Recently, it was suggested that neurons can release and transfer damaged mitochondria to astrocytes for disposal and recycling 1. This ability to exchange mitochondria may represent a potential mode of cell-cell signaling in the central nervous system (CNS). Here, we show that astrocytes can also release functional mitochondria that enter into neurons. Astrocytic release of extracellular mitochondria particles was mediated by a calcium-dependent mechanism involving CD38/cyclic ADP ribose signaling. Transient focal cerebral ischemia in mice induced astrocytic mitochondria entry to adjacent neurons that amplified cell survival signals. Suppression of CD38 signaling with siRNA reduced extracellular mitochondria transfer and worsened neurological outcomes. These findings suggest a new mitochondrial mechanism of neuroglial crosstalk that may contribute to endogenous neuroprotective and neurorecovery mechanisms after stroke.

In vitro, actin filament tension correlates with the binding and apparent activity of the filament-severing protein cofilin, suggesting a molecular mechanism by which cells respond to changes in mechanical force.

Laboratory studies are increasingly indicating that the quality of nutrientlimited algae is suboptimal for zooplankton production. However, little is known about how quality is affected by nutrient limitation of phytoplankton in more natural situations. To test for phosphorus (P) limitation of zooplankton growth under realistic food conditions, we performed a set of 5-d experiments using Daphnia dentifera and suspended particulate matter (seston) from three lakes at the Experimental Lakes Area (Ontario, Canada). Neonate Daphnia fed for 6 h per day on freshly collected seston enriched or unenriched with PO 4 and spent the rest of the day feeding on unaltered natural seston. PO 4 enrichment did not affect food abundance or concentrations and composition of essential fatty acids but dramatically lowered seston C:P ratio and significantly stimulated Daphnia growth. These results demonstrate that, even with field-collected seston, the effects of algal phosphorus limitation can extend to herbivores through reduced food quality.

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At low levels, carbon monoxide (CO) has physiological roles as a second messenger and neuromodulator. Here we assess the effects of CO in a mouse model of traumatic brain injury (TBI). Treatment with CO-releasing molecule (CORM)-3 reduced pericyte death and ameliorated the progression of neurological deficits. In contrast, although treatment with the radical scavenger N-tert-butyl-a-phenylnitrone (PBN) also reduced pericyte death, neurological outcomes were not rescued. As compared to vehicle-treated control and PBN-treated mice, CORM-3-treated mice showed higher levels of phosphorylated neural nitric oxide synthase within neural stem cells (NSCs). Inhibition of nitric oxide synthase diminished the CORM-3-mediated increase in the number of cells that stained positive for both the neuronal marker NeuN and 5-bromo-2'-deoxyuridine (BrdU; a marker for proliferating cells) in vivo, consequently interfering with neurological recovery after TBI. Because NSCs seemed to be in close proximity to pericytes, we asked whether cross-talk between pericytes and NSCs was induced by CORM-3, thereby promoting neurogenesis. In pericyte cultures that were undergoing oxygen and glucose deprivation, conditioned cell culture medium collected after CORM-3 treatment enhanced the in vitro differentiation of NSCs into mature neurons. Taken together, these findings suggest that CO treatment may provide a therapeutic approach for TBI by preventing pericyte death, rescuing cross-talk with NSCs and promoting neurogenesis.

Mechanosensitive (MS) channels are expressed in various cells in a wide range of phylogenetic lineages from bacteria to humans. Understanding the molecular and biophysical mechanisms of their activation is an important research pursuit. It is controversial whether eukaryotic MS channels need accessory proteins – typically cytoskeletal structures – for activation, because MS channel activities are modulated by pharmacological treatments that affect the cytoskeleton. Here we demonstrate that direct mechanical stimulation (stretching) of an actin stress fiber using optical tweezers can activate MS channels in cultured human umbilical vein endothelial cells (HUVECs). Furthermore, by using high-speed total internal reflection microscopy, we visualized spots of Ca2+ influx across individual MS channels distributed near focal adhesions in the basal surface of HUVECs. This study provides the first direct evidence that the cytoskeleton works as a force-transmitting and force-focusing molecular device to activate MS channels in eukaryotic cells.

Oligodendrocyte precursor cells (OPCs) are thought to maintain homeostasis and contribute to long-term repair in adult white matter; however, their roles in the acute phase after brain injury remain unclear. Mice that were subjected to prolonged cerebral hypoperfusion stress developed white matter demyelination over time. Prior to demyelination, we detected increased MMP9 expression, blood-brain barrier (BBB) leakage, and neutrophil infiltration in damaged white matter. Notably, at this early stage, OPCs made up the majority of MMP9-expressing cells. The standard MMP inhibitor GM6001 reduced the early BBB leakage and neutrophil infiltration, indicating that OPC-derived MMP9 induced early BBB disruption after white matter injury. Cellculture experiments confirmed that OPCs secreted MMP9 under pathological conditions, and conditioned medium prepared from the stressed OPCs weakened endothelial barrier tightness in vitro. Our study reveals that OPCs can rapidly respond to white matter injury and produce MMP9 that disrupts the BBB, indicating that OPCs may mediate injury in white matter under disease conditions.

Crosstalk between the brain and systemic responses in blood is increasingly suspected of playing critical roles in stroke. However, how this communication takes place remains to be fully understood. Here, we show that reactive astrocytes can release a damage-associated molecular-pattern molecule called high-mobilitygroup-box-1 (HMGB1) that promotes endothelial progenitor cell (EPC)-mediated neurovascular remodeling during stroke recovery. Conditioned media from reactive astrocytes increase EPC proliferation in vitro. siRNA suppression of HMGB1 in astrocytes or blockade of the HMGB1 receptor for advanced glycation endproducts in EPCs prevents this effect. In a mouse model of focal cerebral ischemia, reactive astrocytes in the peri-infarct cortex upregulate HMGB1 at 14 d poststroke, along with an accumulation of endogenous EPCs. In vivo siRNA suppression of HMGB1 blocks this EPC response, reduces peri-infact angiogenesis, and worsens neurological deficits. Taken together, these molecular and in vivo findings support a previously undescribed mechanism of crosstalk between reactive astrocytes and EPCs wherein HMGB1 promotes neurovascular remodeling and functional recovery after stroke and brain injury.reactive glia | vascular repair | brain remodeling