Microglia are brain resident macrophages originated from primitive progenitor cells in the yolk sac. Microglia can be activated within hours and recruited to the lesion site. Traditionally, microglia ...activation is considered to play a deleterious role in ischemic stroke, as inhibition of microglia activation attenuates ischemia induced brain injury. However, increasing evidence show that microglia activation is critical for attenuating neuronal apoptosis, enhancing neurogenesis, and promoting functional recovery after cerebral ischemia. Differential polarization of microglia could likely explain the biphasic role of microglia in ischemia. We comprehensively reviewed the mechanisms involved in regulating microglia activation and polarization. The latest discoveries of microRNAs in modulating microglia function are discussed. In addition, the interaction between microglia and other cells including neurons, astrocytes, oligodendrocytes, and stem cells were also reviewed. Future therapies targeting microglia may not exclusively aim at suppressing microglia activation, but also at modulating microglia polarization at different stages of ischemic stroke. More work is needed to elucidate the cellular and molecular mechanisms of microglia polarization under ischemic environment. The roles of microRNAs and transplanted stem cells in mediating microglia activation and polarization during brain ischemia also need to be further studied.
Microglial activation participates in white matter injury after cerebral hypoperfusion. However, the underlying mechanism is unclear. Here, we explore whether activated microglia aggravate white ...matter injury via complement C3-C3aR pathway after chronic cerebral hypoperfusion.
: Adult male Sprague-Dawley rats (n = 80) underwent bilateral common carotid artery occlusion for 7, 14, and 28 days. Cerebral vessel density and blood flow were examined by synchrotron radiation angiography and three-dimensional arterial spin labeling. Neurobehavioral assessments, CLARITY imaging, and immunohistochemistry were performed to evaluate activation of microglia and C3-C3aR pathway. Furthermore, C3aR knockout mice were used to establish the causal relationship of C3-C3aR signaling on microglia activation and white matter injury after hypoperfusion.
: Cerebral vessel density and blood flow were reduced after hypoperfusion (
0.05). Spatial learning and memory deficits and white matter injury were shown (
0.05). These impairments were correlated with aberrant microglia activation and an increase in the number of reactive microglia adhering to and phagocytosed myelin in the hypoperfusion group (
0.05), which were accompanied by the up-regulation of complement C3 and its receptors C3aR (
0.05). Genetic deletion of
significantly inhibited aberrant microglial activation and reversed white matter injury after hypoperfusion (
0.05). Furthermore, the C3aR antagonist SB290157 decreased the number of microglia adhering to myelin (
0.05), attenuated white matter injury and cognitive deficits in chronic hypoperfusion rats (
0.05).
: Our results demonstrated that aberrant activated microglia aggravate white matter injury via C3-C3aR pathway during chronic hypoperfusion. These findings indicate C3aR plays a critical role in mediating neuroinflammation and white matter injury through aberrant microglia activation, which provides a novel therapeutic target for the small vessel disease and vascular dementia.
The pathological role of reactive gliosis in CNS repair remains controversial. In this study, using murine ischemic and hemorrhagic stroke models, we demonstrated that microglia/macrophages and ...astrocytes are differentially involved in engulfing synapses in the reactive gliosis region. By specifically deleting MEGF10 and MERTK phagocytic receptors, we determined that inhibiting phagocytosis of microglia/macrophages or astrocytes in ischemic stroke improved neurobehavioral outcomes and attenuated brain damage. In hemorrhagic stroke, inhibiting phagocytosis of microglia/macrophages but not astrocytes improved neurobehavioral outcomes. Single-cell RNA sequencing revealed that phagocytosis related biological processes and pathways were downregulated in astrocytes of the hemorrhagic brain compared to the ischemic brain. Together, these findings suggest that reactive microgliosis and astrogliosis play individual roles in mediating synapse engulfment in pathologically distinct murine stroke models and preventing this process could rescue synapse loss.
Abstract
Background
Neuroinflammation is the major pathogenesis of cerebral ischemia. Microglia are activated and polarized to either the pro-inflammatory M1 phenotype or anti-inflammatory M2 ...phenotype, which act as a critical mediator of neuroinflammation. Sestrin2 has pro-survival properties against ischemic brain injury. However, whether sestrin2 has an anti-inflammatory function by shifting microglia polarization and its underlying mechanism is unknown.
