RESUMEN
Aging compromises the repair and regrowth of brain vasculature and white matter during stroke recovery, but the underlying mechanisms remain elusive. To understand how aging jeopardizes brain tissue repair after stroke, we performed single-cell transcriptomic profiling of young adult and aged mouse brains at acute (3 d) and chronic (14 d) stages after ischemic injury, focusing a priori on the expression of angiogenesis- and oligodendrogenesis-related genes. We identified unique subsets of endothelial cells (ECs) and oligodendrocyte (OL) progenitors in proangiogenesis and pro-oligodendrogenesis phenotypic states 3 d after stroke in young mice. However, this early prorepair transcriptomic reprogramming was negligible in aged stroke mice, consistent with the impairment of angiogenesis and oligodendrogenesis observed during the chronic injury stages after ischemia. In the stroke brain, microglia and macrophages (MG/MΦ) may drive angiogenesis and oligodendrogenesis through a paracrine mechanism. However, this reparative cell-cell cross talk between MG/MΦ and ECs or OLs is impeded in aged brains. In support of these findings, permanent depletion of MG/MΦ via antagonism of the colony-stimulating factor 1 receptor resulted in remarkably poor neurological recovery and loss of poststroke angiogenesis and oligodendrogenesis. Finally, transplantation of MG/MΦ from young, but not aged, mouse brains into the cerebral cortices of aged stroke mice partially restored angiogenesis and oligodendrogenesis and rejuvenated sensorimotor function and spatial learning and memory. Together, these data reveal fundamental mechanisms underlying the age-related decay in brain repair and highlight MG/MΦ as effective targets for promoting stroke recovery.
Asunto(s)
Células Endoteliales , Accidente Cerebrovascular , Animales , Ratones , Encéfalo , Macrófagos , Análisis de Secuencia de ARNRESUMEN
BACKGROUND: Stroke is the primary cause of chronic disability in the elderly, as there are no neurorestorative treatments for those who do not qualify for recanalization therapy. Experimental evidence in stroke animals suggests that transplantation of bone marrow-derived human mesenchymal stem cells (hMSCs) holds promise, but hMSC transplantation has not been systematically tested in aged animals. We tested the hypothesis that poststroke hMSC transplantation improves stroke recovery in aged mice by promoting brain repair. METHODS: Permanent focal cerebral ischemia was induced in 20-month-old C57BL/6 male mice by distal middle cerebral artery occlusion. Bone marrow-derived hMSCs were expanded in vitro and then administrated intravenously into mice (1×106 cells in PBS) 24 hours after distal middle cerebral artery occlusion. Sensorimotor and cognitive functions, brain atrophy, and brain repair processes (neurogenesis, angiogenesis, oligodendrogenesis) were assessed for up to 56 days after stroke. RESULTS: Poststroke hMSC transplantation did not mitigate brain atrophy or improve neuronal survival at 56 days after distal middle cerebral artery occlusion. However, hMSC-treated mice displayed superior neurobehavioral performances in the open field, rotarod, adhesive removal, novel object, and Morris water maze tests compared with PBS-treated controls. hMSCs promoted white matter integrity and enhanced angiogenesis and oligodendrogenesis-but not neurogenesis-in the stroke brain. Positive correlations between neurobehavioral performance and brain repair profiles or white matter integrity were observed in stroke mice. CONCLUSIONS: Poststroke hMSC transplantation improves long-term stroke recovery in aged mice, likely via mechanisms involving enhanced microvascular regeneration and white matter restoration.
Asunto(s)
Isquemia Encefálica , Células Madre Mesenquimatosas , Accidente Cerebrovascular , Ratones , Humanos , Masculino , Animales , Anciano , Lactante , Infarto de la Arteria Cerebral Media/cirugía , Ratones Endogámicos C57BL , Encéfalo , Accidente Cerebrovascular/terapia , Isquemia Encefálica/cirugía , Modelos Animales de EnfermedadRESUMEN
AIMS: This study aimed to investigate the effects of mild selective brain hypothermia on aged female ischemic mice. METHODS: A distal middle cerebral artery occlusion (dMCAO) model was established in aged female mice, who were then subjected to mild selective brain hypothermia immediately after the dMCAO procedure. Neurological behavioral examinations were conducted prior to and up to 35 days post-ischemia. Infarct volume, brain atrophy, pro-inflammation, and anti-inflammation microglia/macrophages phenotype and white matter injury were evaluated by immunofluorescence staining. Correlations between neurological behaviors and histological parameters were evaluated by Pearson product linear regression analysis. RESULTS: Sensorimotor and cognitive function tests confirmed the protective effect of mild selective brain hypothermia in elderly female ischemic mice. In addition, hypothermia decreased the infarct volume and brain atrophy induced by focal cerebral ischemia. Furthermore, hypothermia alleviated ischemia-induced short-term and long-term white matter injury, which was correlated with behavioral deficits. Finally, hypothermia suppressed the harmful immunological response by promoting the transformation of pro-inflammatory microglia/macrophages to anti-inflammatory phenotype. This polarization was negatively correlated with neuronal loss and white matter injury. CONCLUSION: Mild selective brain hypothermia promoted long-term functional recovery by alleviating white matter damage in an aged female mouse model of ischemia.
