Science et RechercheLe Pouls AEEMUMComment

New Murine Model for Multiple Sclerosis Based on T Lymphocytes Gene Methylation Changes

Science et RechercheLe Pouls AEEMUMComment
New Murine Model for Multiple Sclerosis Based on T Lymphocytes Gene Methylation Changes

New Murine Model for Multiple Sclerosis Based on T Lymphocytes Gene Methylation Changes: A Tool for Better Understanding the Pathogenesis of the Disease

par Ines Ait Driss, Daniela Iachimov, Andreea Stepanov, Xiao Yu Xie

Faculté de médecine, Université de Montréal

With over 77 000 cases, Canada presents one of the highest prevalence of Multiple Sclerosis (MS) in the world.1 The early onset of this incurable autoimmune disease [1] engenders debilitating consequences, affecting the patient's quality of life. Although the precise causes of this inflammatory demyelinating affliction remain elusive, studies strongly suggest that environmental factors causing epigenetic changes contribute to the disease [2, 3]. It has been proposed that lymphocyte DNA methylation is an important factor in its pathogenesis [2]. Unfortunately, the current models for MS are based on mice immunisation against Central nervous system (CNS) antigens and do not reflect accurately the etiology of the disease [4]. In order to palliate the situation, this study proposes the creation of a chimeric murine model using an allograft of modified hematopoietic stem cells that recreate some of the methylation patterns seen in MS [5-7]. The desired epigenetic modifications (hypermethylation of HLA-DRB1, DNHD1 and APC2 genes) [2] will be achieved via the CRISPR-Cas12a system with a modified U-rich crRNA guide [8]. After ensuring that hypermethylation and gene silencing was successful through immunofluorescence, the obtained phenotypes will be compared with controls by histopathology [9]. In the new model, increased occurrence of nerve demyelination and infiltration of the CNS by T cells, myelin antigen-specific CD4+ T cells and MS specific cytokines is expected [10]. If successful, this will be the first step in creating a new model that will not only allow for a better understanding of the origin of MS, but could also open the way for new treatments targeting those epigenetic modifications.

Key words: multiple sclerosis, demyelinating autoimmune disease, murine model, DNA methylation, CRISPR-Cas12a epigenetic modifications.

Références

1. Public Health Agency of Canada. Multiple Sclerosis in Canada 2018 [updated 2019-12-09]. Available from: https://www.canada.ca/en/public-health/services/publications/diseases-conditions/multiple-sclerosis-infographic.html#shr-pg0.

2. Li X, Xiao B, Chen XS. DNA Methylation: a New Player in Multiple Sclerosis. Mol Neurobiol. 2017;54(6):4049-59.

3. van den Elsen PJ, van Eggermond MC, Puentes F, van der Valk P, Baker D, Amor S. The epigenetics of multiple sclerosis and other related disorders. Mult Scler Relat Disord. 2014;3(2):163-75.

4. Burrows DJ, McGown A, Jain SA, De Felice M, Ramesh TM, Sharrack B, et al. Animal models of multiple sclerosis: From rodents to zebrafish. Mult Scler. 2019;25(3):306-24.

5. Bara JJ, Richards RG, Alini M, Stoddart MJ. Concise review: Bone marrow-derived mesenchymal stem cells change phenotype following in vitro culture: implications for basic research and the clinic. Stem Cells. 2014;32(7):1713-23.

6. Beilhack GF, Scheffold YC, Weissman IL, Taylor C, Jerabek L, Burge MJ, et al. Purified allogeneic hematopoietic stem cell transplantation blocks diabetes pathogenesis in NOD mice. Diabetes. 2003;52(1):59-68.

7. Schroeder MA, Ashami K, Staser K. Modeling Chronic Graft Versus Host Disease in Mice Using Allogeneic Bone Marrow and Splenocyte Transfer. Curr Protoc Pharmacol. 2018;83(1):e47.

8. Ha DI, Lee JM, Lee NE, Kim D, Ko JH, Kim YS. Highly efficient and safe genome editing by CRISPR-Cas12a using CRISPR RNA with a ribosyl-2'-O-methylated uridinylate-rich 3'-overhang in mouse zygotes. Exp Mol Med. 2020.

9. Vojta A, Dobrinic P, Tadic V, Bockor L, Korac P, Julg B, et al. Repurposing the CRISPR-Cas9 system for targeted DNA methylation. Nucleic Acids Res. 2016;44(12):5615-28.

10. Korn T, Mitsdoerffer M, Kuchroo VK. Immunological basis for the development of tissue inflammation and organ-specific autoimmunity in animal models of multiple sclerosis. Results Probl Cell Differ. 2010;51:43-74.

Image de couverture : https://today.uconn.edu/2019/05/new-culprit-multiple-sclerosis-relapses/#

Science et RechercheLe Pouls AEEMUMComment

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Science et RechercheLe Pouls AEEMUMComment

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Science et RechercheLe Pouls AEEMUMComment
Central tolerance induction by manipulation of thymic cell DNA and expression of GAD antigen by thymic epithelial cells
Science et RechercheLe Pouls AEEMUMComment

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Science et RechercheLe Pouls AEEMUMComment
An Approach to Parkinson’s Disease Using the Differential Potential of Dental Pulp Stem Cells to Generate Dopaminergic Neurons