Haotong Yi, Mengyan Hu, Liling Yuan, Xiaotao Su, Shilin Wu, Tiemei Li, Shisi Wang, Xinmei Kang, Yuxin Liu, Zhiruo Liu, Qin Qin, Weihua Yu, Li Xiao, Wei Qiu, Wei Cai, Zhengqi Lu
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.