Asunto(s)
Lesiones Encefálicas , Isquemia Encefálica , Hipotermia Inducida , Hipotermia , Femenino , Ratones , Animales , Encéfalo/patología , Isquemia Encefálica/patología , Microglía , Infarto de la Arteria Cerebral Media/terapia , Infarto de la Arteria Cerebral Media/patología , Hipotermia Inducida/métodos , Antiinflamatorios/farmacologíaRESUMEN
Immunomodulation holds therapeutic promise against brain injuries, but leveraging this approach requires a precise understanding of mechanisms. We report that CD8+CD122+CD49dlo T regulatory-like cells (CD8+ TRLs) are among the earliest lymphocytes to infiltrate mouse brains after ischemic stroke and temper inflammation; they also confer neuroprotection. TRL depletion worsened stroke outcomes, an effect reversed by CD8+ TRL reconstitution. The CXCR3/CXCL10 axis served as the brain-homing mechanism for CD8+ TRLs. Upon brain entry, CD8+ TRLs were reprogrammed to upregulate leukemia inhibitory factor (LIF) receptor, epidermal growth factor-like transforming growth factor (ETGF), and interleukin 10 (IL-10). LIF/LIF receptor interactions induced ETGF and IL-10 production in CD8+ TRLs. While IL-10 induction was important for the antiinflammatory effects of CD8+ TRLs, ETGF provided direct neuroprotection. Poststroke intravenous transfer of CD8+ TRLs reduced infarction, promoting long-term neurological recovery in young males or aged mice of both sexes. Thus, these unique CD8+ TRLs serve as early responders to rally defenses against stroke, offering fresh perspectives for clinical translation.
Asunto(s)
Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Animales , Linfocitos T CD8-positivos/metabolismo , Femenino , Interleucina-10/genética , Interleucina-10/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Neuroprotección , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/metabolismoRESUMEN
Vascular cognitive impairment and dementia (VaD) is the second most common type of dementia caused by chronic vascular hypoperfusion. Adiponectin, one of the cytokines produced by adipocytes (adipocytokine), plays a role in CNS pathologies, but its specific function in VaD is unknown. Here, transcriptomic analyses on human brain tissues showed downregulation of adipocytokine/PPAR signaling in VaD patients, with prominent upregulation of pro-inflammatory responses. Using the murine asymmetric common carotid artery stenosis (ACAS) model, we discovered that the adiponectin/PPARγ axis is essential in reducing chronic hypoperfusion-induced cognitive deficits via modulation of microglial function. Adiponectin levels in the plasma increased early after VaD induction, but decreased in the cerebrospinal fluid in the late phase of VaD. Adiponectin deficiency worsened hippocampus-dependent cognitive deficits, exacerbated neuroinflammation and microglia/macrophage activation, and amplified neuronal loss, but these behavioral and histological outcomes were rescued by adipoRon, a small molecule agonist of the adiponectin receptors. AdipoRon boosted PPARγ expression and inhibited pro-inflammatory microglial responses in vitro, thereby protecting ischemic neurons in primary microglia-neuron cocultures. Microglia/macrophage-specific knockout of PPARγ abolished the neuroprotective effects of adipoRon. Collectively, these data confirm the importance of adiponectin/PPARγ signaling in maintaining cognitive functions in chronic hypoperfusion-induced dementia, and thus provide novel therapeutic targets for VaD.
