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Cartilage, Tendons, and Ligaments: Stem and Progenitor Cells in Adults
Cartilage, Tendons, and Ligaments: Stem and Progenitor Cells in Adults
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Cartilage, Tendons, and Ligaments: Stem and Progenitor Cells in Adults
Injury to cartilage, tendons, and ligaments encompasses a significant portion of orthopedic morbidity within the population. Unlike other connective tissues, such as skin or bone, that may have almost complete regenerations rapidly after injury, cartilage, tendons, and ligaments do not repair as quickly or fully. Even utilizing best practices in treatment today, prognosis is still not optimal. Due to these challenges, researchers have pointed to stem cell therapies as a potential treatment in the future. Studies attempting to identify an effective method to utilize stem cells to promote healing and cell regeneration in damaged cartilage, tendons, and ligaments have increased dramatically over the past decade.
Cell Type Selection: Mesenchymal Stem Cells
In order to utilize stem cells in the regeneration of cartilage, tendons, and ligaments, a cell line needs to be identified that differentiates into these connective tissues. Mesenchymal stem cells (MSCs), also known as bone marrow stromal stem cells, marrow-isolated adult multipotent inducible cells, multipotent adult progenitor cells, and mesenchymal adult stem cells, were recognized as non-hematopoietic stem cells with the ability to differentiate into a number of connective tissue cells, including chondrocytes (cartilage), tenocytes (tendons and ligaments), osteocytes (bone), myocytes (muscle), and adipocytes (fat).
The Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy had proceeded to standardize MSCs based on the following three criteria: (1) must adhere to plastic when maintained in standard culture conditions; (2) must express the surface proteins CD105, CD73, and CD90 in greater than 95 percent of the culture and lack the expression of CD45, CD34, CD14, or CD11b, CD79α or CD19, and HLA-DR in greater than 95 percent of the culture; (3) must differentiate to osteoblasts, adipocytes, and chondroblasts in vitro. Since the identification of these chondrocyte and tenocyte progenitors, scientists have now been able to extract mesenchymal stem cells not only from bone marrow but also from adipocytes, umbilical cord blood, periodontal ligament, peripheral blood, and synovial fluid, among others.
In addition to the ability of the mesenchymal stem cells to differentiate into a large number of connective tissues, MSCs have an immunosuppressive effect toward the immune effector cells: CD4+ and CD8+ T lymphocytes, Natural Killer (NK) cells, B lymphocytes, monocytes, and dendritic cells. This immunosuppressive effect is integral to the MSCs’ ability to decrease the rate that the implanted stem cells are rejected, via graft-versus-host disease. A decrease in the graft-versus-host disease would increase the likelihood of a successful transplant.
Stem Cell Delivery
One of the largest impediments to the regeneration of connective tissue is the ability for the new cells to re-form the same three-dimensional structure through the healing process. In order to produce the conditions necessary for mesenchymal stem cells to regenerate cartilage, tendons, and ligaments appropriately, support scaffolds of collagen-based materials, fibrin glue, or synthetic materials are currently being utilized as guides during implantation of stem cells. Additionally, due to the fact that MSCs can form a wide variety of connective tissues, researchers struggle with the ability to specify differentiation and invoke proliferation. Transcription factors that are believed to induce stem cell differentiation into cartilage (Sox5, Sox6, Sox9) and tendon or ligament (Scx) have been identified. Researchers have begun to utilize these transcription factors along with other growth factors in order to potentially increase the effective dose.
Cartilage Repair With Stem Cells
Although research in the utilization of stem cell treatment for disease and injury to cartilage has increased over the past decade, the majority of the research to date has been conducted on animal models. Based upon results that showed significant improvements in repair of articular cartilage damage in animal models, there has been a recent expansion in the number of clinical trials in humans. In order to be deemed an effective method of treatment in humans, a method for the utilization of MSCs must at least be equal to the current treatment methods of cartilage repair, including debridement of the site, autologous chondrocyte implantation (ACI), and marrow-stimulating procedures. Recent clinical trials have attempted to identify methods for MSC treatment that produce the greatest regenerative effect by adjusting the originating source of the stem cells, method of delivery (surgery vs. injection), the type of scaffold utilized, and including additional cellular proteins and/or steroid hormones (growth and transcription factors) to aid in stem cell proliferation and guide differentiation to chondrocytes.
The majority of the completed clinical trials have utilized bone marrow–derived mesenchymal stem cells (BMSCs) for treatment. Surgical implantation has been the most common route of delivery of the BMSCs and has been conducted in eight clinical trials on conditions including osteoarthritic knees, patello-femoral cartilage deficits, and full-thickness knee defects. These trials have utilized scaffolds consisting of collagen gel, hydroxyapatite ceramic, and platelet fibrin glue in order to allow BMSC growth and differentiation to chondrocytes. Studies were analyzed either to identify cartilage regeneration, histologically or via clinical and subjective symptom improvement. Although only one study was compared via a control, all showed significant improvement over the duration of follow-up, which included periods from six months to two years.
One study that compared MSC to ACI treatment found similar improvement in both cases. However, it was noted that although ACI showed more effective treatment outcomes in patients under 45 years of age than in patients over 45, MSC did not show the same age bias. Three additional small studies have analyzed the effect of injection treatment of BMSCs for damaged knee cartilage. These studies also showed positive results in factors analyzed, including range of motion, pain, thickness of cartilage, and functional status.
Another group of clinical trials have utilized bone marrow concentrate (BMC) as a potential source of stem cells. Surgical treatment was the choice method of implantation for the majority of the BMC clinical trials. However, only one study utilized a control group method of treatment, ACI, in order to attempt to compare the effectiveness of treatment. This study utilized BMC with platelet-rich fibrin as a scaffold and hyaluronic acid, which is used commonly in attempts to treat osteoarthritis. Researchers found positive results in the regeneration of cartilage in both groups that
