J Neuroinflamm丨LU Zhengqi / CAI Wei / QIU Wei Team Unveils Novel Regulatory Mechanism for Central Immune Organs, Proposing a Cell-Free Strategy for Post-Stroke Immunotherapy

After acute ischemic stroke (AIS), the activation of the sympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis aims to mitigate neuroinflammatory injury. However, this response can lead to an "overcorrection," resulting in an immunosuppressed state.  This condition causes lymphopenia and post-stroke immunosuppression (PICS), significantly increasing patients' susceptibility to infections, exacerbating neurological deficits, and even raising mortality risks. Current therapies that directly inhibit these neuroendocrine axes have notable limitations, as they may simultaneously interfere with endogenous neuroprotective pathways. Reversing immunosuppression without disrupting beneficial protective mechanisms remains a major challenge in stroke treatment.

On November 15, 2025, a research team led by Professor LU Zhengqi, Associate Researcher CAI Wei, and Professor QIU Wei from the Department of Neurology at the Center for Brain Diseases of The Third Affiliated Hospital of Sun Yat-sen University published a groundbreaking study in the prestigious Journal of Neuroinflammation (a top journal in CAS Zone 1). Their research reveals that bone marrow mesenchymal stem cells (BM-MSCs) utilize migrasomes to bypass the blood-thymus barrier, enabling the precise delivery of therapeutic molecules to the thymus. This approach overcomes the limitations of traditional cell therapies in targeting central immune organs. Notably, migrasome-based monotherapy not only replicates the dual benefits of BM-MSCs—neuroprotection and immune reconstitution—but also avoids the ethical and safety concerns associated with stem cell transplantation. These findings elucidate a novel mechanism by which BM-MSCs regulate central immune organs and propose a promising cell-free strategy for immunotherapy after stroke.

Original link

https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-025-03604-2

Key Findings

This study revealed that the thymus, which serves as a "training camp" for immune cells, rapidly atrophies after stroke due to overactivated neuroendocrine signaling. This atrophy impairs the generation of new T cells and exacerbates peripheral immunosuppression. The research team focused on thymic epithelial cells (TECs), the core stromal cells that constitute the thymic microenvironment. The study demonstrated that BM-MSCs-derived migrasomes deliver the PIN1 protein to medullary thymic epithelial cells (mTECs), thereby promoting their functional recovery.

Figure 1: BM-MSC-derived migrasomes cross the blood-thymus barrier and specifically home in on mTECs.

Using high-resolution imaging and molecular tracking techniques, the team confirmed that BM-MSC-derived migrasomes cross the blood-thymus barrier and are efficiently taken up by mTECs. These migrasomes significantly enhanced mTEC proliferation, leading to rapid restoration of stroke-induced thymic atrophy and recovery of thymic output of functional T cells. This process fundamentally alleviated peripheral immunosuppression. Through proteomic and single-cell RNA sequencing analyses, the researchers identified PIN1—a key protein regulating the cell cycle—as the critical functional molecule within migrasomes. By delivering PIN1 to mTECs, BM-MSCs effectively "rebooted" the cell cycle of mTECs, restoring their proliferative capacity.

Future Perspectives

This study is the first to systematically elucidate the novel mechanism by which BM-MSCs regulate the thymus—a central immune organ—via migrasomes. The migrasome-based monotherapy not only replicates the dual benefits of stem cell therapy, namely neuroprotection and immune reconstruction, but also circumvents the ethical and safety risks associated with live cell transplantation. This approach provides a groundbreaking "cell-free" strategy for post-stroke immunotherapy.

Notably, this strategy has demonstrated potential in reversing thymic atrophy even in aged mouse models. Currently, the research team is actively optimizing the targeted delivery system for migrasomes and advancing the translation of this original discovery into clinical applications. It is anticipated that this innovative approach may offer new hope for numerous stroke patients in the future.

Corresponding author

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