Asunto(s)
Disfunción Cognitiva , Adiponectina , Animales , Cognición , Demencia , Humanos , Ratones , Microglía , Enfermedades Neuroinflamatorias , Fármacos Neuroprotectores , PPAR gammaRESUMEN
Stroke is a leading cause of disability and mortality, with limited treatment options. After stroke injury, microglia and CNS-resident macrophages are rapidly activated and regulate neuropathological processes to steer the course of functional recovery. To accelerate this recovery, microglia can engulf dying cells and clear irreparably-damaged tissues, thereby creating a microenvironment that is more suitable for the formation of new neural circuitry. In addition, monocyte-derived macrophages cross the compromised blood-brain barrier to infiltrate the injured brain. The specific functions of myeloid lineage cells in brain injury and repair are diverse and dependent on phenotypic polarization statuses. However, it remains to be determined to what degree the CNS-invading macrophages occupy different functional niches from CNS-resident microglia. In this review, we describe the physiological characteristics and functions of microglia in the developing and adult brain. We also review (a) the activation and phenotypic polarization of microglia and macrophages after stroke, (b) molecular mechanisms that control polarization status, and (c) the contribution of microglia to brain pathology versus repair. Finally, we summarize current breakthroughs in therapeutic strategies that calibrate microglia/macrophage responses after stroke.
Asunto(s)
Lesiones Encefálicas/patología , Macrófagos/patología , Microglía/patología , Accidente Cerebrovascular/patología , Adulto , Animales , Lesiones Encefálicas/etiología , Polaridad Celular , Humanos , Activación de Macrófagos , Accidente Cerebrovascular/complicacionesRESUMEN
As an integral part of the innate immune system of the brain, resident microglia must react rapidly to the onset of brain injury and neurological disease. These dynamic cells then continue to shift their phenotype along a multidimensional continuum with overlapping pro- and anti-inflammatory states, allowing them to adapt to microenvironmental changes during the progression of brain disorders. However, the ability of microglia to shift phenotype through nimble molecular, structural, and functional changes comes at a cost, as the extreme pro-inflammatory states may prevent these professional phagocytes from clearing toxic debris and secreting tissue-repairing neurotrophic factors. Evolution has strongly favored heterogeneity in microglia in both the spatial and temporal dimensions-they can assume diverse roles in different brain regions, throughout the course of brain development and aging, and during the spatiotemporal progression of brain injuries and neurological diseases. Age and sex differences add further diversity to microglia functional status under physiological and pathological conditions. This article reviews recent advances in our knowledge of microglia with emphases on molecular mediators of phenotype shifts and functional diversity. We describe microglia-targeted therapeutic opportunities, including pharmacologic modulation of phenotype and repopulation of the brain with fresh microglia. With the advent of powerful new tools, research on microglia has recently accelerated in pace and may translate into potential therapeutics against brain injury and neurological disease.
Asunto(s)
Lesiones Encefálicas , Enfermedades del Sistema Nervioso , Envejecimiento , Encéfalo , Femenino , Humanos , Masculino , MicroglíaRESUMEN
BACKGROUND: Regulated upon activation, normal T-cell expressed, and secreted (RANTES) is a chemokine actively involved in the initiation and progression of atherosclerosis (AS), which is the major cause of ischemic cerebrovascular disease (ICVD). This study aimed to determine the associations between circulating RANTES level and overall AS conditions of cardiac and cerebral vessel beds in patients with ICVD. METHODS: Patients with ICVD admitted to the department of neurology of Xuanwu Hospital from April 1, 2019 to June 30, 2019 were prospectively enrolled in the study. Plasma RANTES level was measured by enzyme-linked immunosorbent assay to represent the circulating RANTES level. The integrated AS burden of the cervicocephalic and coronary arteries was examined using computed tomography angiography and reflected by "cardio-cerebral AS burden (CCAB)" as a continuous variable. Then, the relationship of plasma RANTES level and CCAB in patients with ICVD was analyzed by correlation analyses and general linear models. RESULTS: A total of 40 patients with ICVD were included in the study. There was a significant positive correlation between CCAB and plasma RANTES level in ICVD (r = 0.786, P < 0.001), independent of age, sex, acute or chronic phase of ICVD, and mono or dual antiplatelet therapy (adjusted B for ln RANTES, 12.063; 95% confidence interval, 7.572-16.533). The association of plasma RANTES level with AS conditions (burden, severity, and extent) in single cardiac or cerebral vessel bed was similar to that with CCAB, but the correlation coefficient for CCAB was higher (increment ranged from 0.126 to 0.397). CONCLUSIONS: Plasma RANTES level was an independent indicator for the integrated AS burden of the cervicocephalic and coronary arteries in ICVD. Comprehensive evaluation of AS conditions using the novel continuous index CCAB might be important in revealing the systematic relationship between circulating RANTES and AS in patients with ICVD.