本文作者:福建医科大学 YANG
Review expert of this article: Professor Li Jing from the Affiliated Hospital of Jiangsu University
introduction
Musculoskeletal disorders are one of the most common causes of disability worldwide, including injuries to muscles, bones, nerves, ligaments, tendons, and more. Recently, a review published in the international journal "Stem Cell Reviews and Reports" demonstrated the potential therapeutic value of mesenchymal stem cells and their exosomes for a variety of musculoskeletal diseases, including fractures, loose fractures, musculoskeletal soft tissue injuries, etc. This article reviews the therapeutic mechanisms and literature cases of mesenchymal stem cells in these musculoskeletal diseases, and helps you understand the development status of mesenchymal stem cells in this field.
Musculoskeletal disorders are one of the most common causes of disability worldwide, including injuries to muscles, bones, nerves, ligaments, tendons, and more. Generally, the damage to these tissues is due to their injury or degeneration. The prevalence of these diseases increases with age. At present, the treatment of musculoskeletal diseases includes drug therapy, surgical treatment, etc. However, these treatments have many drawbacks, such as large trauma and limited efficacy. Therefore, the search for new therapies for the treatment of musculoskeletal diseases has become the focus of research by scholars at home and abroad.
Recently, a review published in the international journal Stem Cell Reviews and Reports [1] demonstrated the potential therapeutic value of mesenchymal stem cells (MSCs) and their exosomes (MSC-EVs) for a variety of musculoskeletal diseases, including fractures, loose fractures, and musculoskeletal soft tissue injuries.
Introduction to the function of mesenchymal stem cells and exosomes
Mesenchymal stem cells (MSCs) are a class of cells with multidirectional differentiation potential that have been shown to differentiate into adipocytes, osteoblasts, chondrocytes, tendon cells, skeletal muscle cells, cardiomyocytes, smooth muscle cells, and even neurons. MSCs can be targeted to recruit damaged tissues, increase angiogenesis, prevent fibrosis, neuroprotective, suppress the immune system, and inhibit hematopoietic stem cell apoptosis.
In addition, exosomes (MSC-EVs) are smaller in size and contain fewer proteins in the membrane than MSCs. As a result, they are easier to isolate and store and have lower immunogenicity than cell therapies. Currently, MSCs and their EVs have been used in the treatment of a wide range of diseases, including musculoskeletal disorders [1].
Image from Ref. [1]
MSCs for fracture/bone regeneration
01. Mechanism: Fracture healing/bone regeneration is a complex process, and studies have shown [2] that MSCs can increase bone regeneration in a variety of ways:
1) Reduces inflammatory and immunomodulatory properties, increases macrophage differentiation to the M2 phenotype and decreases the production of pro-inflammatory cytokines.
2) Migrating to the site of bone injury via specific chemokine receptors.
3) Stimulates the differentiation of osteoblasts of damaged cells.
4) Increase angiogenesis.
5) Create a regenerative microenvironment.
In addition, MSCs can be used to deliver genes to promote bone regeneration, and selected genes that promote bone regeneration can be transferred to MSCs using either viral vectors (e.g., adenovirus) or non-viral vectors (e.g., liposomes) [3].
Image from Ref. [1]
02. Clinical application case: A study [4] included 28 patients with delayed union/nonunion after long bone fractures, using autologous bone marrow-derived mesenchymal stem cells combined with bioceramic implants for treatment. Bone formation at the site of fracture was 25.0% (7/28) at 3 months, 67.8% (19/28) at 6 months, and 92.8% (26/28) at 12 months.
Image from Ref. [4]
The study confirmed that MSCs, combined with biomaterials, can effectively promote fracture healing and bone regeneration.
MSCs for the treatment of joint/cartilage injuries
01. Mechanism: Osteoarthritis, often referred to as "disabling arthritis", is a common degenerative disease in the elderly, which can lead to severe joint and cartilage damage, and studies have found that [5], the possible mechanism of MSCs in the treatment of osteoarthritis is as follows:
- secretes a large amount of mediators to prevent cartilage degeneration and stimulate its repair;
2. Reduces the production of pro-inflammatory cytokines by chondrocytes, thereby blocking their inflammatory activity, and converts macrophages of the M1 phenotype (inflammatory) to the M2 phenotype (non-inflammatory), thereby helping to reduce local inflammation.
3. Significantly reduced markers of fibrosis and hypertrophy associated with osteoarthritis, such as I, III, VI collagen fibers, etc.
4. Slows down the aging of chondrocytes.
Image from Ref. [5]
02. Clinical application case: A phase I clinical trial completed abroad [6] injected two doses of mesenchymal stem cells into the intra-articular cavity of 13 patients with stage II and III knee osteoarthritis at an interval of 1 month, and each patient was followed up for at least 24 months. The results showed that intra-articular injection of mesenchymal stem cells was safe for the treatment of knee osteoarthropathy, significantly improved Koos score and increased knee cartilage thickness.
Image from Ref. [6]
MSCs for the treatment of tendon injuries
01. Mechanism: Tendon injuries occur in athletes and sports activities and cause severe pain. Several studies [1] have demonstrated that MSCs can promote post-tendon injury repair through a variety of mechanisms, among which MSC-EVs play an important role.
