ABSTRACT
Microglial cells play a pivotal role in the brain's health and operation through all stages of life and in the face of illness. The contributions of microglia during the developmental phase of the brain markedly contrast with their contributions in the brain of adults after injury. Enhancing our understanding of the pathological mechanisms that involve microglial activity in brains as they age and in cerebrovascular conditions is crucial for informing the creation of novel therapeutic approaches. In this work we provide results on microglia transcriptomics in the juvenile vs injured adult brain and its impact on adult brain regeneration after cerebral ischemia. During fetal brain development, microglia cells are involved in gliogenesis, angiogenesis, axonal outgrowth, synaptogenesis, neurogenesis and synaptic reorganization by engulfing neuronal extensions. Within the mature, intact brain, microglial cells exhibit reduced movement of their processes in response to minimal neuronal activity, while they continuously monitor their surroundings and clear away cellular debris. Following a stroke in the adult brain, inflammation, neurodegeneration, or disruptions in neural equilibrium trigger alterations in both the genetic blueprint and the structure and roles of microglia, a state often described as "activated" microglia. Such genetic shifts include a notable increase in the pathways related to phagosomes, lysosomes, and the presentation of antigens, coupled with a rise in the expression of genes linked to cell surface receptors. We conclude that a comparison of microglia transcriptomic activity during brain development and post-stroke adult brain might provide us with new clues about how neurodegeneration occurs in the adult brain. This information could very useful to develop drugs to slow down or limit the post-stroke pathology and improve clinical outcome.
ABSTRACT
The risk of having a stroke event doubles each decade after the age of 55. Therefore, it is of great interest to develop neurorestorative therapies of stroke which occurs mostly in elderly people. However, to date, patients at risk for these sequels of stroke are not duly diagnosed and treated due to the lack of reliable biomarkers. Extracellular vesicles (EVs) are lipid bilayer-delimited particles that are shed by the brain cells and are able to cross the blood-brain barrier and enter the blood stream; thus, they may be used to interrogate molecular and cellular events in the brain damaged area. In this review, we summarize the major molecular and cellular responses of astroglia and neurons to cerebral ischemia and assess their impact on post-stroke recovery and rehabilitation. In particular, we ask if EVs secreted by brain cells are responses to cerebral ischemia, and they may shed new light on the interplay between exosomes-mediated interactions between brain cells and the question of how to exploit it in order to predict the individual course of the disease and to introduce specific preventive or therapeutic strategies. Given these findings, we are left with two options: either to (i) transplant neuronal precursors into the damaged cortical area or (ii) to covert abundantly present proliferating astrocytes in the perilesional area into neurons by using recently developed genetic technologies. However, given the complexity of molecular and cellular responses to cerebral ischemia and our limited capabilities to restore brain structure and function, we are left with only one realistic aim: to invest more in prevention.
ABSTRACT
Worldwide, millions of individuals suffer an ischemic stroke each year, causing major disability, especially in the elderly, where stroke is the number one cause of disability. However, to date, no effective therapy exists that targets the functional recovery after stroke. After necrosis, neuroinflammation is a common feature of the acute stroke and a major obstacle to tissue restoration. In the lesioned area, the dying neurons release chemotactic signals, such as fractalkine/CX3CL1, which evoke "eat-me" signals that are recognized by microglia expressing complement C3a receptor (C3aR), resulting in phagocytosis of the dying but still viable neurons, known as secondary phagocytosis. Using a mouse model of stroke and two-photon microscopy, we aimed to attenuate poststroke phagocytosis of the dying but still viable neurons by using SB 290157, an antagonist of C3aR. We found that intracortical administration of SB 290157 reduced the number of inflammatory microglial cells expressing ED1 and Iba1 antigens at the lesion site. We could show, in vivo, that two days after a needle-induced cortical lesion there were less microglial cells present around the injury site, displaying less high-order branches and an increase in the lower order ones, suggesting an attenuated phagocytic phenotype in treated animals as compared with controls. We conclude that the C3aR antagonist, SB 290157, may be used in the future to limit the neuronal death by limiting secondary phagocytosis after stroke.
