Co-transplantation of autologous treg cells: A groundbreaking cell therapy for brain diseases.

Cell therapy and regenerative medicine have made remarkable progress in treating neurodegenerative disorders. Induced pluripotent stem cells (iPSCs) offer a promising source for cell replacement therapies, but their practical application faces challenges due to poor survival and integration after transplantation. Park et al. propose a novel therapeutic strategy involving the co-transplantation of regulatory T cells (Tregs) and iPSC-derived dopamine neurons. This combined approach enhances the survival of transplanted cells and protects against neuroinflammation-induced damage. In PD animal models, the co-transplantation approach significantly suppressed the host immune response, resulting in improved behavioral recovery. Additionally, Tregs demonstrate acute neuroprotection and contribute to delayed neuro-restoration in ischemic stroke. This combined approach of cell therapy with immunomodulation offers a promising avenue for advancing our understanding of neurological diseases and promoting the development of novel treatments.

Novel CH25H+ and OASL+ microglia subclusters play distinct roles in cerebral ischemic stroke.

BACKGROUND: Microglial polarization is one of the most promising therapeutic targets for multiple central nervous system (CNS) disorders, including ischemic stroke. However, detailed transcriptional alteration of microglia following cerebral ischemic stroke remains largely unclear. METHODS: Focal cerebral ischemia was induced by transient middle cerebral artery occlusion (tMCAO) for 60 min in mice. Single-cell RNA sequencing (scRNA-seq) was performed using ischemic brain tissues from tMCAO and sham mice 3 days after surgery. Ch25h-/- mice were used to investigate the role of specific microglia subcluster on post-stroke infarct volume and neuroinflammation. RESULTS: We identified a relatively homeostatic subcluster with enhanced antigen processing and three "ischemic stroke associated microglia" (ISAM): MKI67+, CH25H+ and OASL+ subclusters. We found the MKI67+ subcluster undergo proliferation and differentiation into CH25H+ and OASL+ subclusters. CH25H+ microglia was a critical subcluster of ISAM that exhibited increased phagocytosis and neuroprotective property after stroke. Ch25h-/- mice developed significantly increased infarct volume following ischemic stroke compared to Ch25h+/-. Meanwhile, the OASL+ subcluster accumulated in the ischemic brain and was associated with the evolving of neuroinflammation after stroke, which was further aggravated in the aged mice brain. CONCLUSIONS: Our data reveal previously unrecognized roles of the newly defined CH25H+ and OASL+ microglia subclusters following ischemic stroke, with novel insights for precise microglia modulation towards stroke therapy.

Neutrophil-derived cathelicidin promotes cerebral angiogenesis after ischemic stroke.

Neutrophils play critical roles in the evolving of brain injuries following ischemic stroke. However, how they impact the brain repair in the late phase after stroke remain uncertain. Using a prospective clinical stroke patient cohort, we found significantly increased cathelicidin antimicrobial peptide (CAMP) in the peripheral blood of stroke patients compared to that of healthy controls. While in the mouse stroke model, CAMP was present in the peripheral blood, brain ischemic core and significantly increased at day 1, 3, 7, 14 after middle cerebral artery occlusion (MCAO). CAMP-/- mice exhibited significantly increased infarct volume, exacerbated neurological outcome, reduced cerebral endothelial cell proliferation and vascular density at 7 and 14 days after MCAO. Using bEND3 cells subjected to oxygen-glucose deprivation (OGD), we found significantly increased angiogenesis-related gene expression with the treatment of recombinant CAMP peptide (rCAMP) after reoxygenation. Intracerebroventricular injection (ICV) of AZD-5069, the antagonist of CAMP receptor CXCR2, or knockdown of CXCR2 by shCXCR2 recombinant adeno-associated virus (rAAV) impeded angiogenesis and neurological recovery after MCAO. Administration of rCAMP promoted endothelial proliferation and angiogenesis and attenuated neurological deficits 14 days after MCAO. In conclusion, neutrophil derived CAMP represents an important mediator that could promote post-stroke angiogenesis and neurological recovery in the late phase after stroke.