MSC-EVs prevent inflammation by increasing the migration of anti-inflammatory macrophages to tendon regeneration sites.
MSC-EVs can affect macrophages and convert them to the M2 phenotype to participate in tendon anti-inflammatory and regenerative responses.
MSC-EVs promote the production of type I and type III collagen to regenerate the extracellular matrix in injured tendons.
Image from Ref. [1]
02. Case study: A study [7] used autologous stem cells to treat 14 patients with complete tear of the shoulder muscle, preferably through small incisions through bone sutures, followed by injection of cells into the damaged tendon. The results showed that stem cell injections could help patients heal damaged tendons better, reduce pain and inflammation, increase collagen production, and improve tendon strength and flexibility.
MSC-EVs also have potential for the treatment of a variety of musculoskeletal disorders
Mesenchymal stem cell-derived exosomes (MSC-EVs) have become another major therapeutic method after mesenchymal stem cells (MSCs), and it has been found that most of the previous therapeutic mechanisms of MSCs should be attributed to MSC-EVs.
In addition, exosomes can be artificially modified/processed, such as loading various drugs into exosomes to improve efficacy, etc. Therefore, future research may focus on combining MSC-EVs with various other treatments to improve the efficacy of the treatment of musculoskeletal disorders.
brief summary
In recent years, the rapid development of stem cell therapies for musculoskeletal disorders has provided an opportunity for the regeneration of various damaged musculoskeletal tissues that are difficult or slow to heal. So far, the results of completed clinical trials have shown that mesenchymal stem cells are safe and effective in the treatment of musculoskeletal diseases. Therefore, future research will focus on conducting larger-scale clinical trials to verify their safety and efficacy, so as to promote the translation of clinical applications. At the same time, the application of stem cell exosomes also has great potential, which needs to be further verified in the future. It is believed that with the further progress of research in the future, it will be able to promote its clinical transformation and benefit more patients with musculoskeletal diseases.
Bibliography:
[1] Malekpour K, Hazrati A, Zahar M, Markov A, Zekiy AO, Navashenaq JG, Roshangar L, Ahmadi M. The Potential Use of Mesenchymal Stem Cells and Their Derived Exosomes for Orthopedic Diseases Treatment. Stem Cell Rev Rep. 2022 Mar; 18(3):933-951. doi: 10.1007/s12015-021-10185-z. Epub 2021 Jun 24. PMID: 34169411; PMCID: PMC8224994.
[2] Oryan A, Kamali A, Moshiri A, Baghaban Eslaminejad M. Role of Mesenchymal Stem Cells in Bone Regenerative Medicine: What Is the Evidence? Cells Tissues Organs. 2017; 204(2):59-83. doi: 10.1159/000469704. Epub 2017 Jun 24. PMID: 28647733.
[3] Zomorodian E, Baghaban Eslaminejad M. Mesenchymal stem cells as a potent cell source for bone regeneration. Stem Cells Int. 2012;2012:980353. doi: 10.1155/2012/980353. Epub 2012 Feb 16. PMID: 22448175; PMCID: PMC3289837.
[4] Gómez-Barrena E, Flouzat-Lachaniette CH, Chevallier N, Donati DM, Spazzoli B, Ciapetti G, Fleury S, Fernandez MN, Cabrera JR, Avendaño-Solá C, Montemurro T, Panaitescu C, Veronesi E, Rojewski MT, Lotfi R, Dominici M, Schrezenmeier H, Layrolle P. Early efficacy evaluation of mesenchymal stromal cells (MSC) combined to biomaterials to treat long bone non-unions. Injury. 2020 Apr; 51 Suppl 1:S63-S73. doi: 10.1016/j.injury.2020.02.070. Epub 2020 Feb 26. PMID: 32139130.
[5] Maumus M, Pers YM, Ruiz M, Jorgensen C, Noël D. Mesenchymal stem cells and regenerative medicine - What future for osteoarthritis? [Mesenchymal stem cells and regenerative medicine: future perspectives in osteoarthritis]. Med Sci (Paris). 2018 Dec; 34(12):1092-1099. French. DOI: 10.1051/MEDSCI/2018294. Epub 2019 Jan 9. PMID: 30623767.
[6] Al-Najar M, Khalil H, Al-Ajlouni J, Al-Antary E, Hamdan M, Rahmeh R, Alhattab D, Samara O, Yasin M, Abdullah AA, Al-Jabbari E, Hmaid D, Jafar H, Awidi A. Intra-articular injection of expanded autologous bone marrow mesenchymal cells in moderate and severe knee osteoarthritis is safe: a phase I/II study. J Orthop Surg Res. 2017 Dec 12; 12(1):190. doi: 10.1186/s13018-017-0689-6. PMID: 29233163; PMCID: PMC5727956.‘
[7] Ellera Gomes JL, da Silva RC, Silla LM, Abreu MR, Pellanda R. Conventional rotator cuff repair complemented by the aid of mononuclear autologous stem cells. Knee Surg Sports Traumatol Arthrosc. 2012 Feb; 20(2):373-7. doi: 10.1007/s00167-011-1607-9. Epub 2011 Jul 20. PMID: 21773831; PMCID: PMC3262133.