Introduction: Traumatic spinal cord injury (SCI) damages the cord vascular barrier and allows local accumulation of destructive inflammatory cells with release of toxic molecules that infiltrate into the cord, contributing to the neuronal loss, axon severing, and demyelination that can lead to paralysis. Intravenous infusions of mesenchymal stem cells (MSCs) can reduce the severity of SCI, but the involved mechanisms are not fully understood.
Methods: Groups of 8 young adult rats were subjected to a homogeneously delivered moderate contusive SCI at the T9 level. Then cell treatment was attempted by i.v. infusion of 1x106 rat bone marrow derived MSCs or exosomes isolated from MSC-conditioned media, compared to media alone, at one week post-SCI. Animals then were assessed for functional recovery and vascular permeability by Evans blue dye extravasation. Distribution of DiR-labeled MSCs vs MSCexos was assessed by in vivo and ex vivo imaging of organs and by fluorescence microscopy monoclonal antibody staining of frozen sections.
Results: SCI resulted in profound weakness and large vascular leakage that were reduced in MSC transplanted rats beginning 1 week post-MSC infusion. However, i.v infused MSCs were not detected within the spinal cord at any time point, but appeared to traffic just transiently to the lungs. In contrast, MSCexos produced comparable improvements and were readily detected at sites of SCI; especially localizing to M2 macrophages (Mf) associated with healing vs. pro-inflammatory M1 Mf.
Summary: Infusion of MSCexos one week after contusive SCI reduced, like i.v. injection of MSC increased vascular permeability and improved functional recovery with strong localization at site of SCI; preferentially to local M2 Mf of healing and not M1 Mf of inflammation
Conclusion: The data suggest that the therapeutic effect of MSCs on SCI likely is mediated by their secreted MSCexos that preferentially target healing M2 and not inflammatory M1 macrophages.