scholarly journals Scleraxis Lineage Cells Contribute to Organized Bridging Tissue During Tendon Healing, and Identifies Subpopulations of Resident Tendon Cells

2018 ◽  
Author(s):  
Katherine T. Best ◽  
Alayna E. Loiselle
Keyword(s):  
Calcium Binding ◽  
Tendon Repair ◽  
Tendon Healing ◽  
Scar Tissue ◽  
Scar Formation ◽  
Cellular Environment ◽  
Scar Region ◽  
Tendon Cells ◽  
Pathological Scar ◽  
The Relationship

AbstractDuring tendon healing, it is postulated that intrinsic tendon cells drive tissue regeneration while extrinsic cells drive pathological scar formation. Intrinsic tendon cells are frequently described as a homogenous, fibroblast population that is positive for the marker Scleraxis. It is controversial whether intrinsic Scleraxis localize within the forming scar tissue during adult tendon healing. We have previously demonstrated that calcium binding protein S100a4 is a driver of tendon scar formation and marks a subset of intrinsic tendon cells. However, the relationship between Scleraxis and S100a4 has not been explored. In this study, we aimed to investigate the localization of Scleraxis lineage cells following adult murine flexor tendon repair and to establish the relationship between Scleraxis and S100a4 throughout both homeostasis and healing. We have shown that adult Scleraxis lineage cells localize within the scar tissue and organize into a highly aligned cellular bridge during tendon healing. Additionally, we demonstrate that markers Scleraxis and S100a4 label distinct populations in tendon during homeostasis and localize differently within tendon scar tissue, with Scleraxis found specifically in the organized bridging tissue and S100a4 localized throughout the entire scar region. These studies define a heterogeneous tendon cell environment and demonstrate discreet contributions of subpopulations during healing. Taken together, these data enhance our understanding and ability to target the complex cellular environment of the tendon during homeostasis and healing.

scholarly journals Magnetic Stimulation Drives Macrophage Polarization in Cell to–Cell Communication with IL-1β Primed Tendon Cells

2020 ◽  
Vol 21 (15) ◽  
pp. 5441 ◽  
Author(s):  
Adriana Vinhas ◽  
Ana F. Almeida ◽  
Ana I. Gonçalves ◽  
Márcia T. Rodrigues ◽  
Manuela E. Gomes
Keyword(s):  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Tendon Repair ◽  
Cell Communication ◽  
Tendon Healing ◽  
Cell Contact ◽  
Cellular Interactions ◽  
Tendon Cells ◽  
Pulsed Electromagnetic ◽  
The Impact

Inflammation is part of the natural healing response, but it has been simultaneously associated with tendon disorders, as persistent inflammatory events contribute to physiological changes that compromise tendon functions. The cellular interactions within a niche are extremely important for healing. While human tendon cells (hTDCs) are responsible for the maintenance of tendon matrix and turnover, macrophages regulate healing switching their functional phenotype to environmental stimuli. Thus, insights on the hTDCs and macrophages interactions can provide fundamental contributions on tendon repair mechanisms and on the inflammatory inputs in tendon disorders. We explored the crosstalk between macrophages and hTDCs using co-culture approaches in which hTDCs were previously stimulated with IL-1β. The potential modulatory effect of the pulsed electromagnetic field (PEMF) in macrophage-hTDCs communication was also investigated using the magnetic parameters identified in a previous work. The PEMF influences a macrophage pro-regenerative phenotype and favors the synthesis of anti-inflammatory mediators. These outcomes observed in cell contact co-cultures may be mediated by FAK signaling. The impact of the PEMF overcomes the effect of IL-1β-treated-hTDCs, supporting PEMF immunomodulatory actions on macrophages. This work highlights the relevance of intercellular communication in tendon healing and the beneficial role of the PEMF in guiding inflammatory responses toward regenerative strategies.

scholarly journals Tendon Cell Deletion of IKKβ/NF-κB Drives Functionally Deficient Tendon Healing and Altered Cell Survival Signaling In Vivo

