Repair Of Injured Tendons Research Articles

Mechanical stretch promotes tenocyte migration via chromatin remodeling-mediated nuclear morphology changes.

Wound healing and function recovery of injured tendons is still a big challenge for orthopaedic surgery. Evidence in clinic shows that early controlled motion has significant favorable effects on tendon healing, however, the mechanisms involved in are not fully understood. In the present study, it was shown that an appropriate mechanical stretch (10% strain, 0.5 Hz for 1 h) evidently promotes rat tenocyte migration and nuclear morphology changes. The farther research discovered that mechanical stretch had no effect on Lamin A/C expression, but it could promote chromatin decondensation. Moreover, the histone modification plays an important role in mechanical stretch-mediated chromatin decondensation. Inhibition histone modification could inhibit mechanical stretch-promoted nuclear morphology changes and tenocyte migration. These results indicating that mechanical stretch may promote tenocyte migration via chromatin remodeling-mediated nuclear morphology changes, which contribute to a better understanding of the role of mechanical stretch on tenocyte migration and repair of injured tendon. This article is protected by copyright. All rights reserved.

Regulation of the tenogenic gene expression in equine tenocyte-derived induced pluripotent stem cells by mechanical loading and Mohawk

Cell-based therapeutic strategies afford major potential advantages in the repair of injured tendons. Generation of induced pluripotent stem cells (iPSCs) expands cell sources for “regenerative” therapy. However, its application in tendon repair is still limited and the effects remain unclear. In this study, equine tenocyte-derived iPSCs (teno-iPSCs) were generated by expressing four Yamanaka factors. Compared to parental tenocytes and bone marrow derived mesenchymal stem cells (BMSCs), the transcriptional activities of lineage-specific genes, including Mkx, Col1A2, Col14, DCN, ELN, FMOD, and TNC, were highly repressed in the resulting teno-iPSCs. Exposure to cyclic uniaxial mechanical loading increased the expression of Scx, Egr1, Col1A2, DCN, and TNC in teno-iPSCs and the expression of Scx, Egr1, DCN, and TNC in BMSCs. Reintroduction of tenogenic transcription factor Mohawk (Mkx) upregulated the expression of DCN in teno-iPSCs and the expression of Scx, Col14, and FMOD in BMSCs. Mechanical loading combined with ectopic expression of equine Mkx further enhanced the expression of Egr1, Col1A2, DCN, and TNC in teno-iPSCs and the expression of Scx, Egr1, and TNC in BMSCs. These data suggest that the repressed lineage-specific genes in the teno-iPSCs can be re-activated by mechanical loading and ectopic expression of Mkx. Our findings offer new insights into the application of iPSCs for basic and clinic research in tendon repair.

Directed Differentiation and Paracrine Mechanisms of Mesenchymal Stem Cells: Potential Implications for Tendon Repair and Regeneration.

Tendon is composed of connective tissue, is able to retract with high tensile force, and plays a significant role in musculoskeletal motion. However, inappropriate physical training or accidents often result in tendon injuries. So far, the functional healing of injured tendon is still a great challenge in orthopedics. Mesenchymal stem cells (MSCs) are multilineage cells with the ability to self-renew and differentiate into a variety of cell types, including tenocytes. The plasticity of MSCs gives rise to the chance of improved healing of injured tendons and even tissue-engineered tendons. Recently, more and more works have shown that the paracrine mechanisms of MSCs also play a critical role in driving the tendon repair process. The purpose of this review is to summarize the current knowledge of the induction of tenogenic differentiation of MSCs by mechanical, chemical and mechanochemical stimulations. The role of paracrine mechanisms of MSCs during the repair of injured tendons is also discussed. The multilineage potential and the paracrine effects of MSCs create the chance for improved healing of injured tendons and even tissue-engineered tendons. The understanding of the regulation of the two different repair mechanisms (directed differentiation and paracrine) of MSCs has important implications for tendon repair and regeneration.

CTGF Positively Regulates BMP12 Induced Tenogenic Differentiation of Tendon Stem Cells and Signaling

Background/Aims: Disordered differentiation of tendon stem cells (TSCs) during repair of injured tendon can result in the pathogenesis of chronic tendinopathy. Understanding tenocyte differentiation may provide new therapeutic insights for the prevention and treatment of chronic tendinopathy. The aim of our study was to determine if CTGF exerts a similar effect on BMP12-driven differentiation of rat TSCs. Methods: In overexpressing and RNA interference CTGF TSCs, tenogenic differentitation and the expression of related genes were determined by immunofluorescence staining, quantitative PCR, and western blotting, with or without BMP12 treatment. The interaction in vitro between CTGF and BMP12 was detected by Chemical crosslinking assay. Results: Our results showed that BMP12 effectively increased the expression of the tenocyte lineage markers scleraxis (Scx) and tenomodulin (Tnmd) at both mRNA and protein levels. Over-expression of CTGF from a lentiviral vector increased the expression of Scx and Tnmd as well as tendon proteins type I collagen (ColI) and tenascin-C (Tn-C) in TSCs compared to non-treated control cells with or without simultaneous BMP12 stimulation. Knockdown of CTGF expression decreased the expression of Scx, Tnmd, ColI and Tn-C compared to control cells. Chemical crosslinking experiments demonstrated a direct interaction between CTGF and BMP12. Conclusion: In conclusion, BMP12 plays a crucial role in tenogenesis via the Smad1/5/8 pathway, and CTGF positively promotes this effect.

