Mesenchymal stem cells and cell-derived extracellular vesicles protect hippocampal neurons from oxidative stress and synapse damage induced by amyloid-ß oligomers.

Alzheimer's disease (AD) is a disabling and highly prevalent neurodegenerative condition, for which there are no effective therapies. Soluble oligomers of the amyloid-ß peptide (AßOs) are thought to be proximal neurotoxins involved in early neuronal oxidative stress and synapse damage, ultimately leading to neurodegeneration and memory impairment in AD. The aim of the current study was to evaluate the neuroprotective potential of mesenchymal stem cells (MSCs) against the deleterious impact of AßOs on hippocampal neurons. To this end, we established transwell cocultures of rat hippocampal neurons and MSCs. We show that MSCs and MSC-derived extracellular vesicles protect neurons against AßO-induced oxidative stress and synapse damage, revealed by loss of pre- and postsynaptic markers. Protection by MSCs entails three complementary mechanisms: 1) internalization and degradation of AßOs; 2) release of extracellular vesicles containing active catalase; and 3) selective secretion of interleukin-6, interleukin-10, and vascular endothelial growth factor to the medium. Results support the notion that MSCs may represent a promising alternative for cell-based therapies in AD.

Bone-marrow mononuclear cells reduce neurodegeneration in hippocampal CA1 layer after transient global ischemia in rats.

Global cerebral ischemia (GCI) results in death of the pyramidal neurons in the CA1 layer of the hippocampus. In this study we used the four-vessel occlusion (4VO) model of GCI to investigate a potential neuroprotective role of bone-marrow mononuclear cells (BMMCs) transplantation. BMMCs (3×10(7)) were injected through the carotid artery, 1 or 3 days after ischemia (DAI), and the number of cells undergoing degeneration was investigated in brains at 7 DAI. A significant decrease in the number of dying cells was observed in the treated group, compared to animals treated with saline. Biodistribution of the injected cells (1 or 3 DAI) was investigated by (99m)Technetium labeling of the BMMCs and subsequent image analysis 2h after transplantation. In addition, the presence of CellTrace(™)-labeled BMMCs was investigated in tissue sections of the hippocampal area of these transplanted animals. BMMCs treatment significantly reduced the number of FJ-C positive cells in the hippocampal CA1 layer at 7 DAI. We also observed a decrease in the number of activated microglia/macrophage (ED1-positive cells) in the BMMCs-treated group compared with the untreated group. Our data show that BMMCs are able to modulate the microglial response and reduce neurodegeneration in the CA1 layer.

Intravenous and intra-arterial administration of bone marrow mononuclear cells after focal cerebral ischemia: Is there a difference in biodistribution and efficacy?

Intravascular delivery of cells has been increasingly used in stroke models and clinical trials. We compared the biodistribution and therapeutic effects of bone marrow mononuclear cells (BMMCs) delivered by intra-arterial (IA) or intravenous (IV) injection after cortical ischemia. For the biodistribution analyses, BMMCs were labeled with (99m)Technetium ((99m)Tc). At 2 h, gamma-well counting of the brain and of the other organs evaluated did not show differences between the non-ischemic and ischemic groups or between injection routes, and the organs with the highest uptake were the liver and lungs, with low uptake in the brain. At 24 h, the liver maintained the highest activity, and a marked decrease was seen in pulmonary uptake in all groups. At this time point, although the activity in the brain remained low, the lesioned hemisphere showed greater homing than the contralateral hemisphere, for both the IV and IA ischemic groups. Histological analysis by CellTrace labeling indicated similar homing between both routes in the peri-infarct region 24 h after transplantation and functional recovery was observed in both groups up to 11 weeks after the lesion. In conclusion, transplantation of BMMCs by IA or IV routes may lead to similar brain homing and therapeutic efficacy after experimental stroke.