2020 ◽  
Author(s):  
Katherine T. Best ◽  
Emma Knapp ◽  
Constantinos Ketonis ◽  
Jennifer H. Jonason ◽  
Hani A. Awad ◽  
...  
Keyword(s):  
Cell Survival ◽  
Flexor Tendon ◽  
Tendon Repair ◽  
Tendon Healing ◽  
Scar Tissue ◽  
Cell Populations ◽  
Tissue Formation ◽  
Matrix Deposition ◽  
Scar Tissue Formation

AbstractAcute tendon injuries are characterized by excessive matrix deposition that impedes regeneration and disrupts functional improvements. Inflammation is postulated to drive pathologic scar tissue formation, with nuclear factor kappa B (NF-κB) signaling emerging as a candidate pathway in this process. However, characterization of the spatial and temporal activation of canonical NF-κB signaling during tendon healing in vivo, including identification of the cell populations activating NF-κB, is currently unexplored. Therefore, we aimed to determine which cell populations activate canonical NF-κB signaling following flexor tendon repair with the goal of delineating cell-specific functions of NF-κB signaling during scar mediated tendon healing. Immunofluorescence revealed that both tendon cells and myofibroblasts exhibit prolonged activation of canonical NF-κB signaling into the remodeling phase of healing. Using cre-mediated knockout of the canonical NF-κB kinase (IKKβ), we discovered that suppression of canonical NF-κB signaling in Scleraxis-lineage cells increased myofibroblast content and scar tissue formation. Interestingly, Scleraxis-lineage specific knockout of IKKβ increased the incidence of apoptosis, suggesting that canonical NF-κB signaling may be mediating cell survival during tendon healing. These findings suggest indispensable roles for canonical NF-κB signaling during flexor tendon healing.One Sentence SummaryScleraxis-lineage specific knockdown of persistent canonical IKKβ/NF-κB drives scar formation and apoptotic signaling during flexor tendon healing.

scholarly journals Non-invasive ultrasound quantification of Scar Tissue Volume predicts functional changes during tendon healing

2018 ◽  
Author(s):  
Jessica E. Ackerman ◽  
Valentina Studentsova ◽  
Alayna E. Loiselle
Keyword(s):  
Tendon Healing ◽  
Cost Effective ◽  
Clinical Problem ◽  
Scar Tissue ◽  
Rapid Screening ◽  
Functional Changes ◽  
Tissue Volume ◽  
Non Invasive ◽  
Effective Manner ◽  
Pathological Scar

AbstractTendon injuries are very common and disrupt the transmission of forces from muscle to bone, leading to impaired function and quality of life. Successful restoration of tendon function after injury is a challenging clinical problem due to the pathological, scar-mediated manner in which tendons heal. Currently, there are no standard treatments to modulate scar tissue formation and improve tendon healing. A major limitation to the identification of therapeutic candidates has been the reliance on terminal end-point metrics of healing in pre-clinical studies, which require a large number of animals and result in destruction of the tissue. To address this limitation, we have identified quantification of Scar Tissue Volume (STV) from ultrasound imaging as a longitudinal, non-invasive metric of tendon healing. STV was strongly correlated with established endpoint metrics of gliding function including Gliding Resistance (GR) and Metatarsophalangeal (MTP) Flexion Angle. However, no associations were observed between STV and tensile mechanical properties. To define the sensitivity of STV to identify differences between functionally discrete tendon healing phenotypes, we utilized S100a4 haploinsufficient mice (S100a4GFP/+), which heal with improved gliding function relative to wildtype (WT) littermates. A significant decrease in STV was observed in S100a4GFP/+repairs, relative to WT at day 14. Taken together, these data suggest US quantification of STV as a means to facilitate the rapid screening of biological and pharmacological interventions to improve tendon healing, and identify promising therapeutic targets, in an efficient, cost-effective manner.

