Abstract
Tendons, the collagenous musculoskeletal tissues that connect muscle to bone to enable movement, are frequently injured and heal poorly, leading to long-term loss of function (1). Mesenchymal stem cells (MSCs) are attractive for regenerative therapies to treat tendon injuries, as they are easily isolated and can differentiate into a variety of tissue lineages, including tendon. However, the limited understanding of the cell signaling pathways involved in tenogenesis (differentiation toward the tendon lineage) is a challenge for tissue engineering and regenerative approaches. Transforming growth factor (TGF)β2 induces tenogenesis in MSCs (2), and the TGFβ family appears to act via the Smad2/3 cell signaling pathway (3). However, we previously found that when Smad3 is blocked during TGFβ2-induced tenogenesis, cell morphology appears tenogenic, and levels of tenomodulin, a tenogenic marker protein, increased at earlier timepoints, compared to prior studies (3,4). A different study knocked down Smad4, a downstream effector of Smad2/3 signaling, in mouse embryonic fibroblasts, and found that TGFβ2-induced tenogenesis proceeded, but TGFβ2-induced cell proliferation was disrupted (5). Additionally, we found that inhibiting Akt signaling disrupts cell morphology during TGFβ2- induced tenogenesis (6), indicating some involvement of the Akt pathway in tenogenesis of MSCs. In a different study, Akt was activated by TGFβ1 treatment of MSCs (7). P70S6K is a downstream effector of Akt. Therefore, it is possible that P70S6K may be activated during TGFβ2-induced tenogenesis. However, P70S6K has not been investigated in the context of tenogenic differentiation, though it may contribute to proliferation and migration of other fibroblastic cells, such as lung fibroblasts (8). Taken together, these studies suggest additional signaling pathways may be involved in TGFβ2-induced tenogenesis of stem cells. We hypothesized that P70S6K would be activated during TGFβ2-induced tenogenesis independent of Smad3 signaling. To test this, we treated mouse MSCs with TGFβ2 and chemically inhibited Smad3 for up to 7 days (d), and examined cell morphology, P70S6K, phosphorylated-P70S6K, and tendon markers, scleraxis and tenomodulin.
Original language | American English |
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State | Published - Jun 2020 |
Externally published | Yes |
Event | Summer Biomechanics, Bioengineering and Biotransport Conference (SB3C) - Virtual Duration: 1 Jun 2020 → … |
Conference
Conference | Summer Biomechanics, Bioengineering and Biotransport Conference (SB3C) |
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Period | 1/06/20 → … |
EGS Disciplines
- Biomedical Engineering and Bioengineering
- Mechanical Engineering