Macrophage Development Rewritten Macrophages provide protection against a wide variety of infections and critically shape the inflammatory environment in many tissues. These cells come in many flavors, as determined by differences in gene expression, cell surface phenotype and specific function. Schulz et al. (p. 86, published online 22 March) investigated whether adult macrophages all share a common developmental origin. Immune cells, including most macrophages, are widely thought to arise from hematopoietic stem cells (HSCs), which require the transcription factor Myb for their development. Analysis of Myb-deficient mice revealed that a population of yolk-sac–derived, tissue-resident macrophages was able to develop and persist in adult mice in the absence of HSCs. Importantly, yolk sac–derived macrophages also contributed substantially to the tissue macrophage pool even when HSCs were present. In mice, a population of tissue-resident macrophages arises independently of bone marrow–derived stem cells. Macrophages and dendritic cells (DCs) are key components of cellular immunity and are thought to originate and renew from hematopoietic stem cells (HSCs). However, some macrophages develop in the embryo before the appearance of definitive HSCs. We thus reinvestigated macrophage development. We found that the transcription factor Myb was required for development of HSCs and all CD11bhigh monocytes and macrophages, but was dispensable for yolk sac (YS) macrophages and for the development of YS-derived F4/80bright macrophages in several tissues, such as liver Kupffer cells, epidermal Langerhans cells, and microglia—cell populations that all can persist in adult mice independently of HSCs. These results define a lineage of tissue macrophages that derive from the YS and are genetically distinct from HSC progeny.

A lineage of myeloid cells independent of Myb and hematopoietic stem cells

The blood-brain barrier (BBB) prevents neurotoxic plasma components, blood cells, and pathogens from entering the brain. At the same time, the BBB regulates transport of molecules into and out of t...

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Blood-Brain Barrier: From Physiology to Disease and Back

Therapeutic strategies for enhancing angiogenesis in wound healing.

Rationale: Microglia play a critical role in modulating cell death and neurobehavioral recovery in response to brain injury either by direct cell-cell interaction or indirect secretion of trophic factors. Exosomes secreted from cells are well documented to deliver bioactive molecules to recipient cells to modulate cell function. Here, we aimed to identify whether M2 microglia exert neuroprotection after ischemic attack through an exosome-mediated cell-cell interaction. Methods: M2 microglia-derived exosomes were intravenously injected into the mouse brain immediately after middle cerebral artery occlusion. Infarct volume, neurological score, and neuronal apoptosis were examined 3 days after ischemic attack. Exosome RNA and target protein expression levels in neurons and brain tissue were determined for the mechanistic study. Results: Our results showed that the M2 microglia-derived exosomes were taken up by neurons in vitro and in vivo. M2 microglia-derived exosome treatment attenuated neuronal apoptosis after oxygen-glucose deprivation (p<0.05). In vivo results showed that M2 microglia-derived exosome treatment significantly reduced infarct volume and attenuated behavioral deficits 3 days after transient brain ischemia (p<0.05), whereas injection of miR-124 knockdown (miR-124k/d) M2 microglia-derived exosomes partly reversed the neuroprotective effect. Our mechanistic study further demonstrated that ubiquitin-specific protease 14 (USP14) was the direct downstream target of miR-124. Injection of miR-124k/d M2 exosomes plus the USP14 inhibitor, IU1, achieved comparable neuroprotective effect as injection of M2 exosomes alone. Conclusions: We demonstrated that M2 microglia-derived exosomes attenuated ischemic brain injury and promoted neuronal survival via exosomal miR-124 and its downstream target USP14. M2 microglia-derived exosomes represent a promising avenue for treating ischemic stroke.

M2 microglia-derived exosomes protect the mouse brain from ischemia-reperfusion injury via exosomal miR-124.

Stroke is a leading cause of morbidity and mortality worldwide, and consists of two types, ischemic and hemorrhagic. Currently, there is no effective treatment to increase the survival rate or improve the quality of life after ischemic and hemorrhagic stroke in the subacute to chronic phases. Therefore, it is necessary to establish therapeutic strategies to facilitate functional recovery in patients with stroke during both phases. Cell-based therapies, using microglia and monocytes/macrophages preconditioned by optimal stimuli and/or any therapies targeting these cells, might be an ideal therapeutic strategy for managing stroke. Microglia and monocytes/macrophages polarize to the classic pro-inflammatory type (M1-like) or alternative protective type (M2-like) by optimal condition. Cell-based therapies using M2-like microglia and monocytes/macrophages might be protective therapeutic strategies against stroke for three reasons. First, M2-like microglia and monocytes/monocytes secrete protective remodeling factors, thus prompting neuronal network recovery via tissue (including neuronal) and vascular remodeling. Second, these cells could migrate to the injured hemisphere through the blood–brain barrier or choroid–plexus. Third, these cells could mitigate the extent of inflammation-induced injuries by suitable timing of therapeutic intervention. Although future translational studies are required, M2-like microglia and monocytes/macrophages therapies are attractive for managing stroke based on their protective functions.

Microglia and Monocytes/Macrophages Polarization Reveal Novel Therapeutic Mechanism against Stroke.

The biphasic function of microglia in ischemic stroke.

