Mesenchymal Stem Cells and Osteoarthritis Image

Mesenchymal Stem Cells and Osteoarthritis

Mesenchymal Stem Cells and Osteoarthritis


Chauncy L. Eakins, MD & Steven M. Webster, RN

Introductory Points

  • Adult mesenchymal stem cells are remnants of embryological/fetal mesenchyme – the tissue that gave rise to tissues such as bone, cartilage, and muscle
  • The therapeutic benefits of mesenchymal stem cells have been studied for over 50 years
  • Mesenchymal stem cells create a nutritive environment that allows the body’s tissues to repair themselves
  • Studies have shown that treatment of joint disorders such as osteoarthritis with mesenchymal stem cells is both safe and effective

Mesenchyme and Mesenchymal Stem Cells

Your body started out as ONE cell that became TRILLIONS of cells through the process of differentiation, a type of directed change and development that led to three distinct tissue types: endoderm (examples: linings of the digestive and respiratory tracts), mesoderm (examples: muscle and connective tissues, including bone and cartilage), and ectoderm (examples: brain and skin). Embryological and fetal development are fascinating processes that occur in a stepwise fashion, during which cells become more and more specific to a particular role in the building of your body. An example of this role-building is the formation of mesenchyme, the parent tissue to all of your connective tissues, including bone and cartilage.

Remnants of embryological and fetal mesenchyme are still present in your body. Called mesenchymal stem cells, they, like their predecessors, have the ability to develop into other cells or tissues including bone, cartilage, and muscle, among others. Mesenchymal stem cells were first identified in the late 1960s [1] and research directed towards their possible therapeutic uses has blossomed ever since. A March 2020 search for “mesenchymal stem cells” on clinicaltrials.gov (US National Library of Medicine and National Institutes of Health), yielded 1,058 studies submitted to the website, which contains information about medical studies in human volunteers.

Adult mesenchymal stem cells can be found in a variety of locations in your body, but most clinically used mesenchymal stem cells are harvested from bone marrow or adipose (fat) tissues. Mesenchymal stem cells reintroduced into damaged tissues, such as those found in osteoarthritis of the knee, interestingly do not actually engraft into the damaged tissue and become new cartilage cells [2]. They do however create a trophic (nutritive) environment that may help your tissues repair themselves [2]. Mesenchymal stem cells rescue and/or repair injured cells and tissues through diverse mechanisms including the transfer of organelles (mitochondria), electrolytes, and genetic materials, and release of bioactive trophic chemicals [2]. Bioactive trophic chemicals released from mesenchymal stem cells include chemokines, cytokines, exosomes, growth factors, and glycosaminoglycans [3]. These chemicals have an immunomodulatory effect that suppresses inflammatory immune system responses and scar formation, and modifies new blood vessel formation, programmed cell death, and cell growth [3]. Thus, mesenchymal stem cells have the potential to repair damaged connective tissues like the cartilage that is being worn away in osteoarthritis.

Osteoarthritis

Osteoarthritis is the most common type of arthritis in the United States. It is a leading cause of disability and can negatively impact people’s physical and mental well-being [4]. Also known as wear and tear arthritis, osteoarthritis occurs from repetitive contact between proximal and distal portions of bones in joints, leading to a wearing away of the protective cartilage coverings over the ends of the bones. Osteoarthritis has a multifactorial causation and risk factors include older age, genetics, obesity, vitamin deficiencies, joint shape, muscle weakness, and injuries, among others [4].

The most common treatments for early to middle stage osteoarthritis include changes in modifiable risk factors like obesity and management of symptoms such as pain with medications. The most frequently performed procedure for advanced osteoarthritis is total joint replacement [5]. While making healthful changes in your diet, weight, and vitamin usage, are always going to be mainstays of treatment for osteoarthritis, and frankly most disease processes, the reliance upon pain medications and invasive surgeries as common management methods for osteoarthritis symptoms, warrants a second look at alternative medical treatment options.

Treating Osteoarthritis with Mesenchymal Stem Cells
Joint cartilage is both avascular (lacking a direct blood supply) and inherently poor in cartilage cell (chondrocyte) numbers, thus natural repair processes are both slow and inefficient. Added external stressors thus contribute to and promote progressive cartilage damage. Let’s revisit two of the main causes of osteoarthritis: aging and injury (through obesity or other mechanical damage from sports, etc.).

Studies using joint chondrocytes suggest that aging cells show elevated oxidative stress that promotes cell decline and alters mitochondrial function [6]. Mitochondria are the cellular powerhouses that produce the primary direct source of energy used in our body in the form of adenosine triphosphate (ATP). Cells will become less functional and eventually die without an adequate source of ATP. As seen above, aging chondrocytes display alterations in mitochondrial function. Recall that one of the functions of mesenchymal stem cells is the transference of organelles, including mitochondria, to damaged cells. And that mesenchymal stem cells also create a trophic environment that provides growth factors and other bioactive chemicals, that may be lacking in aging cells.

