Review on microglia and their modulation of oligodendroglial lineage cell responses driving central nervous system myelin generation and regeneration.
Microglia are the resident macrophages of the ...CNS and members of the innate immune system. As such, they serve important functions in surveillance for indicators of damage and subsequent initiation of an inflammatory response. Although often implicated in neural damage, recent studies have also suggested beneficial roles of activated microglia and inflammation in developmental and regenerative processes in the CNS. These include regulating events leading to the generation and regeneration of myelin, the insulation surrounding nerve fibers which is critical for nerve health and function. This critical review discusses the evidence for the supportive role of microglia in these processes and the cellular and molecular components involved.
Microglia are resident macrophages of the CNS that are involved in its development, homeostasis and response to infection and damage. Microglial activation is a common feature of neurological ...disorders, and although in some instances this activation can be damaging, protective and regenerative functions of microglia have been revealed. The most prominent example of the regenerative functions is a role for microglia in supporting regeneration of myelin after injury, a process that is critical for axonal health and relevant to numerous disorders in which loss of myelin integrity is a prevalent feature, such as multiple sclerosis, Alzheimer disease and motor neuron disease. Although drugs that are intended to promote remyelination are entering clinical trials, the mechanisms by which remyelination is controlled and how microglia are involved are not completely understood. In this Review, we discuss work that has identified novel regulators of microglial activation - including molecular drivers, population heterogeneity and turnover - that might influence their pro-remyelination capacity. We also discuss therapeutic targeting of microglia as a potential approach to promoting remyelination.
•Astrocytes contribute to myelination via gap junctions with oligodendrocytes, transfer of lipids and secretion of factors.•Astrocytes regulate remyelination by secretion of factors, cholesterol ...efflux, and recruitment of peripheral immune cells.•Astrocyte-microglia cross-talk occurs in development and following injury throughout the lifespan to regulate white matter health.
Astrocytes are known to play critical roles in central nervous system development, homeostasis, and response to injury. In addition to well-defined functions in synaptic signalling and blood-brain barrier control, astrocytes are now emerging as important contributors to white matter health. Here, we review the roles of astrocytes in myelin formation and regeneration (remyelination), focusing on both direct interactions with oligodendrocyte lineage cells, and indirect influences via crosstalk with central nervous system resident macrophages, microglia.
Microglia are tissue-resident macrophages implicated in central nervous system (CNS) development, homeostasis, and response to injury. Recent advances in transcriptomics, multiplex protein expression ...analysis, and experimental depletion of microglia have cemented their importance. However, it is still unclear which models are best suited to investigate microglia and explore their function in human disease. Here, we discuss issues regarding off-targeting during experimental manipulation, and differences and similarities between human and rodent microglia. With new developments in transgenic lines and human–rodent chimeras, we anticipate that in coming years, a clearer picture of microglia function in health and disease will emerge.
In the central nervous system, experimentally tracking or targeting microglia can be confounded by off-target effects on other resident macrophages or those derived from blood monocytes.Human and mouse microglia share many similarities, yet important differences exist that should be considered and these relate to gene expression, aging, and cell turnover rate.We posit that new transgenic tools and the development of human microglia models will help elucidate microglia-specific responses in health and disease.
Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in the central nervous system have ...been implicated in myelin health
, it is unknown which macrophage populations are involved and which aspects they influence. Here we show that resident microglia are crucial for the maintenance of myelin health in adulthood in both mice and humans. We demonstrate that microglia are dispensable for developmental myelin ensheathment. However, they are required for subsequent regulation of myelin growth and associated cognitive function, and for preservation of myelin integrity by preventing its degeneration. We show that loss of myelin health due to the absence of microglia is associated with the appearance of a myelinating oligodendrocyte state with altered lipid metabolism. Moreover, this mechanism is regulated through disruption of the TGFβ1-TGFβR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions in which myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease
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Microglia are resident macrophages of the central nervous system that have key functions in its development, homeostasis and response to damage and infection. Although microglia have been ...increasingly implicated in contributing to the pathology that underpins neurological dysfunction and disease, they also have crucial roles in neurological homeostasis and regeneration. This includes regulation of the maintenance and regeneration of myelin, the membrane that surrounds neuronal axons, which is required for axonal health and function. Myelin is damaged with normal ageing and in several neurodegenerative diseases, such as multiple sclerosis and Alzheimer disease. Given the lack of approved therapies targeting myelin maintenance or regeneration, it is imperative to understand the mechanisms by which microglia support and restore myelin health to identify potential therapeutic approaches. However, the mechanisms by which microglia regulate myelin loss or integrity are still being uncovered. In this Review, we discuss recent work that reveals the changes in white matter with ageing and neurodegenerative disease, how this relates to microglia dynamics during myelin damage and regeneration, and factors that influence the regenerative functions of microglia.
