Osteoarthritis (OA) of the temporomandibular joint (TMJ) is a degenerative disease indicated by progressive cartilage degradation, subchondral bone remodeling, synovitis, and chronic pain. Due to the limited self-healing capacity in condylar cartilage, traditional clinical treatments have limited symptom-modifying and structure-modifying effects to restore impaired cartilage as well as other TMJ tissues. In recent years, stem cell-based therapy has drawn much attention as an alternative approach to tissue repair and regeneration. Mesenchymal stem cells (MSCs), derived from the bone marrow, synovium, and even umbilical cord, play the role of the seed cells for the cartilage regeneration of TMJ OA.
MSCs have the potential for multilineage differentiation including osteogenic and chondrogenic. In addition, the trophic modulations of MSCs exert anti-inflammatory and immunomodulatory effects under aberrant conditions. Furthermore, MSCs combined with appropriate scaffolds can form cartilaginous or even osseous compartments to repair damaged tissue and impair function of TMJ. Degenerative disease is not just happened in the mouth cavity but is generally often found in joint/disc.
Today, the application of mesenchymal stromal/stem cells (MSCs) and their exosomes to treat degenerative diseases has received attention. Due to the characteristics of these cells, such as self-renewability, differentiative, immunomodulatory effects, and their use in laboratory and clinical studies shows promising results. However, the allogeneic transplantation problems of MSCs limit the use of these cells in the clinic. Scientists propose the application of exosomes of MSCs to overcome their degeneration. One of the degenerative tissue diseases in which MSCs and their exosomes are used in their treatment is intervertebral disc disease (IDD). Different factors such as genetics, nutrition, aging, and environmental factors play significant roles in the onset and progression of this disease. These factors affect the cellular and molecular properties of the disc, leading to tissue destruction. Nucleus pulposus cells (NPCs) are among the most important cells involved in the pathogenesis of disc degeneration. MSCs exert their therapeutic effects by differentiating, reducing apoptosis, increasing proliferation, and decreasing senescence in NPCs. Furthermore, the use of MSCs and their exosomes also affects the annulus fibrosus and cartilaginous endplate cells in disc tissue and prevents disc degeneration progression.
This action of MSCs leads to a quantitative increase in IVD cells at the injury site and helps in IDD treatment. These MSCs also help improve and regenerate IVD by preventing cell apoptosis and modulating the immune microenvironment. Therefore, today MSC produced soluble mediators such as extracellular vesicles (EVs) and their supernatant which is used for therapeutic applications.
This study is a literature review by gathering evidence from recent studies. Firstly, we will discuss degenerative diseases such as IVD and therapy in general, proceeded to the development of therapy using MSCs and special exosomes in the last decade reports. In a modern lifestyle, IVD cases are increasing and become a public health concern. IVD degeneration is associated with lower back pain. Currently, there is no cure yet for this disease, while the treatment provided focuses on pain relief. Besides, treatments such as surgery have many side effects. None of the current IDD therapy focuses on tissue regeneration, while regenerative therapy can significantly improve disease conditions. MSCs are one of the candidates for use in IDD due to their high differentiation ability and immunomodulatory potential. Besides, these cells produce exosomes and their application in various regenerated tissues shows positive therapeutic results. These cells and their exosomes promote proliferation, ECM synthesis and reduce apoptosis, ECM degradation, and cell senescence in NPCs. Also, they reduce environmental inflammation, increase cell migration to the area of injury, and enhance the differentiation of MSCs into NPCs. The whole mechanisms play essential roles in IVD tissues regeneration. The dose dependence of MSCs and exosomes is a complex issue in their clinical application.
Apoptotic body, microvesicles (MVs), and exosomes are three types of EVs are divided based on their size, content, and formation. Apoptotic bodies are typically produced in the last stage of apoptosis from apoptotic cells and are 50–4000 nm in size. Apoptotic bodies are heterogeneous and contain membrane contents, cellular organelles, and nuclear molecules. Unlike apoptotic bodies, MVs are obtained directly from the healthy cells membrane. These EVs sizes range from 100 nm to 1000 nm and have a heterogeneous morphology. Exosomes are the other type of EVs whose size range from 30 to 150 nm are the smallest EVs produced during late endosome membrane inward invagination and the multiple vesicular bodies (MVBs) formation. MSCs-derived exosomes have a therapeutic effect in many degenerative tissue diseases. Exosome injection for IDD treatment is a cell-free procedure that does not have the disadvantages of stem cell therapy. In addition, according to the character of exosomes, they can be used as drug carriers. The biocompatibility of these vesicles, their small size, and their ability to migrate and carry various substances to damaged tissue have made exosomes a promising therapeutic agent.
Some factors should be considered during the production process to produce safe and reliable MSCs sources for clinical application, including the following: (1) Identical tissue source for mesenchymal stromal/stem cell isolation. (2) Donor age and age of MSCs. (3) Donor-to-donor diversity and previous pathological conditions. (4) Allogeneic source versus autologous sources. (5) The same MSC separation steps. (6) Heterogeneity in MSC culture.
MSC-derived exosomes certainly play an immunomodulatory role, and we are confident that the research of MSC-derived exosomes will make a significant breakthrough in the future. For clinical safety, the production of MSCs for therapeutic purposes must comply with good manufacturing practices (GMPs) to ensure the provision of safe, repeatable and efficient products.
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https://www.sciencedirect.com/science/article/pii/S1567576922000212
Gunawan Widjaja , Walid Kamal Abdelbasset, Abduladheem Turki Jalil, Hendrik Setia Budi, Andri Praja Satria, Syahril Efendi, Wanich Suksatan, Rauza Sukma Rita, Mohammed Nader Shalaby, Surendar Aravindhan, Marwan Mahmood Saleh, Alexei Valerievich Yumashev. Mesenchymal stromal/stem cells and their exosomes application in the treatment of intervertebral disc disease: A promising frontier. Int Immunopharmacol. 2022;105:108537. doi:10.1016/j.intimp.2022.108537