Injuries to cartilage, either from chronic stressors like obesity or through acute sports injuries, have a common trigger for deterioration: inflammation [6]. The cell mediated component of inflammation is primarily related to the functions of immune cells such as B and T lymphocytes, antigen presenting cells, natural killer cells, and neutrophils [7]. These cells produce pro-inflammatory chemicals including interleukin-6, tumor necrosis factor, C-reactive protein, type I interferons, and oxygen reactive species, among others [7]. The end result of prolonged inflammation is tissue damage and pain. Mesenchymal stem cells mediate the actions of immune cells, decrease expression of pro-inflammatory chemicals, promote expression of anti-inflammatory chemicals, decrease induced cell death, and reduce the release of oxygen reactive species [8].

Conventional medicine ignores treatment of the aging aspects of cartilage tissue and relies heavily upon anti-inflammatory (nonsteroidal anti-inflammatory drugs [NSAID] and corticosteroids) and opiate medications for osteoarthritis symptom management. Common side effects of NSAID usage include stomach pain and ulcers, increased bleeding tendencies, headaches and dizziness, tinnitus, allergic reactions, liver and/or kidney problems, high blood pressure, and leg swelling. Prolonged use of corticosteroids can lead to osteoporosis, high blood pressure, diabetes, weight gain, increased vulnerability to infection, cataracts and glaucoma, thinning of the skin, bruising easily, and muscle weakness. Common side effects of opioid use include sedation, dizziness, nausea, vomiting, constipation, physical dependence, tolerance, and respiratory depression. Whereas, a meta-analysis of clinical trials (36 studies, 1012 participants) found the main side effect of mesenchymal stem cell administration was a transient fever [9, 10]. Furthermore, a meta-analysis of 11 research studies encompassing 582 patients with knee osteoarthritis demonstrated that mesenchymal stem cell transplantation was safe and reported improvements across a range of clinical outcome measures [11].

Not everyone is a candidate for mesenchymal stem cell transplantation therapy, especially those with advanced osteoarthritis where the cartilage is so worn away as to not be recoverable. Early intervention, including lifestyle changes and mesenchymal stem cell transplantation therapy, however, may lead to a reversal of or limit the rate of deterioration in joints affected by osteoarthritis. Whether you have experienced a knee injury, or you are suffering from a degenerative disease, regenerative medicine may help.

Take Home Points
  • Adult mesenchymal stem cells are remnants of embryological/fetal mesenchyme – the tissue that gave rise to tissues such as bone, cartilage, and muscle
  • The therapeutic benefits of mesenchymal stem cells have been studied for over 50 years
  • Mesenchymal stem cells create a nutritive environment that allows the body’s tissues to repair themselves
  • Studies have shown that treatment of joint disorders such as osteoarthritis with mesenchymal stem cells is both safe and effective


References

1 Friedenstein, L., Piatetzky, S., & Petrakova, K. (1966). Osteogenesis in transplants of bone marrow cells. Journal of Embryology and Experimental Morphology, 16(3), 381-390.

2 Spees, J., Lee, R., & Gregory, C. (2016). Mechanisms of mesenchymal stem/stromal cell function. Stem Cell Research & Therapy, 7(125).

3 Samsonraj, R., Raghunath, M., Nurcombe, V., Hui, J., van Wunen, A., & Cool, S. (2017). Concise review: Multifaceted characterization of human mesenchymal stem cells for use in regenerative medicine. Tissue Engineering and Regenerative Medicine, 6, 2173-2185.

4 Vina, E., & Kwoh, C. (2018). Epidemiology of osteoarthritis: Literature update. Current Opinion in Rheumatology, 30(2), 160–167.

5 Katz, J. (2006). Total joint replacement in osteoarthritis. Best Practice & Research Clinical Rheumatology, 20(1), 145-153.

6 Chen, D., Shen, J., Zhao, W., Wang, T., Han, L., Hamilton, J., & Im, H. (2017). Osteoarthritis: Toward a comprehensive understanding of pathological mechanism. Bone Research, 5(16044).

7 Tsoupras, A., Lordan, R., & Zabetakis, I. (2018). Inflammation, not cholesterol, is a cause of chronic disease. Nutrients, 10(604).

8 Weil, B., Manukyan, M., Herrmann, J., Abarbanell, A., Poynter, J., Wang, Y., & Meldrum, D. (2011). The immunomodulatory properties of mesenchymal stem cells: Implications for surgical disease. Journal of Surgical Research, 167(1), 78-86.

9 Lalu, M., McIntyre, L., Pugliese, C., Fergusson, D., Winston, B., Marshall, J., Granton, J., Stewart, D., & Canadian Critical Care Trials Group (2012). Safety of cell therapy with mesenchymal stromal cells (SafeCell): A systematic review and meta-analysis of clinical trials. PLOS One, 7(10).

10 Thomspon, M. et al. (2018). Safety of cell therapy with mesenchymal stromal cells: An updated systematic review and meta-analysis of randomized controlled trials (SafeCell update). Cytotherapy, 20(5), 53-54.

11 Yubo, M., Yanyan, L., Li, L., Tao, S., Bo, L., & Lin, C. (2017). Clinical efficacy and safety of mesenchymal stem cell transplantation for osteoarthritis treatment: A meta-analysis. PLOS One, 12(4).



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