Methods
Adult male C57BL/6 mice (
N
= 108) underwent transient middle cerebral artery occlusion (tMCAO) and were treated with exogenous sestrin2. Neurological deficit scores and infarct volume were determined. Cell apoptosis was examined by TUNEL staining and Western blotting. The expression of inflammatory mediators, M1/M2-specific markers, and signaling pathways were detected by reverse transcription-polymerase chain reaction, immunostaining, and Western blotting. To explore the underlying mechanism, primary neurons were subjected to oxygen-glucose deprivation (OGD) and then treated with oxygenated condition medium of BV2 cells incubated with different doses of sestrin2.
Results
Sestrin2 attenuated the neurological deficits, infarction volume, and cell apoptosis after tMCAO compared to those in the control (
p
< 0.05). Sestrin2 had an anti-inflammatory effect and could suppress M1 microglia polarization and promote M2 microglia polarization
.
Condition medium from BV2 cells cultured with sestrin2 reduced neuronal apoptosis after OGD in vitro. Furthermore, we demonstrated that sestrin2 drives microglia to the M2 phenotype by inhibiting the mammalian target of rapamycin (mTOR) signaling pathway and restoring autophagic flux.
Conclusions
Sestrin2 exhibited neuroprotection by shifting microglia polarization from the M1 to M2 phenotype in ischemic mouse brain, which may be due to suppression of the mTOR signaling pathway and the restoration of autophagic flux.
Organic solar cells (OSCs) with nonfullerene acceptors (NFAs) exhibit efficient charge generation under small interfacial energy offsets, leading to over 18 % efficiency for the single‐junction ...devices based on the state‐of‐the‐art NFA of Y6. Herein, to reveal the underlying charge generation mechanisms, we have investigated the exciton binding energy (Eb) in Y6 by a joint theoretical and experimental study. The results show that owing to strong charge polarization effects, Y6 has remarkable small Eb of −0.11–0.15 eV, which is even lower than perovskites in many cases. Moreover, it is peculiar that the photoluminescence is enhanced with temperature, and the energy barrier for separating excitons into charges is evidently lower than the thermal energy according to the temperature dependence of photoluminescence, manifesting direct photogeneration of charge carriers enabled by weak Eb in Y6. Thus, charge generation in NFA‐based OSCs shows little dependence on interfacial driving forces.
Direct photogeneration of free charge carriers enabled by remarkably low exciton binding energies is demonstrated in the state‐of‐the‐art nonfullerene acceptor of Y6 by a joint experimental and theoretical study. This results in efficient charge generation under small interfacial energy offsets in the high‐efficiency nonfullerene organic solar cells.
Migratory birds play an important role in the spread of multidrug-resistant (MDR) bacteria. To investigate the prevalence of MDR Escherichia coli in migratory birds in China and potential ...relationships with the environment, a total of 1387 samples (fecal samples, cloacal swabs, or throat swabs) were collected from migratory birds from three different river basins in China. The collected samples were processed and subjected to bacteriological examinations. Antimicrobial susceptibility testing of the recovered isolates was performed using the E-test for the detection of minimum inhibitory concentrations (MICs). Some antibiotic resistance genes were detected and the PCR products were confirmed by sequencing. In total, 478 (34.7%) E. coli isolates were recovered. The results showed that the drug-resistant E. coli isolates were highly resistant to β-lactams (43.7%) and tetracycline (22.6%), and 73 (15.3%) were MDR, including eight that were extended spectrum β-lactamase-positive. The retrieved strains harbored the blaCTX-M, blaTEM-1, tet(A), tet(B), tet(M), sul1, sul2, sul3, cmlA, floR, and intI1 genes with a prevalence of 5.9%, 36.4%, 80.5%, 11.9%, 6.8%, 6.8%, 47.5%, 12.7%, 50.8%, 37.3%, and 61.0%, respectively. The drug resistance rate of the isolates from southern China was higher than those from northern China. The E. coli samples collected for migratory birds in the Pearl River Basin had the highest proportion (46.7%) MDR isolates. Furthermore, MDR bacteria carried by migratory birds were closely related to the antibiotic content in the basin, which confirms that MDR bacteria carried by migratory birds are likely acquired from the environment. This study also confirmed that migratory birds are potential transmitters of MDR bacteria, demonstrating the need to reduce the use and emission of antibiotics and further in-depth studies on the mechanisms underlying drug resistance of bacteria.