scholarly journals Stem Cells for Augmenting Tendon Repair

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Lawrence V. Gulotta ◽  
Salma Chaudhury ◽  
Daniel Wiznia
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Growth Factors ◽  
Adhesion Formation ◽  
Tendon Repair ◽  
Tendon Healing ◽  
Scar Tissue ◽  
Mechanical Stimuli ◽  
Injury Site ◽  
Attractive Option

Tendon healing is fraught with complications such as reruptures and adhesion formation due to the formation of scar tissue at the injury site as opposed to the regeneration of native tissue. Stem cells are an attractive option in developing cell-based therapies to improve tendon healing. However, several questions remain to be answered before stem cells can be used clinically. Specifically, the type of stem cell, the amount of cells, and the proper combination of growth factors or mechanical stimuli to induce differentiation all remain to be seen. This paper outlines the current literature on the use of stem cells for tendon augmentation.

scholarly journals NF-κB activation persists into the remodeling phase of tendon healing and promotes myofibroblast survival

2020 ◽  
Vol 13 (658) ◽  
pp. eabb7209
Author(s):  
Katherine T. Best ◽  
Anne E. C. Nichols ◽  
Emma Knapp ◽  
Warren C. Hammert ◽  
Constantinos Ketonis ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Tendon Repair ◽  
Tendon Healing ◽  
Nuclear Factor Κb ◽  
Scar Tissue ◽  
Persistent Inflammation ◽  
Independent Functions ◽  
The Matrix ◽  
Human Tendon ◽  
Late Stages

Although inflammation is necessary during the early phases of tissue repair, persistent inflammation contributes to fibrosis. Acute tendon injuries often heal through a fibrotic mechanism, which impedes regeneration and functional recovery. Because inflammation mediated by nuclear factor κB (NF-κB) signaling is implicated in this process, we examined the spatial, temporal, and cell type–specific activation profile of canonical NF-κB signaling during tendon healing. NF-κB signaling was maintained through all phases of tendon healing in mice, including the remodeling phase, and tenocytes and myofibroblasts from the Scleraxis (Scx) lineage were the predominant populations that retained NF-κB activation into the late stages of repair. We confirmed persistent NF-κB activation in myofibroblasts in human tendon scar tissue. Deleting the canonical NF-κB kinase, IKKβ, in Scx-lineage cells in mice increased apoptosis and the deposition of the matrix protein periostin during the late stages of tendon repair, suggesting that persistent NF-κB signaling may facilitate myofibroblast survival and fibrotic progression. Consistent with this, myofibroblasts in human tendon scar samples displayed enhanced prosurvival signaling compared to control tissue. Together, these data suggest that NF-κB may contribute to fibrotic tendon healing through both inflammation-dependent and inflammation-independent functions, such as NF-κB–mediated cell survival.

scholarly journals Loureirin B Inhibits Hypertrophic Scar Formation via Inhibition of the TGF-β1-ERK/JNK Pathway

2015 ◽  
Vol 37 (2) ◽  
pp. 666-676 ◽  
Author(s):  
Ting He ◽  
Xiaozhi Bai ◽  
Longlong Yang ◽  
Lei Fan ◽  
Yan Li ◽  
...  
Keyword(s):  
Hypertrophic Scar ◽  
Ex Vivo ◽  
Scar Tissue ◽  
Scar Formation ◽  
Jnk Pathway ◽  
Protein Levels ◽  
Mapk Inhibitors ◽  
Hypertrophic Scar Tissue ◽  
Loureirin B ◽  
Tgf Β1

