Tendon injuries represent a common clinical problem that affects 30 million people annually (1). The injuries can occur as a result of trauma, overuse, and aging, and are typically characterized by pain, inflammation, and dysfunction (2). Tendon injuries are currently managed by conservative treatment and surgical intervention. Conservative treatments include injection corticosteroids, over-the-counter nonsteroidal anti-inflammatory drugs, and physical therapy. However, tendon healing is usually slow and injured tendons may fail to regain their full function with only conservative treatment. Surgical options are frequently considered for severe acute tendon injuries, such as rupture. Surgical repair with grafts is the current gold standard treatment for tendon ruptures. However, there are significant limitations with this approach, which include continued pain and risk of re-rupture, tendon adhesions, formation of scar tissue, ectopic bone formation, and the lack of regeneration of fibrocartilage at the tendon-to-bone junction (2). Furthermore, these conservative and surgical treatment approaches usually cannot completely restore tendons to their native composition, structure, and mechanical properties. Therefore, there is a critical need for more effective treatments. Advances in stem cell-based therapeutic approaches have shown great potential for tissue repair and regeneration and may be a promising new intervention for tendon repair and regeneration (2).
Embryonic stem cells (ESCs) represent a single source of cells that can differentiate into any cell type in the body, and therefore have a significantly broad potential in regenerative medicine, including the repair and regeneration of tendons (2). In fact, Chen et al. demonstrated that human ESCs (hESCs) that are appropriately differentiated and incorporated into a fibrin gel or onto a knitted silk-collagen sponge scaffold, and implanted into a tendon defect can improve tendon structural and mechanical properties in rats (3). Induced pluripotent stem cells (iPSCs) are pluripotent stem cells that can be generated directly from adult cells by introducing four specific genes encoding transcription factors (2). The implantation of cells differentiated from iPSCs have negligible immunogenicity compared to regular ESCs, which is one reason why iPSCs have become attractive cell sources for tissue repair. However, a recent study using equine iPSCs in vitro indicated that although equine iPSCs expressed tendon-associated genes and proteins in two-dimensional differentiation assays, in contrast to equine embryonic stem cells, equine iPSCs failed to generate artificial tendons when cultured in three-dimensional collagen gels (4). A thorough investigation of the regulatory mechanism that is critical for iPSCs to obtain the reparative and regenerative capacity for tendon repair is required. Mesenchymal stem cells (MSCs) are multipotent stem cells that can develop into more than one cell type, but their differentiation potential is more limited compared to pluripotent cells (2). MSCs bear the potential for differentiating into a variety of connective tissue cell types, including tenocytes. MSCs can be derived from various tissue sources, such as bone marrow, tendons, and adipose tissue. Numerous animal studies have demonstrated that cell-based approaches using MSCs can improve tendon repair (2).
Appropriate delivery and the promotion of a stem cell’s tenogenic (tendon-generating) potential during transplantation is critical for stem cell-based tendon repair, which remains extremely challenging. Stem cell-based treatments are usually supplemented with other factors, such as pretreating the cells with growth factors, modulating stem cell fate and lineage potential through genetic, epigenetic or physical means, combining treatment with bioactive molecules, or seeding stem cells on functional scaffolds (2). Gene transfer has also been used to overexpress certain transcription factors, such as scleraxis (Scx), early growth response-1 (Egr1), and Smad8 to promote tenogenic differentiation before implantation. For instance, the transplantation of Scx-transduced TSPCs promoted healing at the early stage of the tendon repair process in a rat patellar tendon injury model (5). Additionally, various scaffolds have been used in tendon repair to provide mechanical support and topographical cues to mimic the native tendon microenvironment, and to enhance tenogenic differentiation of stem cells. Aligned silk scaffolds, for example, have been demonstrated to induce tenogenic differentiation without overexpression of growth factors (2).
Although significant progress has been made recently, clinical data regarding the therapeutic efficacy of using stem cells to treat tendon injuries and diseases is still limited. For example, further studies are needed in order to see if the transplantation of stem cells isolated from different tissues exhibit different outcomes of tendon healing in animal models. As ESC-based therapies are particularly susceptible to generating tumors if the graft contains any undifferentiated cells, a strategy to effectively remove the undifferentiated cells is needed (6). Moreover, as there are many significant biological differences between acute or chronic tendon injuries, and the repair mechanisms following these injuries, specific stem-cell therapy approaches may need to be tailored for each particular type of tendon injury. Finally, as a very critical step, it is important to establish standard methodologies and treatment protocols for harvesting, amplification, pretreatment, delivery, and post cell delivery treatment in preclinical studies and in clinical trials (2).
- Maffulli N., Wong J., Almekinders L.C. Types and epidemiology of tendinopathy. Clin Sports Med. 2003;22(4):675–692.
- Lui PP. Stem cell technology for tendon regeneration: current status, challenges, and future research directions. Stem Cells Cloning. 2015; 8:163‐174. Published 2015 Dec 11. doi:10.2147/SCCAA.S60832
- Hentze H, Graichen R, Colman A. Cell therapy and the safety of embryonic stem cell-derived grafts. Trends Biotechnol. 2007; 25:24–32.
- Araki R, Uda M, Hoki Y, et al. Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells. Nature. 2013; 494:100–104.
- Sakaguchi Y, Sekiya I, Yagishita K, Muneta T. Comparison of human stem cells derived from various mesenchymal tissues: superiority of synovium as a cell source. Arthritis Rheum. 2005; 52:2521–2529.
- Liu L, Hindieh J, Leong DJ, Sun HB. Advances of stem cell based-therapeutic approaches for tendon repair. J Orthop Translat. 2017; 9:69‐75. Published 2017 Apr 13. doi: 10.1016/j.jot.2017.03.007