Trends in perivascular macrophages research from 1997 to 2021: A bibliometric analysis.

INTRODUCTION: Perivascular macrophages (PVMs) play pivotal roles in maintaining the physiological function of the brain. Dysfunction of PVMs is emerging as an important mechanism in various disease conditions in the brain. METHODS: In this work, we analyzed recent research advances in PVMs, especially in the brain, from the Web of Science (WoS) core database using bibliometric analysis based on the search terms "perivascular macrophages" and "perivascular macrophage" on October 27, 2021. Visualization and collaboration analysis were performed by Citespace (5.8 R3 mac). RESULTS: We found 2384 articles published between 1997 and 2021 in the field of PVMs, which were selected for analysis. PVMs were involved in several physio-pathological fields, in which Neurosciences and Neurology, Neuroscience, Immunology, Pathology, and Cardiovascular System and Cardiology were most reported. The research focuses on PVMs mainly in the central nervous system (CNS), inflammation, macrophage or T-cell, and disease, and highlights the related basic research regarding its activation, oxidative stress, angiotensin II, and insulin resistance. Tumor-associated macrophage, obesity, myeloid cell, and inflammation were relatively recent highlight keywords that attracted increasing attention in recent years. Harvard Univ, Vrije Univ Amsterdam, occupied important positions in the research field of PVMs. Meanwhile, PVM research in China (Peking Univ, Sun Yat Sen Univ, Shanghai Jiao Tong Univ, and Shandong Univ) is on the rise. Cluster co-citation analysis revealed that the mechanisms of CNS PVMs and related brain diseases are major specialties associated with PVMs, while PVMs in perivascular adipose tissue and vascular diseases or obesity are another big category of PVMs hotspots. CONCLUSION: In conclusion, the research on PVMs continues to deepen, and the hotspots are constantly changing. Future studies of PVMs could have multiple disciplines intersecting.

Neuronal Serpina3n is an endogenous protector against blood brain barrier damage following cerebral ischemic stroke.

Ischemic stroke results in blood-brain barrier (BBB) disruption, during which the reciprocal interaction between ischemic neurons and components of the BBB appears to play a critical role. However, the underlying mechanisms for BBB protection remain largely unknown. In this study, we found that Serpina3n, a serine protease inhibitor, was significantly upregulated in the ischemic brain, predominantly in ischemic neurons from 6 hours to 3 days after stroke. Using neuron-specific adeno-associated virus (AAV), intranasal delivery of recombinant protein, and immune-deficient Rag1-/- mice, we demonstrated that Serpina3n attenuated BBB disruption and immune cell infiltration following stroke by inhibiting the activity of granzyme B (GZMB) and neutrophil elastase (NE) secreted by T cells and neutrophils. Furthermore, we found that intranasal delivery of rSerpina3n significantly attenuated the neurologic deficits after stroke. In conclusion, Serpina3n is a novel ischemic neuron-derived proteinase inhibitor that counterbalances BBB disruption induced by peripheral T cell and neutrophil infiltration after ischemic stroke. These findings reveal a novel endogenous protective mechanism against BBB damage with Serpina3n being a potential therapeutic target in ischemic stroke.

Impact of less social connectedness and fear of COVID-19 test on employees task performance: A multi-mediation model.

The core objective of this study is to examine the impact of less social connectedness and testing fear on employee health. This study also investigates the mediating role of psychological strain between the relationship of less social connectedness, testing fear and employee health. Furthermore, this study also assesses the impact of employee health on employee performance. The study's target audience consisted of employees in the electronics industry in China. The convenience sample method was used in this study to collect data from respondents. Data analysis of this study was performed by using the structural equation modeling technique. The statistical software used for data analysis is Smart PLS 3. The results of this study show that less COVID-19 testing fear has a negatively significant impact on employee health, but less social connectedness has not significant direct impact on employee health. Furthermore, psychological strain was discovered to mediate the relationship between less social connectedness and employee health and testing fear and employee health. In addition, this impact of employee health on employee performance was found significant. This study provides theoretical and practical implications. In the context of practical implications, this study provides valuable insights for the organizational management to develop a healthy and positive working environment and adopt healthy behavior among their employees which ultimately foster their job performance.

