Cell- and gene-based approaches to tendon regeneration

Comparative Orthopaedics Laboratory, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA.
Journal of shoulder and elbow surgery / American Shoulder and Elbow Surgeons ... [et al.] (Impact Factor: 2.29). 02/2012; 21(2):278-94. DOI: 10.1016/j.jse.2011.11.015
Source: PubMed


Repair of rotator cuff tears in experimental models has been significantly improved by the use of enhanced biologic approaches, including platelet-rich plasma, bone marrow aspirate, growth factor supplements, and cell- and gene-modified cell therapy. Despite added complexity, cell-based therapies form an important part of enhanced repair, and combinations of carrier vehicles, growth factors, and implanted cells provide the best opportunity for robust repair. Bone marrow-derived mesenchymal stem cells provide a stimulus for repair in flexor tendons, but application in rotator cuff repair has not shown universally positive results. The use of scaffolds such as platelet-rich plasma, fibrin, and synthetic vehicles and the use of gene priming for stem cell differentiation and local anabolic and anti-inflammatory impact have both provided essential components for enhanced tendon and tendon-to-bone repair in rotator cuff disruption. Application of these research techniques in human rotator cuff injury has generally been limited to autologous platelet-rich plasma, bone marrow concentrate, or bone marrow aspirates combined with scaffold materials. Cultured mesenchymal progenitor therapy and gene-enhanced function have not yet reached clinical trials in humans. Research in several animal species indicates that the concept of gene-primed stem cells, particularly embryonic stem cells, combined with effective culture conditions, transduction with long-term integrating vectors carrying anabolic growth factors, and development of cells conditioned by use of RNA interference gene therapy to resist matrix metalloproteinase degradation, may constitute potential advances in rotator cuff repair. This review summarizes cell- and gene-enhanced cell research for tendon repair and provides future directions for rotator cuff repair using biologic composites.

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Available from: Ashlee Watts, Feb 19, 2015
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    • "Moreover, MSCs are able to secrete trophic molecules , such as growth factors (GFs) and chemotactic molecules, which can recruit additional reparative cells into the lesion site [7]. Bone marrowederived MSCs (BMSCs) are the most commonly used cells in tissue engineering, and the implantation of BMSCs into tendon injury has provided promising results in several in vivo studies, thus indicating that the microenvironment and cellular interactions play an important role in MSC differentiation [8]. Among other potential sources of MSCs [9], adipose-derived MSCs (ADSCs) appear to be the most promising stem cell population to have clinical relevance as an alternative for tendon repair. "
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    ABSTRACT: Tendon is a complex tissue with a reduced regenerative ability. Nowadays, little or nothing is known about the regenerative effect of adipose-derived mesenchymal stromal cells (ADSCs) on tendons. The study aimed to evaluate the in vitro mutual interaction of ADSCs and tenocytes in standard culture conditions and a microwound healing model. Tenocyte viability, microwound recovery and the expression of genes encoding for the main extracellular matrix components and ADSC viability, differentiation and growth factor gene expression were evaluated. The effects of ADSCs on tenocytes were observed more in the microwound healing model, in which the rate of microwound healing and the expression of decorin, tenascin and collagens were significantly increased. The influence of tenocytes on ADSCs was also found in standard culture conditions: ADSCs were directed toward a tenogenic lineage, and growth factor expression increased. This study clarifies some aspects of the mutual interaction of ADSCs and tenocytes and provides in vitro evidence for a possible future application of ADSCs as a therapeutic strategy for tendon repair. Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.
    Cytotherapy 12/2014; 17(2). DOI:10.1016/j.jcyt.2014.10.006 · 3.29 Impact Factor
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    • "However, the risk of poor histologic characteristics and mechanical properties is a major problem of these neo-tendons. A better comprehension of basic tendon biology should lead to the development of optimal methods for solving these problems and for improving tendon therapy (Nixon et al. 2012; Tozer and Duprez 2005). "
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    ABSTRACT: Tendons that connect muscles to bone are often the targets of sports injuries. The currently unsatisfactory state of tendon repair is largely attributable to the limited understanding of basic tendon biology. A number of tendon lineage-related transcription factors have recently been uncovered and provide clues for the better understanding of tendon development. Scleraxis and Mohawk have been identified as critical transcription factors in tendon development and differentiation. Other transcription factors, such as Sox9 and Egr1/2, have also been recently reported to be involved in tendon development. However, the molecular mechanisms and application of these transcription factors remain largely unclear and this prohibits their use in tendon therapy. Here, we systematically review and analyze recent findings and our own data concerning tendon transcription factors and tendon regeneration. Based on these findings, we provide interaction and temporal programming maps of transcription factors, as a basis for future tendon therapy. Finally, we discuss future directions for tendon regeneration with differentiation and trans-differentiation approaches based on transcription factors.
    Cell and Tissue Research 04/2014; 356(2). DOI:10.1007/s00441-014-1834-8 · 3.57 Impact Factor
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    • "These data highlight the potent anti-inflammatory and immunosuppressive effects of these cells. Given these potent immunomodulatory effects of MSCs, it is not surprising that these cells are being used in clinical studies of graft-versus-host disease, which is usually a fatal condition after organ transplantation [43]. "
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    ABSTRACT: Tendon injury is a major cause of lameness and decreased performance in athletic equines. Various therapies for tendonitis have been described; however, none of these therapies results in complete tissue regeneration, and the injury recurrence rate is high even after long recovery periods involving rest and physiotherapy. A lesion was induced with collagenase gel in the superficial digital flexor tendon in the center portion of the metacarpal region of eight equines of mixed breed. After two weeks, the lesions of the animals in the treated and control groups were treated through the intralesional administration of mesenchymal stem cells derived from adipose tissue (adMSCs) suspended in platelet concentrate (PC) and with phosphate buffered saline (PBS), respectively. Serial ultrasound analyses were performed every two weeks. After 16 weeks of therapy, a biopsy was performed for histopathological, immunohistochemical, and gene expression (type I collagen (COL1A1), type III collagen (COL3A1), tenascin-C (TNC), tenomodulin (TNMD), and scleraxis (SCX)) analyses. Differences in the ultrasound and histopathological analyses were observed between the groups. Improved results were reported in the group treated with adMSCs suspended in PC. There was no difference in the gene expression levels observed after the different treatments. The main results observed from the histopathological evaluation of the treated group were as follows: a prevention of the progression of the lesion, a greater organization of collagen fibers, and a decreased inflammatory infiltrate. A lack of progression of the lesion area and its percentage was observed in the ultrasound, and increased blood flow was measured by Power Doppler. The use of adMSCs combined with PC for the therapy of experimentally induced tendonitis prevented the progression of the tendon lesion, as observed in the ultrasound examination, and resulted in a greater organization and decreased inflammation, as observed in the histopathological evaluation. These data demonstrate the therapeutic potential of this therapy for the treatment of equine tendonitis.
    Stem Cell Research & Therapy 07/2013; 4(4):85. DOI:10.1186/scrt236 · 3.37 Impact Factor
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