Background and Purpose
Neuronal regeneration from endogenous precursors is an attractive strategy for the treatment of ischaemic stroke. However, most stroke‐generated newborn neurons die over time. ...Therefore, a drug that is both neuroprotective and pro‐neurogenic may be beneficial after stroke. Here, we assessed the neurogenic and oligodendrogenic effects of tetramethylpyrazine nitrone (TBN), a neuroprotective drug candidate for stroke, in a rat model of ischaemic stroke.
Experimental Approach
We used Sprague Dawley rats with middle cerebral artery occlusion (MCAO). TBN was administered by tail vein injection beginning at 3 h post ischaemia. Therapeutic effect of TBN was evaluated by neurological behaviour and cerebral infarction. Promotion of neurogenesis and oligodendrogenesis was determined by double immunofluorescent staining and Western blotting analyses. Primary cultures of cortical neurons were used to assess the effect of TBN on neuronal differentiation in vitro.
Key Results
TBN reduced cerebral infarction, preserved and/or restored neurological function and promoted neurogenesis and oligodendrogenesis in rats after MCAO. In addition, TBN stimulated neuronal differentiation on primary culture of cortical neurons in vitro. Pro‐neurogenic effects of TBN were attributed to its activation of the AKT/cAMP responsive element‐binding protein through increasing brain‐derived neurotrophic factor (BDNF) expression, as shown by the abolition of the effects of TBN by a specific inhibitor of BDNF receptor ANA‐12 and by the PI3K inhibitor LY294002.
Conclusion and Implications
As TBN can simultaneously provide neuroprotection and pro‐neurogenic effects, it may be a promising treatment for both acute phase neuroprotection and long‐term functional recovery after ischaemic stroke.
Single-cell RNA sequencing (scRNA-seq) technologies are poised to reshape the current cell-type classification system. However, a transcriptome-based single-cell atlas has not been achieved for ...complex mammalian systems. Here, we developed Microwell-seq, a high-throughput and low-cost scRNA-seq platform using simple, inexpensive devices. Using Microwell-seq, we analyzed more than 400,000 single cells covering all of the major mouse organs and constructed a basic scheme for a mouse cell atlas (MCA). We reveal a single-cell hierarchy for many tissues that have not been well characterized previously. We built a web-based “single-cell MCA analysis” pipeline that accurately defines cell types based on single-cell digital expression. Our study demonstrates the wide applicability of the Microwell-seq technology and MCA resource.
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•Development of Microwell-seq, a high-throughput and low-cost scRNA-seq platform•Construction of a single-cell mouse cell atlas (scMCA) covering major cell types•Characterization of cellular heterogeneity with minimal batch effect•Characterization of cross-tissue cellular network at the single-cell level
Development of Microwell-seq allows construction of a mouse cell atlas at the single-cell level with a high-throughput and low-cost platform.
Reactive astrogliosis is a common response to insults to the central nervous system, but the mechanism remains unknown. In this study, we found the temporal and spatial differential expression of ...glial fibrillary acidic protein (GFAP) and Vimentin in the intracerebral hemorrhage (ICH) mouse brain, indicating that the de-differentiation and astroglial-mesenchymal transition (AMT) of astrocytes might be an early event in reactive astrogliosis. Further we verified the AMT finding in purified astrocyte cultures exposed to hemoglobin (Hb). Additionally, Connexin 43 (Cx43) downregulation and YAP nuclear translocation were observed in Hb-activated astrocytes. Knocking down Cx43 by siRNA triggered YAP nuclear translocation. Cx43 and YAP were physically associated as determined by immunofluorescence and co-immunoprecipitation. We propose that astrocytes undergo AMT during Hb-induced activation where Cx43 downregulation facilitates YAP nuclear translocation is a novel mechanism involved in this process. Cx43-YAP interaction may represent a potential therapeutic target for modulating astrocyte activation.
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