Perivascular macrophages in the CNS: From health to neurovascular diseases.

Brain perivascular macrophages (PVMs) are attracting increasing attention as this emerging cell population in the brain has multifaced roles in supporting the central nervous system structure, brain development, and maintaining physiological functions. They also widely participate in neurological diseases such as neurodegeneration and ischemic stroke. Moreover, PVMs have been reported to have both beneficial and detrimental effects under different pathological contexts. Advanced research technologies allowed the further in-depth study of PVMs and revealed novel concepts in their origins, differentiation, and regulatory mechanisms. Deepened understanding of the roles of PVMs in different brain pathological conditions can reveal novel phenotypic changes and regulatory signaling, which might pave the way for the development of novel treatment strategies targeting PVMs.

Microglial phagocytosis and regulatory mechanisms after stroke.

Stroke, including ischemic stroke and hemorrhagic stroke can cause massive neuronal death and disruption of brain structure, which is followed by secondary inflammatory injury initiated by pro-inflammatory molecules and cellular debris. Phagocytic clearance of cellular debris by microglia, the brain's scavenger cells, is pivotal for neuroinflammation resolution and neurorestoration. However, microglia can also exacerbate neuronal loss by phagocytosing stressed-but-viable neurons in the penumbra, thereby expanding the injury area and hindering neurofunctional recovery. Microglia constantly patrol the central nervous system using their processes to scour the cellular environment and start or cease the phagocytosis progress depending on the "eat me" or "don't eat me'' signals on cellular surface. An optimal immune response requires a delicate balance between different phenotypic states to regulate neuro-inflammation and facilitate reconstruction after stroke. Here, we examine the literature and discuss the molecular mechanisms and cellular pathways regulating microglial phagocytosis, their resulting effects in brain injury and neural regeneration, as well as the potential therapeutic targets that might modulate microglial phagocytic activity to improve neurological function after stroke.

Perioperative stroke: A perspective on challenges and opportunities for experimental treatment and diagnostic strategies.

Perioperative stroke is an ischemic or hemorrhagic cerebral event during or up to 30 days after surgery. It is a feared condition due to a relatively high incidence, difficulties in timely detection, and unfavorable outcome compared to spontaneously occurring stroke. Recent preclinical data suggest that specific pathophysiological mechanisms such as aggravated neuroinflammation contribute to the detrimental impact of perioperative stroke. Conventional treatment options are limited in the perioperative setting due to difficult diagnosis and medications affecting coagulation in may cases. On the contrary, the chance to anticipate cerebrovascular events at the time of surgery may pave the way for prevention strategies. This review provides an overview on perioperative stroke incidence, related problems, and underlying pathophysiological mechanisms. Based on this analysis, we assess experimental stroke treatments including neuroprotective approaches, cell therapies, and conditioning medicine strategies regarding their potential use in perioperative stroke. Interestingly, the specific aspects of perioperative stroke might enable a more effective application of experimental treatment strategies such as classical neuroprotection whereas others including cell therapies may be of limited use. We also discuss experimental diagnostic options for perioperative stroke augmenting classical clinical and imaging stroke diagnosis. While some experimental stroke treatments may have specific advantages in perioperative stroke, the paucity of established guidelines or multicenter clinical research initiatives currently limits their thorough investigation.

RAGE-mediated T cell metabolic reprogramming shapes T cell inflammatory response after stroke.

