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

A Preliminary Report: The Hippocampus and Surrounding Temporal Cortex of Patients With Schizophrenia Have Impaired Blood-Brain Barrier

Schizophrenia (SZ) is one of the most severe forms of mental illness, yet mechanisms remain unclear. A widely established brain finding in SZ is hippocampal atrophy, and a coherent explanation similarly is lacking. Epidemiological evidence suggests increased cerebrovascular and cardiovascular complications in SZ independent of lifestyle and medication, pointing to disease-specific pathology. Endothelial cell contributions to blood-brain barrier (BBB) compromise may influence neurovascular unit and peripheral vascular function, and we hypothesize that downstream functional and structural abnormalities may be explained by impaired BBB

Genetic dysmyelination alters the molecular architecture of the nodal region

We have examined the molecular organization of axons in the spinal cords of myelin-deficient (md) rats, which have profound CNS dysmyelination associated with oligodendrocyte cell death. Although myelin sheaths are rare, most large axons are at least partially surrounded by oligodendrocyte processes. At postnatal day 7 (P7), almost all node-like clusters of voltagegated Na � channels and ankyrin G are adjacent to axonal segments ensheathed by oligodendrocytes, but at P21, many node-like clusters are found in axonal segments that lack oligodendrocyte ensheathment. In P21 wild-type (WT) rats, the voltage-gated Na � channels Na v1.2, Na v1.6, and Na v1.8, are found in different subpopulations of myelinated axons, and md rats have a similar distribution. The known molecular components of paranodes—contactin, Caspr, and neurofascin 155— are not clustered in md spinal cords, and no septate-like junction

Author correction: One sixth of Amazonian tree diversity is dependent on river floodplains

In the version of the article initially published, the affiliation of Edgardo Manuel Latrubesse was incorrect and has now been amended to Environmental Sciences Graduate Program-CIAMB, Federal University of Goiás, Goiânia, Brazil in the HTML and PDF versions of the article

One sixth of Amazonian tree diversity is dependent on river floodplains

Amazonia’s floodplain system is the largest and most biodiverse on Earth. Although forests are crucial to the ecological integrity of floodplains, our understanding of their species composition and how this may differ from surrounding forest types is still far too limited, particularly as changing inundation regimes begin to reshape floodplain tree communities and the critical ecosystem functions they underpin. Here we address this gap by taking a spatially explicit look at Amazonia-wide patterns of tree-species turnover and ecological specialization of the region’s floodplain forests. We show that the majority of Amazonian tree species can inhabit floodplains, and about a sixth of Amazonian tree diversity is ecologically specialized on floodplains. The degree of specialization in floodplain communities is driven by regional flood patterns, with the most compositionally differentiated floodplain forests located centrally within the fluvial network and contingent on the most extraordinary flood magnitudes regionally. Our results provide a spatially explicit view of ecological specialization of floodplain forest communities and expose the need for whole-basin hydrological integrity to protect the Amazon’s tree diversity and its function

Exosome characterization.

<p>A: Electron micrograph of vesicles in exosome fraction from MSC conditioned media sample on formvar coated grid. B: Histogram of size distribution of 536 presumptive exosomes. Note the average size of the vesicles was 59.09 ± 0.58 nm, consistent with exosomes. C-D: Fluorescence micrographs of intact spinal cord directly injected with exosomes fractions from SytoRNAse (C) and DiR (D) labeled MSCs before perfusion. Note that the presence of detectable levels of 488nm (SytoRNAse) and 650nm (DiR) fluorescence indicates the presence of both RNAs and lipids in the exosome fractions. Scale bar in A indicates 100nm. Scale bars in C &D indicate 1 mm.</p

DiR hotspots transiently localize to kidney and more persistently to spleen.

<p>A-D: DiR fluorescence (cyan) in kidney (A, C) and spleen (B, D) 3hours (A, B) and 24 hours (C, D) after infusion with DiR-MSC^exos. Note the decrease in DiR fluorescence in the kidneys between 3 and 24 hours after DiR-MSC^exos infusion, but increase in the spleen during the same time period. E-F: Spleens at 24 hours after DiR-MSC^exos infusion in SCI rats immunostained with antibodies directed against CD206 (green) and CD8 (red) DiR fluorescence hotspots. E¹-F¹: Enlarged rotated images of boxed areas in E and F. Note that DiR hotspots localize to both CD206⁺ and CD4⁺ cells in the spleen. Scale bars in E 100 μm and applies to A-D. Scale bars in E&F indicate 20 μm.</p

Exosome detection in situ.

<p>A-C: Two photon confocal micrographs of contused spinal cord 3 hours after IV infusion of DiR labeled exosomes showing the colocalization of regions of high endogenous 488 autofluorescence with 650nm DiR hotspots. D-H: Endogenous DiR wavelength in the spleen (D-E) and lungs (F-H) of contused animals with no exosome infusion. High magnification shows sizes and shapes of DiR hotspots in match those of red blood cells. I-J: Endogenous DiR wavelength fluorescence of paraformaldehyde fixed rat red blood cells isolated from peripheral blood. Scale bar in A indicates 100 μm and applies to A-C. Scale bars in D, F indicate 100 μm and applies to A-C. Scale bars in D, F indicate 100 micrographs of contused spinal cord 3 hours DiR hotspots.</p