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Remyelination represents a robust regenerative response to myelin damage; however, during the later stages of MS, this process largely fails. Upon demyelination, oligodendrocyte progenitor cells (OPCs) proliferate, migrate, and differentiate into mature remyelinating oligodendrocytes. Why does remyelination fail in MS? Platelets are small, oval, anucleate cells that circulate in the bloodstream and form a hemostatic plug to stop blood leakage upon endothelial damage. Platelet function is not restricted to hemostasis; they also display tissue\u2010regenerative activities. Here, we review evidence suggesting that platelets act as modulators of OPC function during remyelination. Additionally, we describe platelet alterations associated with MS that may contribute to remyelination failure. Finally, we highlighted our previous study that addressed these issues. This study showed that in response to myelin damage, platelets transiently accumulate within the lesion. Interestingly, platelet depletion leads to a reduction in OPC differentiation, hindering remyelination. In\u00a0vitro studies revealed that transient exposure to platelets boosts OPC differentiation, whereas sustained exposure to platelets suppresses this beneficial effect. Consistent with this observation, in an in\u00a0vivo model of thrombocytosis (\n                    <jats:italic>\n                      Calr\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    ), we found a sustained increase in the number of blood\u2010borne platelets recruited into the CNS (as observed in MS lesions), resulting in a significant decline in OPC differentiation during remyelination. These findings reveal a complex role of platelets in remyelination and provide new insights for understanding the MS pathology as well as for designing regenerative strategies for the treatment of this disease.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70268-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  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