The metabolic reprogramming of peripheral CD4+ T cells that occurs after stroke can lead to imbalanced differentiation of CD4+ T cells, including regulation of T cells, and presents a promising target for poststroke immunotherapy. However, the regulatory mechanism underlying the metabolic reprogramming of peripheral CD4+ T cell remains unknown. In this study, using combined transcription and metabolomics analyses, flow cytometry, and conditional knockout mice, we demonstrate that the receptor for advanced glycation end products (RAGE) can relay the ischemic signal to CD4+ T cells, which underwent acetyl coenzyme A carboxylase 1(ACC1)-dependent metabolic reprogramming after stroke. Furthermore, by administering soluble RAGE (sRAGE) after stroke, we demonstrate that neutralization of RAGE reversed the enhanced fatty acid synthesis of CD4+ T cells and the post-stroke imbalance of Treg/Th17. Finally, we found that post-stroke sRAGE treatment protected against infarct volume and ameliorated functional recovery. In conclusion, sRAGE can serve as a novel immunometabolic modulator that ameliorates ischemic stroke recovery by inhibiting fatty acid synthesis and thus favoring CD4+ T cells polarization toward Treg after cerebral ischemia injury. The above findings provide new insights for the treatment of neuroinflammatory responses after ischemia stroke.

Coming to the Rescue: Regulatory T Cells for Promoting Recovery After Ischemic Stroke.

Immune cell infiltration to the injured brain is a key component of the neuroinflammatory response after ischemic stroke. In contrast to the large amount of proinflammatory immune cells, regulatory T cells, are an important subgroup of T cells that are involved in maintaining immune homeostasis and suppress an overshooting immune reaction after stroke. Numerous previous reports have consistently demonstrated the beneficial role of this immunosuppressive immune cell population during the acute phase after experimental stroke by limiting inflammatory lesion progression. Two recent studies expanded now this concept and demonstrate that regulatory T cells-mediated effects also promote chronic recovery after stroke by promoting a proregenerative tissue environment. These recent findings suggest that boosting regulatory T cells could be beneficial beyond modulating the immediate neuroinflammatory response and improve chronic functional recovery.

Zebrafish as a Model for In-Depth Mechanistic Study for Stroke.

Stroke is one of the world's leading causes of death and disability, posing enormous burden to the society. However, the pathogenesis and mechanisms that underlie brain injury and brain repair remain largely unknown. There's an unmet need of in-depth mechanistic research in this field. Zebrafish (Danio rerio) is a powerful tool in brain science research mainly due to its small size and transparent body, high genome synteny with human, and similar nervous system structures. It can be used to establish both hemorrhagic and ischemic stroke models easily and effectively through different ways. After the establishment of stroke model, research methods including behavioral test, in vivo imaging, and drug screening are available to explore mechanisms that underlie the brain injury and brain repair after stroke. This review focuses on the advantages and the feasibility of zebrafish stroke model, and will also introduce the key methods available for stroke studies in zebrafish, which may drive future mechanistic studies in the pursuit of discovering novel therapeutic targets for stroke patients.

The 100 most-cited articles about the role of neurovascular unit in stroke 2001-2020: A bibliometric analysis.

BACKGROUND: The neurovascular unit (NVU) is emerging as a potential therapeutic target in neurological conditions, such as stroke, brain injury, Alzheimer's disease, and Parkinson's disease; meanwhile, stroke is the second leading cause of death globally. The purpose of the study is to analyze the most influential articles, authors, countries, and topics in the role of NVU in stroke. METHODS: The Web of Science (WoS) database was used for bibliometric analysis using the search terms "Stroke" and "Neurovascular unit" on January 1st, 2021. Data were extracted from the WoS database to identify collaborations between authors, countries, organizations, and keywords using VOSviewer (1.6.16 mac). Two bibliometric indicators, the activity index (AI) and category normalized citation impact (CNCI), were computed. The keywords of bursts were also identified by CiteSpace. RESULTS: A total of 770 articles were analyzed by VOSviewer. AIs and CNCIs were computed of the eighteen countries according to VOSviewer co-authorship analysis results. The majority of authors mainly came from the United States and Japan. Romania, Hungary, and Poland have emerged as rising-star countries. In the 100 most-cited articles, the number of citations ranged from 1873 to 69, with a total of 15,758 citations. Most articles were published in 2011 and 2012 (n = 13 each), followed by 2009 (n = 11) and 2013, 2014, and 2015 (n = 8 each). Stroke and Journal of Cerebral Blood Flow and Metabolism were the two top journals. EH Lo from Harvard University/ Massachusetts General Hospital was the top first author and corresponding author. Harvard University/Massachusetts General Hospital was the most productive affiliated institution with 15 publications. CONCLUSION: There has been growing attention and efforts made in the field of stroke and NVU. The merit of the above findings may help to shape the research policy in ischemic stroke both at the country and institutional level.

