Intravenously delivered mesenchymal stem cell-derived exosomes target M2-type macrophages in the injured spinal cord

In a previous report we showed that intravenous infusion of bone marrow-derived mesenchymal stem cells (MSCs) improved functional recovery after contusive spinal cord injury (SCI) in the non-immunosuppressed rat, although the MSCs themselves were not detected at the spinal cord injury (SCI) site [1]. Rather, the MSCs lodged transiently in the lungs for about two days post-infusion. Preliminary studies and a recent report [2] suggest that the effects of intravenous (IV) infusion of MSCs could be mimicked by IV infusion of exosomes isolated from conditioned media of MSC cultures (MSCexos). In this study, we assessed the possible mechanism of MSCexos action on SCI by investigating the tissue distribution and cellular targeting of DiR fluorescent labeled MSCexos at 3 hours and 24 hours after IV infusion in rats with SCI. The IV delivered MSCexos were detected in contused regions of the spinal cord, but not in the noninjured region of the spinal cord, and were also detected in the spleen, which was notably reduced in weight in the SCI rat, compared to control animals. DiR "hotspots" were specifically associated with CD206-expressing M2 macrophages in the spinal cord and this was confirmed by co-localization with anti-CD63 antibodies labeling a tetraspanin characteristically expressed on exosomes. Our findings that MSCexos specifically target M2-type macrophages at the site of SCI, support the idea that extracellular vesicles, released by MSCs, may mediate at least some of the therapeutic effects of IV MSC administration

Neurophysiology

Contains reports on twenty research projects.Bell Laboratories (Grant)National Institutes of Health (Grant 5 R01 EY01149-03S2)National Institutes of Health (Grant 5 TO1 EY00090-04)National Institutes of Health (Grant 5 RO1 NS12307-03)National Institutes of Health (Grant K04 NS00010)National Multiple Sclerosis Society (Grant RG-1133-A-1)Health Sciences Fund (Grant 78-10

Peripheral Nerve Injuries and Transplantation of Olfactory Ensheathing Cells for Axonal Regeneration and Remyelination: Fact or Fiction?

Abstract: Successful nerve regeneration after nerve trauma is not only important for the restoration of motor and sensory functions, but also to reduce the potential for abnormal sensory impulse generation that can occur following neuroma formation. Satisfying functional results after severe lesions are difficult to achieve and the development of interventional methods to achieve optimal functional recovery after peripheral nerve injury is of increasing clinical interest. Olfactory ensheathing cells (OECs) have been used to improve axonal regeneration and functional outcome in a number of studies in spinal cord injury models. The rationale is that the OECs may provide trophic support and a permissive environment for axonal regeneration. The experimental transplantation of OECs to support and enhance peripheral nerve regeneration is much more limited. This chapter reviews studies using OECs as an experimental cell therapy to improve peripheral nerve regeneration

Development of a middle cerebral artery occlusion model in the nonhuman primate and a safety study of i.v. infusion of human mesenchymal stem cells.

Most experimental stroke research is carried out in rodents, but given differences between rodents and human, nonhuman primate (NHP) models may provide a valuable tool to study therapeutic interventions. The authors developed a surgical method for transient occlusion of the M1 branch of middle cerebral artery (MCA) in the African green monkey to evaluate safety aspects of intravenous infusion of mesenchymal stem cells (hMSCs) derived from human bone marrow.The left Sylvian fissure was exposed by a small fronto-temporal craniotomy. The M1 branch of the MCA was exposed by microsurgical dissection and clipped for 2 to 4 hours. Neurological examinations and magnetic resonance imaging (MRI) were carried out at regular post-operative course. hMSCs were infused 1 hour after reperfusion (clip release) in the 3-hour occlusion model.During M1 occlusion, two patterns of changes were observed in the lateral hemisphere surface. One pattern (Pattern 1) was darkening of venous blood, small vessel collapse, and blood pooling with no venous return in cortical veins. Animals with these three features had severe and lasting hemiplegia and MRI demonstrated extensive MCA territory infarction. Animals in the second pattern (Pattern 2) displayed darkening of venous blood, small vessel collapse, and reduced but incompletely occluded venous flow and the functional deficit was much less severe and MRI indicated smaller infarction areas in brain. The severe group (Pattern 1) likely had less extensive collateral circulation than the less severe group (Pattern 2) where venous pooling of blood was not observed. The hMSC infused animals showed a trend for greater functional improvement that was not statistically significant in the acute phase and no additive negative effects.These results indicate inter-animal variability of collateral circulation after complete M1 occlusion and that hMSC infusion is safe in the developed NHP stroke model