Neural stem cells (NSC) are located in restricted areas of the central nervous system where they self-renew or differentiate into neurons, astrocytes or oligodendrocytes. The stimulation of ...endogenous NSC differentiation is one of the most promising therapeutic approaches to restore neurological function in patients affected by neurodegenerative diseases. Endogenous NSC of the subventricular zone (SVZ) can be selectively targeted by lipid nanocapsules (LNC) coated with the peptide NFLTBS.40-63 (NFL-LNC) after intra-lateral ventricular injection in the brain. NFL-LNC can potentially deliver active compounds to SVZ-NSC and thus promote their differentiation to treat neurodegenerative diseases. The aim of this work was to induce endogenous NSC differentiation by specifically delivering retinoic acid (RA) to SVZ-NSC via NFL-LNC. RA was successfully encapsulated into NFL-LNC and RA-NFL-LNC were incubated with primary rat SVZ-NSC. In vitro, RA-NFL-LNC decreased the number of nestin+ (NSC marker) cells and neurospheres compared to controls and increased the number of GalC+ (oligodendrocytic marker) cells. Then, RA-NFL-LNC were injected in the right lateral ventricle of a lysolecithin-induced rat focal white matter lesion model to evaluate their impact on oligodendrocyte repopulation and remyelination. RA-NFL-LNC significantly increased the percentage of mature oligodendrocytes, stimulating oligodendrogenesis, nearly to the pre-lesion levels. Thus, RA-NFL-LNC represent a promising nanomedicine to be further investigated in the treatment of demyelinating diseases.
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•NFL-lipid nanocapsules (NFL-LNC) efficiently encapsulate retinoic acid (RA).•Primary neural stem cells differentiate towards the oligodendrocyte lineage after incubation with RA-NFL-LNC.•RA-NFL-LNC promote oligodendrocyte repopulation in focal white matter lesioned rats.•RA-NFL-LNC is a promising therapeutic system for the treatment of demyelinating diseases.
•Microglia origins differ in development versus during postnatal homeostasis.•Microglia regulate oligodendroglial lineage cell responses during remyelination.•Macrophages coordinate remyelination via ...phagocytosis, remodelling, growth factors.
Microglia are the resident macrophages of the central nervous system (CNS), implicated in developmental processes, homeostasis, and responses to injury. Derived from the yolk sac during development, microglia self-renew, self-regulate their numbers during homeostatic conditions, and show a robust proliferative capacity even in adulthood. Together with monocyte-derived macrophages (MDM), microglia coordinate the regeneration of CNS myelin around axons, termed remyelination. Gene expression analyses and experimental modelling have identified pro-remyelination roles for microglia/MDM in clearance of myelin debris, secretion of growth factors, and remodelling of the extracellular matrix. Further investigations into the molecular mechanisms controlling these regenerative functions will reveal novel therapeutic strategies to enhance remyelination, by harnessing the beneficial effects of the innate immune response to injury.
Failed remyelination underpins neurodegeneration and central nervous system (CNS) dysfunction with aging and progression of neurological diseases, such as multiple sclerosis and Alzheimer's disease. ...Existing therapies have shown limited efficacy in halting disease progression in humans, highlighting the need to identify pro-remyelination treatments. Microglia are CNS-resident macrophages with critical roles in the regulation of remyelination, representing a promising therapeutic target. However, there are currently no therapeutics which specifically target microglia. Recent studies have revealed that microglia are a heterogenous population with distinct transcriptional states in health and disease conditions, including during remyelination, suggesting functional differences between states. Here, we discuss the potential contributions of different microglia states to degenerative and regenerative processes, examine the potential to target microglia in a state-specific manner to promote remyelination and consider the key issues to be addressed before such therapies can be clinically applied.
•There is a lack of approved therapeutics supporting remyelination.•Remyelination involves a change in microglia transcriptional states.•Further work is needed to target microglia and microglia states therapeutically.
Macrophages and CNS remyelination Miron, Veronique E.; Franklin, Robin J. M.
Journal of neurochemistry,
July 2014, Letnik:
130, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Microglia are the resident macrophages of the central nervous system that survey the microenvironment for signals of injury or infection. The response to such signals induces an inflammatory response ...involving macrophages derived from both resident microglia and recruited circulating monocytes. Although implicated as contributors to autoimmune‐mediated injury, microglia/ macrophages have recently been shown to be critical for the important central nervous system regenerative process of remyelination. This functional dichotomy may reflect their ability to be polarized along a continuum of activation states including the well‐characterized cytotoxic M1 and regenerative M2 phenotypes. Here, we review the roles of microglia, monocytes and the macrophages which they give rise to in creating lesion environments favourable to remyelination, highlighting the specific roles of M1 and M2 phenotypes and how the pro‐regenerative role of the innate immune system is altered by ageing.
Here, we review the roles of microglia, monocytes and the macrophages, which they give rise to in creating lesion environments favourable to remyelination, highlighting the specific roles of activation phenotypes and how the pro‐regenerative role of the innate immune system is altered by ageing.
Here, we review the roles of microglia, monocytes and the macrophages, which they give rise to in creating lesion environments favourable to remyelination, highlighting the specific roles of activation phenotypes and how the pro‐regenerative role of the innate immune system is altered by ageing.
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