Targeting neutrophils as a novel therapeutic strategy after stroke.

Stroke is followed by an intricate immune interaction involving the engagement of multiple immune cells, including neutrophils. As one of the first responders recruited to the brain, the crucial roles of neutrophils in the ischemic brain damage are receiving increasing attention in recent years. Notably, neutrophils are not homogenous, and yet there is still a lack of full knowledge about the extent and impact of neutrophil heterogeneity. The biological understanding of the neutrophil response to both innate and pathological conditions is rapidly evolving as single-cell-RNA sequencing uncovers overall neutrophil profiling across maturation and differentiation contexts. In this review, we scrutinize the latest research that points to the multifaceted role of neutrophils in different conditions and summarize the regulatory signals that may determine neutrophil diversity. In addition, we list several potential targets or therapeutic strategies targeting neutrophils to limit brain damage following ischemic stroke.

Stroke Exacerbates Cancer Progression by Upregulating LCN2 in PMN-MDSC.

Acute ischemic stroke (AIS) is common in patients with cancer, and mounting clinical evidence suggests that it may shorten the survival of cancer patients. But how stroke affects the progression of cancer remains unclear. We inoculated B16 tumor cells (2 × 105) subcutaneously before distal middle cerebral artery occlusion (dMCAO) or sham surgery in C57BL/6 mice and found that compared to sham operated mice, dMCAO mice developed significantly increased tumor volume and were accompanied by lower survival rate. To explore the underlying mechanism, we performed RNA-sequencing analysis of the tumor tissue from mice with or without stroke and found prominent upregulation of lipocalin 2 (LCN2) in the tumor from stroke mice compared to those from sham mice. Using quantitative reverse transcription-PCR, we confirmed increased mRNA expression of LCN2 as well as anti-inflammatory cytokines-Arg1, IL-10, and decreased mRNA level of pro-inflammatory cytokines-IL-6, IL-23 in the tumor of cancer-bearing stroke mice. Both immunofluorescence staining and flow cytometry analysis revealed that increased expression of LCN2 was mainly derived from the polymorphonuclear myeloid derived suppressor cells (PMN-MDSCs) in the tumor. We also found that stroke reduced the PMN-MDSCs in the peripheral blood, but increased PMN-MDSCs in the tumor of the cancer-bearing mice after stroke. In conclusion, cerebral ischemic stroke may exacerbate cancer progression by increasing LCN2 expression in PMN-MDSCs, which turns out to be a promising therapeutic target to suppress cancer progression after ischemic stroke.

Rosiglitazone ameliorates tissue plasminogen activator-induced brain hemorrhage after stroke.