Background/Aims: Our previous study confirmed that Loureirin B (LB) can inhibit hypertrophic scar formation. However, the mechanism of LB-mediated inhibition of scar formation is still unknown. Methods: Immunohistochemistry was used to detect expression of Col1, FN and TGF-β1 in skin and scar tissue. Fibroblasts were stimulated with TGF-β1 to mimic scar formation. LB or MAPK inhibitors were used to study the pathways involved in the process. Western blotting was used to evaluate the expression of p-JNK, p-ERK, p-p38, Col1 and FN. The contractile capacity of fibroblasts was evaluated using a gel contraction assay. Tissues were cultured ex vivo with LB to further investigate the participation of ERK and JNK in the LB-mediated inhibition of scar formation. Results: FN and Col1 were up regulated in hypertrophic scars. LB down regulated p-ERK and p-JNK in TGF-β1-stimulated fibroblasts, while levels of phosphorylated p38 did not change. The down regulation of p-ERK and p-JNK was associated with a reduction of Col1 and FN. Similarly, inhibition of ERK and JNK down regulated the expression of Col1 and FN in TGF-β1-stimulated fibroblasts. LB down regulated protein levels of p-ERK and p-JNK in cultured hypertrophic scar tissue ex vivo. Conclusions: This study suggests that LB can inhibit scar formation through the ERK/JNK pathway.

scholarly journals TGIF1 Gene Silencing in Tendon-Derived Stem Cells Improves the Tendon-to-Bone Insertion Site Regeneration

2015 ◽  
Vol 37 (6) ◽  
pp. 2101-2114 ◽  
Author(s):  
Liyang Chen ◽  
Chaoyin Jiang ◽  
Shashi Ranjan Tiwari ◽  
Amrit Shrestha ◽  
Pengcheng Xu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Gene Silencing ◽  
Healing Process ◽  
Insertion Site ◽  
Tendon Repair ◽  
Scar Tissue ◽  
Connective Tissues ◽  
Expression Rate ◽  
Low Levels ◽  
Derivatives Of

Background/Aims: The slow healing process of tendon-to-bone junctions can be accelerated via implanted tendon-derived stem cells (TDSCs) with silenced transforming growth interacting factor 1 (TGIF1) gene. Tendon-to-bone insertion site is the special form of connective tissues derivatives of common connective progenitors, where TGF-β plays bidirectional effects (chondrogenic or fibrogenic) through different signaling pathways at different stages. A recent study revealed that TGF-β directly induces the chondrogenic gene Sox9. However, TGIF1 represses the expression of the cartilage master Sox9 gene and changes its expression rate against the fibrogenesis gene Scleraxis (Scx). Methods: TGIF1 siRNA was transduced or TGIF1 was over-expressed in tendon-derived stem cells. Following suprapinatus tendon repair, rats were either treated with transduced TDSCs or nontransduced TDSCs. Histologic examination and Western blot were performed in both groups. Results: In this study, the silencing of TGIF1 significantly upregulated the chondrogenic genes and markers. Similarly, TGIF1 inhibited TDSC differentiation into cartilage via interactions with TGF-β-activated Smad2 and suppressed the phosphorylation of Smad2. The area of fibrocartilage at the tendon-bone interface was significantly increased in the TGIF1 (-) group compared with the control and TGIF1-overexpressing groups in the early stages of the animal model. The interface between the tendon and bone showed a increase of new bone and fibrocartilage in the TGIF1 (-) group at 4 weeks. Fibrovascular scar tissue was observed in the TGIF1-overexpressing group and the fibrin glue only group. Low levels of fibrocartilage and fibrovascular scar tissue were found in the TDSCs group. Conclusion: Collectively, this study shows that the tendon-derived stem cell modified with TGIF1 gene silencing has promising effects on tendon-to-bone healing which can be further explored as a therapeutic tool in regenerative medicine.

scholarly journals Non‐Invasive Ultrasound Quantification of Scar Tissue Volume Identifies Early Functional Changes During Tendon Healing

2019 ◽  
Vol 37 (11) ◽  
pp. 2476-2485 ◽  
Author(s):  
Jessica E. Ackerman ◽  
Valentina Studentsova ◽  
Marlin Myers ◽  
Mark R. Buckley ◽  
Michael S. Richards ◽  
...  
Keyword(s):  
Tendon Healing ◽  
Scar Tissue ◽  
Functional Changes ◽  
Tissue Volume ◽  
Non Invasive
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