MSC-CM potential for Myasthenia Gravis Treatment

Myasthenia Gravis (MG) is an autoimmune disorder affecting neuromuscular junctions, leading to the weakness of voluntary muscles (Figure 1). Common symptoms include double vision, drooping eyelids, facial and throat muscle weakness, and overall fatigue [1]. MG patients lose natural muscle control, experiencing varying muscle weakness and fatigue. While there is no cure for MG, treatment methods can provide relief, and some patients may experience remission.

Causes and Treatment of Myasthenia Gravis

Myasthenia Gravis is a relatively rare disorder, with an incidence of about 14 cases per 100,000 people, affecting individuals of all ages. The cause remains unclear, with researchers suspecting viral or bacterial triggers for autoimmune reactions. Additionally, the thymus gland may play a role, and approximately 10-15% of MG patients have an underlying thymic tumor. MG patients also have a link to autoimmune thyroid disease, which occurs in 3-8% of patients. Screening for thyroid abnormalities is part of the initial evaluation. While MG is not hereditary, genetic factors seem to contribute to the disease and other autoimmune conditions.

Common treatment approaches for Myasthenia gravis include oral medications, intravenous infusion medications, and surgical interventions. However, long-term use of oral or intravenous medications can lead to serious side effects such as osteoporosis, weight gain, diabetes, or infections. Doctors only use intravenous infusion therapy in specific cases, such as acute MG exacerbations. When patients have a thymic tumor, doctors typically recommend surgical interventions. Despite these treatments, MG can still relapse and be challenging to manage. Therefore, more effective and less toxic treatment options need to be developed [2, 3].

The Potential of Mesenchymal Stem Cells (MSC) and MSC-CM in Myasthenia Gravis Treatment

Mesenchymal Stem Cells (MSCs) are multipotent adult stem cells isolated from various sources, such as the umbilical cord, placenta, bone marrow, teeth, and adipose tissue [4, 5]. Scientists have conducted tests on MSCs in humans and mice to assess their potential in treating myasthenia gravis. The acute phase of MG involves overactivation of the immune system, particularly the proliferation of specific T cells and acetylcholine receptor (AchR) antibodies, playing a crucial role in disease development.

In a mouse study evaluating the therapeutic potential of MSCs, the cell-treated group showed a significant reduction in AchR antibodies compared to the untreated control group 10 days after the second injection. Both in vivo and in vitro experiments demonstrated that MSCs could effectively inhibit the proliferation of AchR-specific lymphocytes [7]. Another study indicated the involvement of factors like Hepatocyte Growth Factor (HGF), Transforming Growth Factor-beta (TGF-β), Indoleamine 2,3-dioxygenase (IDO), and Interleukin-10 (IL-10) in the suppression process [8]. Remarkably, MSCs substantially improved MG, reducing anti-AChR antibody levels in serum and restoring AChR expression in muscles. The treatment mechanism involved (1) inhibiting cell proliferation, (2) suppressing stimulating molecules associated with B cells, and (3) activating the complement regulator DAF/CD55.

In summary, research suggests that preconditioning enhances MSC therapeutic effects through a combination of anti-inflammatory and immune-suppressive mechanisms, primarily in the thymus. MSCs are a promising strategy for treating myasthenia gravis and other autoimmune diseases. MSC-conditioned media (MSC-CM) in in vitro culture contains mainly secretome components, including soluble proteins such as cytokines and chemokines released by MSCs, and extracellular vesicles (EV). Growth factors and cytokines in the secretome include TGF-β, HGF, and IL-10 [9, 10]. Therefore, CM containing secretome components from MSCs appears to be a promising tool for treating autoimmune diseases like myasthenia gravis. While no clinical trials currently use MSC-CM for MG treatment, positive data from in vitro and in vivo studies highlight the need for further research and evaluation.

References:

[1]      D. B. Drachman, “Myasthenia Gravis,” New England Journal of Medicine, vol. 298, no. 3, pp. 136–142, Jan. 1978, doi: 10.1056/NEJM197801192980305.

[2]      J. P. Sieb, “Myasthenia gravis: An update for the clinician,” Clin Exp Immunol, vol. 175, no. 3, pp. 408–418, Mar. 2014, doi: 10.1111/cei.12217.

[3]      M. Sudres et al., “Preconditioned mesenchymal stem cells treat myasthenia gravis in a humanized preclinical model,” JCI Insight, vol. 2, no. 7, Apr. 2017, doi: 10.1172/jci.insight.89665.

[4]      V. Sueblinvong et al., “Derivation of lung epithelium from human cord blood-derived mesenchymal stem cells,” Am J Respir Crit Care Med, vol. 177, no. 7, pp. 701–711, Apr. 2008, doi: 10.1164/rccm.200706-859OC.

[5]      S. Gronthos, M. Mankani, J. Brahim, P. G. Robey, and S. Shi, “Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo.” [Online]. Available: www.pnas.orgcgidoi10.1073pnas.240309797

[6]      A. Leyendecker, C. C. G. Pinheiro, M. T. Amano, and D. F. Bueno, “The use of human mesenchymal stem cells as therapeutic agents for the in vivo treatment of immune-related diseases: A systematic review,” Front Immunol, vol. 9, no. SEP, Sep. 2018, doi: 10.3389/fimmu.2018.02056.

[7]      J. Yu et al., “Intravenous administration of bone marrow mesenchymal stem cells benefits experimental autoimmune myasthenia gravis mice through an immunomodulatory action,” Scand J Immunol, vol. 72, no. 3, pp. 242–249, 2010, doi: 10.1111/j.1365-3083.2010.02445.x.

[8]      M. K. Majumdar, M. A. Thiede, J. D. Mosca, M. Moorman, and S. L. Gerson, “Phenotypic and functional comparison of cultures of marrow-derived mesenchymal stem cells (MSCs) and stromal cells,” J Cell Physiol, vol. 176, no. 1, pp. 57–66, Jul. 1998, doi: 10.1002/(SICI)1097-4652(199807)176:1<57::AID-JCP7>3.0.CO;2-7.

[9]      M. Z. Ratajczak et al., “Pivotal role of paracrine effects in stem cell therapies in regenerative medicine: can we translate stem cell-secreted paracrine factors and microvesicles into better therapeutic strategies?,” Leukemia, vol. 26, no. 6, pp. 1166–1173, Jun. 2012, doi: 10.1038/leu.2011.389.

[10]     H. Deng et al., “Lipid, Protein, and MicroRNA Composition Within Mesenchymal Stem Cell-Derived Exosomes,” Cell Reprogram, vol. 20, no. 3, pp. 178–186, Jun. 2018, doi: 10.1089/cell.2017.0047.