely Tnmd and thrombospondin 4, which were not detected in untreated cultures over the early time course. ESCs treated with TGF- β3 organized a tendon-like matrix without evidence of bone or cartilage formation. In vitro Barsby et al. 2014
GDF-5 (BMP-14) (100 ng/ml) Rat ADSCs GDF-5 led to increased ADSCs proliferation in a dose- and time-dependent manner. In the time kinetic studies, the proliferation rate of ADSCs treated with 100 ng/ml of GDF-5 increased significantly at all time points. ADSCs demonstrated enhanced ECM production and tenogenic marker gene expression that was increased with longer exposure. GDF-5 also altered the expression of ECM remodelling genes, with no specific dose and time trends observed. The two key tenogenic markers Scx and Tnmd showed clear upregulation with 100 ng/ml GDF-5. Col I expression increased in cells treated with 100 ng/ml of GDF-5 compared to control. No significant difference was found for Col III. In vitro Park et al. 2010
GDF-5 (BMP-14) (0,5,25,50,100 ng/ml) Human BMSCs GDF-5 did not alter the proliferation rate significantly. The use of GDF-5 induced tenogenic differentiation of this cell type without effect on cell doubling. It appears that GDF-5 at a concentration of 100 ng/ml provides the most optimal cell phenotypic response. The tenogenic marker genes Scx and TnC were upregulated at day 4 after GDF-5 treatment. However, at day 7, only Scx was persistently upregulated, the expression of Runx2 and Sox9 genes were significantly downregulated. In conclusion this growth factor augmented the levels tenogenic marker genes and downregulated non-tenogenic marker gene expression. There were no significant differences in total collagen deposition between GDF-5 treated groups with different concentration levels. However to non-treated controls it augmented the total collagen amount. In vitro Tan et al. 2012
GDF-6 (BMP-13) (20 ng/ml) Rabbit BMSCs Cell proliferation was not studied. BMSCs differentiation into tenocytes was studied via gene expression. Expression of Scx and Tnmd was significantly higher under GDF-6 stimulation. Expression levels of TnC and Col I were higher in the control group but not significant. Histological evaluation of patellar tendon injury repair model suggested that transplantation of GDF-6-treated BMSCs improved tendon healing due to increase Col deposition and presence of more organized Col fibers. In vitro and in vivo rat model Jiang et al. 2016
GDF-7 (BMP-12) (50 ng/ml) Equine BMSCs; in vitro Cell proliferation was not studied Equine BMSCs defined by their expression of markers such as Oct4, Sox-2 and Nanog, have the capability to differentiate in tenocytes based on gene expression. Following exposure to BMP-12 the BMSCs upregulated the expression of two tendon-related markers, Tnmd and decorin. Not studied. In vitro Violini et al. 2009
BMP-12 (GDF-7) (50 or 100 ng/) Human ADSCs; in vitro There was no significant difference in proliferation rates of ADSCs after treatment with BMP-12, regardless of the applied doses. BMP-12 activated tenogenesis of ADSCs based on gene expression analyses. ADSCs treated with BMP-12 for 7 days resulted in up-regulation of tenogeinic genes, such as Scx and Mohawk but also Runx2, an osteogenic maker gene was elevated. BMP-12 treatment increased expression of Col I in ADSCs. In vitro Zarychta-Wisniewska et al. 2017
FGF-2 (5 μg/ml) Rat TSPCs In vivo evaluation at 2 and 4 weeks post-operation showed that the FGF-2-treated group has greater numbers of cells in the granulation tissue than the control group. At 6 weeks there was no significant difference in cell number between the FGF-2-treated group and the control group. The expression level of Scx increased in the FGF-2-treated group from 4 to 8 weeks, and Tnmd levels increased significantly from 4 to 12 weeks postoperatively. Sox9 expression was significantly up-regulated at 4 weeks in the FGF-2-treated group. Not studied. In vivo; rat rotator cuff healing model Tokunaga et al. 2015