Abstract
IntroductionAdvances in tendon engineering with mesenchymal stem cells (MSCs) are hindered by a need for cues to direct tenogenesis, and markers to assess tenogenic state. We examined the effects of factors involved in embryonic tendon development on adult MSCs, and compared MSC responses to that of embryonic tendon progenitor cells (TPCs), a model system of tenogenically differentiating cells.MethodsMurine MSCs and TPCs subjected to cyclic tensile loading, transforming growth factor-β2 (TGFβ2), and fibroblast growth factor-4 (FGF4) in vitro were assessed for proliferation and mRNA levels of scleraxis, TGFβ2, tenomodulin, collagen type I and elastin.ResultsBefore treatment, scleraxis and elastin levels in MSCs were lower than in TPCs, while other tendon markers expressed at similar levels in MSCs as TPCs. TGFβ2 alone and combined with loading were tenogenic based on increased scleraxis levels in both MSCs and TPCs. Loading alone had minimal effect. FGF4 downregulated tendon marker levels in MSCs but not in TPCs. Select tendon markers were not consistently upregulated with scleraxis, demonstrating the importance of characterizing a profile of markers.ConclusionsSimilar responses as TPCs to specific treatments suggest MSCs have tenogenic potential. Potentially shared mechanisms of cell function between MSCs and TPCs should be investigated in longer term studies.
Highlights
Advances in tendon engineering with mesenchymal stem cells (MSCs) are hindered by a need for cues to direct tenogenesis, and markers to assess tenogenic state
We identified transforming growth factor-β2 (TGFβ2), and combinations with fibroblast growth factor-(FGF)4 and loading, as potential in vitro tenogenic cues based on upregulation of Scx and modulation of other tendon markers in embryonic tendon progenitor cell (TPC), a model system of tenogenically differentiating cells [16]
Though we demonstrated fibroblast growth factor-4 (FGF4) and TGFβ2 influence embryonic TPC activity [16], the ability for these factors to tenogenically differentiate adult MSCs has not been reported
Summary
Advances in tendon engineering with mesenchymal stem cells (MSCs) are hindered by a need for cues to direct tenogenesis, and markers to assess tenogenic state. Due to the poor innate healing ability of tendons, surgical intervention is the primary approach to repairing injured tendon despite substantial failure rates, limited long-term function recovery, donor site morbidity with autologous transplants, and risk of infections [2,3] These significant drawbacks have motivated efforts to engineer replacement tendon with mesenchymal stem cells (MSCs) [4,5,6,7,8,9]. Adult MSCs are attractive for tissue regeneration strategies as they have the potential to differentiate toward various musculoskeletal lineages, including osteogenic, chondrogenic and adipogenic, in response to established lineage-specific cues Such cues have not been identified for tenogenic differentiation, and tissue engineering approaches to tenogenically differentiate MSCs have not achieved functional tendons [4,5,6,7,8,9,10,11,12,13,14]. Mice with a mutation in the Scx gene have defects in only a subset of tendons, indicating Scx is not a master
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