OBJECTIVE: Delayed thrombolytic therapy with recombinant tissue plasminogen activator (tPA) may exacerbate blood-brain barrier (BBB) breakdown after ischemic stroke and lead to catastrophic hemorrhagic transformation (HT). Rosiglitazone(RSG), a widely used antidiabetic drug that activates peroxisome proliferator-activated receptor-γ (PPAR-γ), has been shown to protect against cerebral ischemia through promoting poststroke microglial polarization toward the beneficial anti-inflammatory phenotype. However, whether RSG can alleviate HT after delayed tPA treatment remains unknown. In this study, we sort to examine the role of RSG on tPA-induced HT after stroke. METHODS AND RESULTS: We used the murine suture middle cerebral artery occlusion (MCAO) models of stroke followed by delayed administration of tPA (10 mg/kg, 2 hours after suture occlusion) to investigate the therapeutic potential of RSG against tPA-induced HT. When RSG(6 mg/kg) was intraperitoneally administered 1 hour before MCAO in tPA-treated MCAO mice, HT in the ischemic territory was significantly attenuated 1 day after stroke. In the tPA-treated MCAO mice, we found RSG significantly mitigated BBB disruption and hemorrhage development compared to tPA-alone-treated stroke mice. Using flow cytometry and immunostaining, we confirmed that the expression of CD206 was significantly upregulated while the expression of iNOS was down-regulated in microglia of the RSG-treated mice. We further found that the expression of Arg-1 was also upregulated in those tPA and RSG-treated stroke mice and the protection against tPA-induced HT and BBB disruption in these mice were abolished in the presence of PPAR-γ antagonist GW9662 (4 mg/kg, 1 hour before dMCAO through intraperitoneal injection). CONCLUSIONS: RSG treatment protects against BBB damage and ameliorates HT in delayed tPA-treated stroke mice by activating PPAR-γ and favoring microglial polarization toward anti-inflammatory phenotype.

Aging Neurovascular Unit and Potential Role of DNA Damage and Repair in Combating Vascular and Neurodegenerative Disorders.

Progressive neurological deterioration poses enormous burden on the aging population with ischemic stroke and neurodegenerative disease patients, such as Alzheimers' disease and Parkinson's disease. The past two decades have witnessed remarkable advances in the research of neurovascular unit dysfunction, which is emerging as an important pathological feature that underlies these neurological disorders. Dysfunction of the unit allows penetration of blood-derived toxic proteins or leukocytes into the brain and contributes to white matter injury, disturbed neurovascular coupling and neuroinflammation, which all eventually lead to cognitive dysfunction. Recent evidences suggest that aging-related oxidative stress, accumulated DNA damage and impaired DNA repair capacities compromises the genome integrity not only in neurons, but also in other cell types of the neurovascular unit, such as endothelial cells, astrocytes and pericytes. Combating DNA damage or enhancing DNA repair capacities in the neurovascular unit represents a promising therapeutic strategy for vascular and neurodegenerative disorders. In this review, we focus on aging related mechanisms that underlie DNA damage and repair in the neurovascular unit and introduce several novel strategies that target the genome integrity in the neurovascular unit to combat the vascular and neurodegenerative disorders in the aging brain.

Brain-derived neurotrophic factor-mediated projection-specific regulation of depressive-like and nociceptive behaviors in the mesolimbic reward circuitry.

Increasing evidence suggests that the mesolimbic reward system plays critical roles in the regulation of depression and nociception; however, its circuitry and cellular mechanisms remain unclear. In this study, we investigated the output-specific regulatory roles of dopaminergic (DA) neurons within the ventral tegmental area (VTA) in depressive-like and nociceptive behaviors in mice subjected to unpredictable chronic mild stress (CMS), using the projection-specific electrophysiological recording, pharmacological manipulation, behavioral test, and molecular biology technologies. We demonstrated that CMS decreased the firing activity in VTA projecting to medial prefrontal cortex (VTA → mPFC), but not in VTA to nucleus accumbens (VTA → NAc), DA neurons. However, both VTA → mPFC and VTA → NAc DA neurons showed increased firing activity in response to morphine perfusion in CMS mice. Behavioral results showed that intra-VTA microinjection of morphine (25.5 ng/0.15 µL) relieved depressive-like behaviors, intriguingly, accompanied by a thermal hyperalgesia. Furthermore, the relief of depressive-like behaviors induced by intra-VTA injection of morphine in CMS mice could be prevented by blocking brain-derived neurotrophic factor (BDNF) signaling and mimicked by the administration of exogenous BDNF in mPFC rather than in NAc shell. Nociceptive responses induced by the activation of VTA DA neurons with morphine in CMS mice could be prevented by blocking BDNF signaling or mimicked by administration of exogenous BDNF in NAc shell, but not in mPFC. These results reveal projection-specific regulatory mechanisms of depression and nociception in the mesolimbic reward circuitry and provide new insights into the neural circuits involved in the processing of depressive and nociceptive information.