Abstract Body:
Introduction: Stroke-induced immunosuppression (SIIS) can lead to increased susceptibility to infections, which ultimately affects functional outcomes and increases mortality rates. Our previous studies suggest that Bone Marrow Mesenchymal Stem Cell (BM-MSCs) protect against SIIS and prevent post-stroke pneumonia.In this study, we propose that BM-MSCs have the potential to repair thymic atrophy after infarction, thereby offering protection against SIIS.
Methods: We conducted a 60-minute transient middle cerebral artery occlusion (tMCAO) on male C57BL/6J mice. Two hours after the tMCAO, separate injections of PBS , BM-MSCs , and GFP-TSPAN4-labeled migrasomes derived from BM-MSCs were administered.The thymuses of the infarcted mice were subsequently collected at 3, 7, and 14 days post-tMCAO for RNA sequencing, and immunofluorescence staining. Liquid chromatography tandem mass spectrometry (LC-MS/MS) was performed to profile the proteome of migrasomes.
Result：We found that in tMCAO mice, the mortality rate decreased and thymic weight was restored after injection of BM-MSCs. Cellular mechanism studies using bulk RNA sequencing revealed that BM-MSC treatment downregulates senesence of thymic cells and enhances cell proliferation. Immunofluorescence analysis indicated that after stroke, thymic medullary epithelial cells (TECs) exhibited remarkable senescence, especially those in the medulla. BM-MSC treatment reversed the senesence of thymic cells. Interestingly, we found that BM-MSCs do not directly enter the thymus, while migrasomes derived from BM-MSCs, which are newly discovered organelle that produced during cellular migration, could cross the blood-thymus barrier, reaching and interacting with TECs. Proteomic analysis of BM-MSC-derived migrasomes revealed that Peptidyl-prolyl cis-trans isomerase (Pin1) was packed in the organelle. Pin1 is a vital cell cycle protein that promotes cell proliferation and division. Based on these findings, we hypothesize that migrasomes derived from BM-MSCs may transfer Pin1 protein to TECs, potentially reversing cellular aging.
Conclusions: BM-MSCs have the potential to reverse thymic atrophy after infarction and protect against the senscence of TECs. Notably, migrasomes derived from BM-MSCs can cross the blood-thymus barrier and transfer the Pin1 protein to TECs. Based on these findings, we propose that BM-MSC-derived migrasomes can restore thymic atrophy and prevent SIIS.