Efficacy of tendon stem cells in fibroblast-derived matrix for tendon tissue engineering

Background aimsAfter injury, tendons often heal with poor tissue quality and inferior mechanical properties. Tissue engineering using tendon stem cells (TSCs) is a promising approach in the repair of injured tendon. Tenogenic differentiation of TSCs needs an appropriate environment. More recently, the acellular extracellular matrix (ECM) generated from fibroblasts has been used to construct various engineering tissues. In this study, we successfully developed an engineered tendon tissue formed by seeding TSCs in de-cellularized fibroblast-derived matrix (dFM). MethodsPatellar TSCs and dermal fibroblast were isolated and cultured. Using the method of osmotic shock, dFM was obtained from dermal fibroblast. ECM proteins in dFM were examined. TSCs at passage 3 were seeded in dFM for 1 week. Proliferative capacity and characterization of TSCs cultured in dFM were determined by population doubling time, immunofluorescence staining and quantitative reverse transcriptase polymerase chain reaction. Engineered tendon tissue was prepared with dFM and TSCs. Its potentials for neo-tendon formation and promoting tendon healing were investigated. ResultsdFM is suitable for growth and tenogenic differentiation of TSCs in vitro. Neo-tendon tissue was formed with tendon-specific protein expression when TSCs were implanted together with dFM. In a patellar tendon injury model, implantation of engineered tendon tissue significantly improved the histologic and mechanical properties of injured tendon. ConclusionsThe findings obtained from our study provide a basis for potential use of engineered tendon tissue containing dFM and TSCs in tendon repair and regeneration.

Local NO synthase inhibition produces histological and functional recovery in Achilles tendon of rats after tenotomy

Repair of injured tendon is a very slow process and involves the release of many molecules, including nitric oxide. We investigate the influence of local nitrergic inhibition in histological and functional recovery of injured Achilles tendon. A standard murine model of tendon injury by rupture was used. The animals were divided into three experimental groups: control, injury + vehicle (normal saline) and injury + Nω-nitro-L-arginine methyl ester (L-NAME). The products were injected into the paratendinous region every 2 days and body weight gain and Achilles functional index (AFI) were evaluated on days 0, 7, 14 and 21 after tendon injury. On day 21 post-injury, the animals were killed to evaluate nitric oxide production and tissue organization. We observed that tendon surgical division led to increased tissue nitrite levels, which were reduced in L-NAME-treated rats. The AFI revealed functional recovery of L-NAME-treated animals on day 21 post-injury, which was not observed in the saline-treated group. Microscopic analysis of hematoxylin-eosin staining and collagen autofluorescence showed that L-NAME-treated rats had more aligned areas of collagen fibers and that the diameter of newly organized collagen in this group was also greater than that in the vehicle-treated one. We demonstrate that local treatment with L-NAME significantly improves the functional parameters and accelerates histomorphological recovery.

PEG-TYPE TRANSDUCER FOR TENSION MEASUREMENT OF AN INTACT TENDON OR LIGAMENT IN OPEN REPAIR SURGERY

A suitable tension is critical to good prognoses of surgical repair of injured tendons or ligaments. The existing transducers have limiting roles in measuring the repair tension of intact tendons or ligaments. This study fabricated a sensor to assist surgeons in measuring tension during repair surgery. A peg-type force transducer made from stainless steel served the advantages of easy application and sterilizability. The electrical signals were stabilized by a bridge circuit coupled with two strain gauges. The performances of the system, which were tested by thin and thick silicon tubes, were linear to the applied forces. The results suggest that this system is reliable for force measurement and is beneficial for optimizing the tension of tendons or ligaments during repair surgeries.

Cell phenotypic variation in normal and damaged tendons

Injuries to tendons are common in both human athletes as well as in animals, such as the horse, which are used for competitive purposes. Furthermore, such injuries are also increasing in prevalence in the ageing, sedentary population. Tendon diseases often respond poorly to treatment and require lengthy periods of rehabilitation. The tendon has a unique extracellular matrix, which has developed to withstand the mechanical demands of such tensile-load bearing structures. Following injury, any repair process is inadequate and results in tissue that is distinct from original tendon tissue. There is growing evidence for the key role of the tendon cell (tenocyte) in both the normal physiological homeostasis and regulation of the tendon matrix and the pathological derangements that occur in disease. In particular, the tenocyte is considered to have a major role in effecting the subclinical matrix degeneration that is thought to occur prior to clinical disease, as well as in the severe degradative events that occur in the tendon at the onset of clinical disease. Furthermore, the tenocyte is likely to have a central role in the production of the biologically inadequate fibrocartilaginous repair tissue that develops subsequent to tendinopathy. Understanding the biology of the tenocyte is central to the development of appropriate interventions and drug therapies that will either prevent the onset of disease, or lead to more rapid and appropriate repair of injured tendon. Central to this is a full understanding of the proteolytic response in the tendon in disease by such enzymes as metalloproteinases, as well as the control of the inappropriate fibrocartilaginous differentiation. Finally, it is important that we understand the role of both intrinsic and extrinsic cellular elements in the repair process in the tendon subsequent to injury.