Abstract
Acute ischemic stroke triggers immunosuppression, yet existing therapies struggle to balance neuroprotection with poststroke immunosuppression. We demonstrated that bone marrow mesenchymal stem cells (BM-MSC) reverse stroke-induced thymic atrophy by promoting T-cell differentiation and restoring peripheral T-cell populations. Bulk RNA sequencing of BM-MSC-treated thymuses revealed enhanced proliferative signatures. Mechanistically, BM-MSC secrete migrasomes (organelles derived from migrating cells) that traverse the blood‒thymus barrier. Single-cell RNA sequencing analysis demonstrated that migrasome-mediated proliferation occurred specifically in medullary thymic epithelial cell I (mTECI) subpopulations. Proteomic profiling via liquid chromatography‒tandem mass spectrometry (LC‒MS/MS) identified Pin1-a cell cycle regulator-as the predominant cargo in BM-MSC-derived migrasomes. In vivo and in vitro studies confirmed migrasome-mediated thymic epithelial proliferation, T-cell niche reconstruction, and immune homeostasis restoration. Migrasome monotherapy improved neurological deficits and survival rates in stroke model mice, demonstrating dual neuroprotective-immunomodulatory efficacy. This work addresses the clinical dilemma between neuroprotection and immunosuppression alleviation, establishing migrasomes as a cell-free therapeutic strategy for poststroke immunotherapy.