Monocytes shape the neuroprotective and immunomodulatory effects of mesenchymal stromal cell-derived extracellular vesicles

Wang, C.; Zhang, Y.; Tertel, T.; Mouloud, Y.; Liu, X.; Hagemann, N.; Mohamud Yusuf, A.; Gronewold, J.; Strecker, J.-K.; Popa-Wagner, A.; Mack, M.; Minnerup, J.; Gunzer, M.; Giebel, B.; Hermann, D.

doi:10.64898/2026.06.01.727369

bioRxiv · 10.64898/2026.06.01.727369

Monocytes shape the neuroprotective and immunomodulatory effects of mesenchymal stromal cell-derived extracellular vesicles

Wang, C.·Zhang, Y.·Tertel, T.·Mouloud, Y.·Liu, X.·Hagemann, N.·Mohamud Yusuf, A.·Gronewold, J.·Strecker, J.-K.·Popa-Wagner, A.·Mack, M.·Minnerup, J.·Gunzer, M.·Giebel, B.·Hermann, D.

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Abstract

BACKGROUNDMesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) exert neuroprotective effects in ischemic stroke largely through immunomodulatory mechanisms. Monocytes are first-line responders to MSC-EVs. Their contribution to MSC-EV-induced neuroprotection remains poorly understood. This study investigated the role of monocytes in shaping neuroprotective responses to MSC-EVs after ischemic stroke. METHODSMale C57BL/6J mice were exposed to transient middle cerebral artery occlusion (MCAO). Monocytes were depleted using pharmacological (clodronate liposomes), immunological (anti-CCR2), or genetic (Mrp8-Cre+/- Nr4a1fl/fl) approaches removing total, CCR2+, or Ly6Clow monocytes, respectively. In additional cohorts, neutrophils and T cells were simultaneously depleted by anti-Ly6G or anti-CD4/CD8 antibodies. Small EVs from clonally expanded immortalized MSCs were administered intravenously. Neurological deficits, ischemic injury, and immune responses were analyzed up to 72 hours post-MCAO. Complementary ex vivo studies were performed, in which MSC-EVs were administered to monocyte-depleted or non-depleted peripheral blood mononuclear cells (PBMCs) obtained from acute ischemic stroke patients. RESULTSIn ischemic mice with intact monocyte compartment, MSC-EVs reduced neurological deficits, infarct volume, neuronal injury, and brain leukocyte infiltrates. These protective effects were abolished in monocyte-depleted mice, particularly following CCR2+ monocyte depletion. Under these conditions, MSC-EV treatment exacerbated neurological deficits, ischemic injury, and leukocyte infiltration, accompanied by neutrophil and T cell expansion and overactivation. Depletion of neutrophils or T cells prevented the EV-induced worsening of stroke outcome in monocyte-deficient mice. Ly6Clow monocytes played a crucial role in orchestrating immune responses to MSC-EVs. Their depletion abolished EV-induced neuroprotection. In stroke patient PBMCs, MSC-EVs induced phenotypic reprogramming of monocytes, whereas they promoted CD4+ and CD8+ T cell activation in the absence of monocytes. CONCLUSIONSMonocytes shape the immunomodulatory actions of MSC-EVs. In their absence, MSC-EVs trigger neutrophil and T cell overactivation that worsens stroke outcome. These findings highlight the importance of monocyte- and T cell-related potency assays for the clinical translation of MSC-EV therapies.

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Wang, C., Zhang, Y., Tertel, T., Mouloud, Y., Liu, X., Hagemann, N., Mohamud Yusuf, A., Gronewold, J., Strecker, J.-K., Popa-Wagner, A., Mack, M., Minnerup, J., Gunzer, M., Giebel, B., Hermann, D.. 2026-06-03. Monocytes shape the neuroprotective and immunomodulatory effects of mesenchymal stromal cell-derived extracellular vesicles. https://doi.org/10.64898/2026.06.01.727369

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