Bringing tendon biology to heel: Leveraging mechanisms of tendon development, healing, and regeneration to advance therapeutic strategies

Tsai, Stephanie; Nödl, Marie-Therese; Galloway, Jenna L.

doi:10.1002/dvdy.269

Cited by 20 publications

(14 citation statements)

References 211 publications

(378 reference statements)

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“…In fact, eAEC-treated tendons showed a more homogeneous COL1 deposition pattern compared to mAEC-and tdAEC-treated tendons, which had parallelly deposited COL1 fibers but alternated with fainter deposition areas. It is conceivable that eAECs produced a better collagenous aligned ECM upon transplantation into injured Achilles tendons, since at day 14 they expressed higher mRNA levels of SCX and TNMD required for proper COL1 matrix assembly and structural integrity [39], as well as prevention of fibrovascular scar formation during early tendon healing [40].…”

Section: Discussionmentioning

confidence: 99%

Tendon Healing Response Is Dependent on Epithelial–Mesenchymal–Tendon Transition State of Amniotic Epithelial Stem Cells

et al. 2022

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Tendinopathies are at the frontier of advanced responses to health challenges and sectoral policy targets. Cell-based therapy holds great promise for tendon disorder resolution. To verify the role of stepwise trans-differentiation of amniotic epithelial stem cells (AECs) in tendon regeneration, in the present research three different AEC subsets displaying an epithelial (eAECs), mesenchymal (mAECs), and tendon-like (tdAECs) phenotype were allotransplanted in a validated experimental sheep Achilles tendon injury model. Tissue healing was analyzed adopting a comparative approach at two early healing endpoints (14 and 28 days). All three subsets of transplanted cells were able to accelerate regeneration: mAECs with a lesser extent than eAECs and tdAECs as indicated in the summary of the total histological scores (TSH), where at day 28 eAECs and tdAECs had better significant scores with respect to mAEC-treated tendons (p < 0.0001). In addition, the immunomodulatory response at day 14 showed in eAEC-transplanted tendons an upregulation of pro-regenerative M2 macrophages with respect to mAECs and tdAECs (p < 0.0001). In addition, in all allotransplanted tendons there was a favorable IL10/IL12 compared to CTR (p < 0.001). The eAECs and tdAECs displayed two different underlying regenerative mechanisms in the tendon. The eAECs positively influenced regeneration mainly through their greater ability to convey in the host tissue the shift from pro-inflammatory to pro-regenerative responses, leading to an ordered extracellular matrix (ECM) deposition and blood vessel remodeling. On the other hand, the transplantation of tdAECs acted mainly on the proliferative phase by impacting the density of ECM and by supporting a prompt recovery, inducing a low cellularity and angle alignment of the host cell compartment. These results support the idea that AECs lay the groundwork for production of different cell phenotypes that can orient tendon regeneration through a crosstalk with the host tissue. In particular, the obtained evidence suggests that eAECs are a practicable and efficient strategy for the treatment of acute tendinopathies, thus reinforcing the grounds to move their use towards clinical practice.

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Section: Discussionmentioning

confidence: 99%

Tendon Healing Response Is Dependent on Epithelial–Mesenchymal–Tendon Transition State of Amniotic Epithelial Stem Cells

et al. 2022

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“…Tendons are a crucial component of the musculoskeletal system [ 1 ], and tendon injury is a common damage in patients of all ages [ 2 ]. Following injury, the tendon heals poorly through a slow process, forming fibrous scar tissue with low biomechanical function [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

MiR-192-5p Alleviated Fibrosis and Inflammatory Responses of Tendon Cells by Targeting NFAT5

Gong

Zhang

et al. 2022

Computational and Mathematical Methods in Medicine

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Objective. To explore the effect of microRNA (miR)-192-5p on the inflammatory and fibrotic responses of tendon cells. Methods. Tendon cells were treated with transforming growth factor-β1 (TGF-β1). The expression of miR-192-5p and nuclear factor of activated T cells 5 (NFAT5) in tendon cells were detected by RT-qPCR. The expressions of inflammatory and fibrosis-related factors were detected by RT-qPCR and Western blot. MiR-192-5p binds to NFAT5 targeting by TargetScan and dual-luciferase reporter gene assay. The expression of the NFAT5 gene was detected by RT-qPCR and Western blot. Detection of apoptosis in tendon cells by flow cytometry. Results. MiR-192-5p was downregulated in tendon cells, and the expression level gradually decreased with the prolong of TGF-β1 treatment. The expression of NFAT5 increased with the treatment time of TGF-β1. The expression of miR-192-5p decreased collagen III (COLIII), α smooth muscle actin (α-SMA), matrix metalloproteinase- (MMP-) 1, and MMP-8 expression, thereby inhibiting TGF-β1-induced fibrosis in tendon cells. The expression of miR-192-5p decreased the expression of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β, thereby alleviating TGF-β1-induced inflammatory response and reduce apoptosis in tendon cells. NFAT5 is a direct target of miR-192-5p in tendon cells. The upregulation of NFAT5 reversed the effect of miR-192-5p on the fibrotic activity and inflammatory response of TGF-β1-stimulated tendon cells. Conclusions. MiR-192-5p alleviates fibrosis and inflammatory responses of tendon cells by targeting NFAT5.

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“…Tendon is a connective tissue rich in matrix, which is mainly composed of closely arranged bundles of parallel collagen fibers (Wang et al, 2012;Tsai et al, 2021). They are attached to muscles and bones, and stabilize joints by cushioning the pressure caused by direct interaction between muscles and bones (Laurencin and Freeman, 2005;Thorpe and Screen, 2016).…”

Section: Tendon Structurementioning

confidence: 99%

The Roles of MicroRNAs in Tendon Healing and Regeneration

Ding

Wang

Qin

et al. 2021

Front. Cell Dev. Biol.

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Tendons connect the muscle abdomen of skeletal muscles to the bone, which transmits the force generated by the muscle abdomen contraction and pulls the bone into motion. Tendon injury is a common clinical condition occurring in certain populations, such as repeated tendon strains in athletes. And it can lead to substantial pain and loss of motor function, in severe cases, significant disability. Tendon healing and regeneration have attracted growing interests. Some treatments including growth factors, stem cell therapies and rehabilitation programs have been tried to improve tendon healing. However, the basic cellular biology and pathology of tendons are still not fully understood, and the management of tendon injury remains a considerable challenge. Regulating gene expression at post-transcriptional level, microRNA (miRNA) has been increasingly recognized as essential regulators in the biological processes of tendon healing and regeneration. A wide range of miRNAs in tendon injury have been shown to play vital roles in maintaining and regulating its physiological function, as well as regulating the tenogenic differentiation potential of stem cells. In this review, we show the summary of the latest information on the role of miRNAs in tendon healing and regeneration, and also discuss potentials for miRNA-directed diagnosis and therapy in tendon injuries and tendinopathy, which may provide new theoretical foundation for tenogenesis and tendon healing.

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Bringing tendon biology to heel: Leveraging mechanisms of tendon development, healing, and regeneration to advance therapeutic strategies

Cited by 20 publications

References 211 publications

Tendon Healing Response Is Dependent on Epithelial–Mesenchymal–Tendon Transition State of Amniotic Epithelial Stem Cells

Tendon Healing Response Is Dependent on Epithelial–Mesenchymal–Tendon Transition State of Amniotic Epithelial Stem Cells

MiR-192-5p Alleviated Fibrosis and Inflammatory Responses of Tendon Cells by Targeting NFAT5

The Roles of MicroRNAs in Tendon Healing and Regeneration

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