MicroRNA-29b (miR-29b) is involved in regulating ischemia process, but the molecular mechanism is unclear. In this work, we explored the function of miR-29b in cerebral ischemia. The level of miR-29b in white blood cells was evaluated in patients and mice after ischemic stroke. Brain infarct volume and National Institute of Health stroke scale (NIHSS) scores were analyzed to determine the relationship between miR-29b expression and the severity of stroke. The relationship of miR-29b and aquaporin-4 (AQP4) was further studied in mice. We found that miR-29b was significantly downregulated in stroke patients (P<0.05). MiR-29b level negatively associated with NIHSS scores (r=−0.349, P<0.01) and brain infarct volume (r=−0.321, P<0.05). In ischemic mice, miR-29b in the brain and blood were both downregulated (r=0.723, P<0.05). MiR-29b overexpression reduced infarct volume (49.50±6.55 versus 35.48±2.28 mm3, P<0.05), edema (164±4% versus 108±4%, P<0.05), and blood–brain barrier (BBB) disruption compared with controls (15±9% versus 7±3%, P<0.05). Aquaporin-4 expression greatly decreased after miR-29b overexpression (28±7% versus 11±3%, P<0.05). Dual-luciferase reporter system showed that AQP-4 was the direct target of miR-29b (P<0.05). We concluded that miR-29b could potentially predict stroke outcomes as a novel circulating biomarker, and miR-29b overexpression reduced BBB disruption after ischemic stroke via downregulating AQP-4.

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.2015.156

MicroRNA-29b is a therapeutic target in cerebral ischemia associated with aquaporin 4

The complement system is an essential part of innate immunity, typically conferring protection via eliminating pathogens and accumulating debris. However, the defensive function of the complement system can exacerbate immune, inflammatory, and degenerative responses in various pathological conditions. Cumulative evidence indicates that the complement system plays a critical role in the pathogenesis of ischemic brain injury, as the depletion of certain complement components or the inhibition of complement activation could reduce ischemic brain injury. Although multiple candidates modulating or inhibiting complement activation show massive potential for the treatment of ischemic stroke, the clinical availability of complement inhibitors remains limited. The complement system is also involved in neural plasticity and neurogenesis during cerebral ischemia. Thus, unexpected side effects could be induced if the systemic complement system is inhibited. In this review, we highlighted the recent concepts and discoveries of the roles of different kinds of complement components, such as C3a, C5a, and their receptors, in both normal brain physiology and the pathophysiology of brain ischemia. In addition, we comprehensively reviewed the current development of complement-targeted therapy for ischemic stroke and discussed the challenges of bringing these therapies into the clinic. The design of future experiments was also discussed to better characterize the role of complement in both tissue injury and recovery after cerebral ischemia. More studies are needed to elucidate the molecular and cellular mechanisms of how complement components exert their functions in different stages of ischemic stroke to optimize the intervention of targeting the complement system.

Significance of Complement System in Ischemic Stroke: A Comprehensive Review

Patients with diabetes suffer the higher risk of dementia and the underlying pathological mechanism of cognitive dysfunction in diabetes is not fully understood. In this study, we explore whether the cognitive impairment in the diabetic rat is associated with increased blood brain barrier (BBB) permeability and the change of the inflammatory cytokine. Experimental diabetic rats were induced by single intraperitoneal injection of streptozotocin (STZ). Cognitive function was evaluated by Morris water maze in the normal and the diabetic rats, respectively. The spatial acquisition trials were conducted over five consecutive days and the probe test was performed on day 6, followed by working memory test on the next 4 days. Escape latency was recorded in the acquisition trials and working memory test; time spent in the target quadrant and the number of crossing the former platform were recorded in the probe test. BBB permeability was assessed by measuring the extravasation of IgG. The image of occludin and claudin-5 staining by a confocal microscope were acquired to measure the gap in the tight junction. Cytokines TNF-α, IL-1β and IL-6 mRNA expression were further examined by Real-time PCR. The time spent in the target quadrant within 30 s decreased in the 8-week STZ rats compared to that of the normal rats (p < 0.05), while no difference was seen in the performance of working memory between the diabetic and normal rats. IgG leakage significantly increased in the brain parenchyma of the 8-week STZ rats compared to the normal rats (p < 0.05). The immunostaining of occludin and claudin-5 suggested the gap in the tight junction increased in the 8-week STZ rats compared to the normal rats (p < 0.05). Moreover, TNF-α and IL-6 mRNA also increased in the brain of 8-week STZ rats compared to the normal rats (p < 0.05). These results suggested that loss of BBB integrity might contribute to progressive impairment of cognitive in the diabetic rats. The increase of TNF-α and IL-6 expression might trigger the disruption of BBB in the brain, which eventually caused cognitive impairment in the 8-week STZ rats.

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Blood-Brain Barrier Disruption Induced Cognitive Impairment Is Associated With Increase of Inflammatory Cytokine

Stem cell-based therapy for ischemic stroke has been widely explored in animal models and provides strong evidence of benefits. In this review, we summarize the types of stem cells, various delivery routes, and tracking tools for stem cell therapy of ischemic stroke. MSCs, EPCs, and NSCs are the most explored cell types for ischemic stroke treatment. Although the mechanisms of stem cell-based therapies are not fully understood, the most possible functions of the transplanted cells are releasing growth factors and regulating microenvironment through paracrine mechanism. Clinical application of stem cell-based therapy is still in its infancy. The next decade of stem cell research in stroke field needs to focus on combining different stem cells and different imaging modalities to fully explore the potential of this therapeutic avenue: from bench to bedside and vice versa.

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Yuanyuan Ma

Papers

The biphasic function of microglia in ischemic stroke.

MicroRNA-29b is a therapeutic target in cerebral ischemia associated with aquaporin 4

Significance of Complement System in Ischemic Stroke: A Comprehensive Review

Blood-Brain Barrier Disruption Induced Cognitive Impairment Is Associated With Increase of Inflammatory Cytokine

Opportunities and Challenges: Stem Cell-Based Therapy for the Treatment of Ischemic Stroke