Dual extra-retinal origins of microglia in the model of retinal microglia repopulation

Huang, Yubin; Xu, Zhen; Xiong, Sidong; Qin, Guangrong; Sun, Fangfang; Yang, Jian; Yuan, Ti‐Fei; Zhao, Lei; Wang, Ke; Liang, Yu‐Xiang; Фу, Лин; Wu, Tianzhun; So, Kwok-Fai; Rao, Yu; Peng, Bo

doi:10.1038/s41421-018-0011-8

Cited by 87 publications

(132 citation statements)

References 48 publications

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“…By contrast, two repopulating origins following microglial depletion in the retina have been described (Huang, Xu, Xiong, Qin, et al, ). One is the resident central‐emerging microglia in the optic nerve and the other is the extra‐retinal periphery‐emerging microglia from the ciliary body/iris (Huang, Xu, Xiong, Qin, et al, ). Two distinct resources including peripheral macrophages could also contribute to robust microglial regeneration independently of irradiation (Cronk et al, ).…”

Section: Microglial Repopulation Resolves Neuroinflammation: New Cellmentioning

confidence: 99%

“…Additionally, embryonically seeded microglia and the newly repopulated cells may respond differently to environmental stimuli, as evidenced by two distinct cell types showing differential motilities in response to laser burn injury in vivo (Cronk et al, ). Using RNA sequencing it was determined that the gene profiles of fully repopulated microglia had been little influenced by administration of PLX5622 because no inflammatory related genes were up‐regulated or down‐regulated during depletion and repopulation processes (Huang, Xu, Xiong, Qin, et al, ). Consistent with this idea, Elmore and colleagues determined that repopulated microglia have relatively larger cell bodies than do resident microglia.…”

Section: Microglial Repopulation Resolves Neuroinflammation: New Cellmentioning

confidence: 99%

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Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

Han

Zhu

Zhang

et al. 2018

Glia

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Microglia are prominent immune cells in the central nervous system (CNS) and are critical players in both neurological development and homeostasis, and in neurological diseases when dysfunctional. Our previous understanding of the phenotypes and functions of microglia has been greatly extended by a dearth of recent investigations. Distinct genetically defined subsets of microglia are now recognized to perform their own independent functions in specific conditions. The molecular profiling of single microglial cells indicates extensively heterogeneous reactions in different neurological disorders, resulting in multiple potentials for crosstalk with other kinds of CNS cells such as astrocytes and neurons. In settings of neurological diseases it could thus be prudent to establish effective cell‐based therapies by targeting entire microglial networks. Notably, activated microglial depletion through genetic targeting or pharmacological therapies within a suitable time window can stimulate replenishment of the CNS niche with new microglia. Additionally, enforced repopulation through provision of replacement cells also represents a potential means of exchanging dysfunctional with functional microglia. In each setting the newly repopulated microglia might have the potential to resolve ongoing neuroinflammation. In this review, we aim to summarize the most recent knowledge of microglia and to highlight microglial depletion and subsequent repopulation as a promising cell replacement therapy. Although glial cell replacement therapy is still in its infancy and future translational studies are still required, the approach is scientifically sound and provides new optimism for managing the neurotoxicity and neuroinflammation induced by activated microglia.

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Section: Microglial Repopulation Resolves Neuroinflammation: New Cellmentioning

confidence: 99%

Section: Microglial Repopulation Resolves Neuroinflammation: New Cellmentioning

confidence: 99%

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

Han

Zhu

Zhang

et al. 2018

Glia

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“…First, the residual microglia in the optic nerve repopulate the retina along the center‐to‐periphery axis, and second, macrophages from the ciliary body and iris relocate to the periphery and migrate toward the center. Furthermore, repopulated microglia fully restore the broad functionalities of naive microglia (Huang et al, ; Zhang et al, ). These repopulation mechanisms are mainly regulated by the neuronal chemokine CX3CL1 and its receptor (CX3CR1) in microglia (Zhang et al, ).…”

Section: Targeting Mononuclear Phagocytes In Retinal Degenerative Dismentioning

confidence: 99%

“…Rd1 and rd10 mice carry mutation in exon 7 and exon 13 of the beta subunit of the rod phosphodiesterase gene, respectively. (Huang et al, 2018a;Zhang et al, 2018). These repopulation mechanisms are mainly regulated by the neuronal chemokine CX3CL1 and its receptor (CX3CR1) in microglia (Zhang et al, 2018).…”

Section: Rd1 and Rd10mentioning

confidence: 99%

Modulation of three key innate immune pathways for the most common retinal degenerative diseases

et al. 2018

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This review highlights the role of three key immune pathways in the pathophysiology of major retinal degenerative diseases including diabetic retinopathy, age‐related macular degeneration, and rare retinal dystrophies. We first discuss the mechanisms how loss of retinal homeostasis evokes an unbalanced retinal immune reaction involving responses of local microglia and recruited macrophages, activity of the alternative complement system, and inflammasome assembly in the retinal pigment epithelium. Presenting these key mechanisms as complementary targets, we specifically emphasize the concept of immunomodulation as potential treatment strategy to prevent or delay vision loss. Promising molecules are ligands for phagocyte receptors, specific inhibitors of complement activation products, and inflammasome inhibitors. We comprehensively summarize the scientific evidence for this strategy from preclinical animal models, human ocular tissue analyses, and clinical trials evolving in the last few years.

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“…More recent studies have shown that newly-born microglia transiently express nestin early in repopulation; however, none of the repopulated microglia derive from nestin progenitors. Instead this static analysis of microglia in fixed tissue suggested that repopulated microglia are derived from the microglia that survive depletion in the cortex (<5%) rather than a specific progenitor population (Huang et al, 2018a;Huang et al, 2018b;. Similar to repopulation in the cortex, microglial repopulation in the retina was shown to be driven by remaining microglia; however, proliferation occurred in the central retina and these new microglia then migrated to repopulate peripheral areas, suggesting a specific site of microglial generation in the eye (Huang et al, 2018b;Zhang et al, 2018).…”

Section: Introductionmentioning

confidence: 94%

In vivoimaging of the kinetics of microglial self-renewal and maturation in the adult visual cortex

Mendes

Atlas

Ladrón-de-Guevara

et al. 2020

Preprint

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Microglia are the resident immune cells in the brain with the capacity to autonomously self-renew. Under basal conditions, microglial self-renewal appears to be slow and stochastic, although microglia have the ability to proliferate very rapidly following depletion or in response to injury. Because microglial self-renewal has largely been studied using static tools, the mechanisms and kinetics by which microglia renew and acquire mature characteristics in the adult brain are not well understood. Using chronic in vivo two-photon imaging in awake mice and PLX5622 (Colony stimulating factor 1 receptor (CSF1R) inhibitor) to deplete microglia, we set out to understand the dynamic self-organization and maturation of microglia following depletion in the visual cortex. We confirm that under basal conditions, cortical microglia show limited turnover and migration. Following depletion, however, microglial repopulation is remarkably rapid and is sustained by the dynamic division of the remaining microglia in a manner that is largely independent of signaling through the P2Y12 receptor. Mathematical modeling of microglial division demonstrates that the observed division rates can account for the rapid repopulation observed in vivo. Additionally, newly-born microglia resemble mature microglia, in terms of their morphology, dynamics and ability to respond to injury, within days of repopulation. Our work suggests that microglia rapidly self-renew locally, without the involvement of a special progenitor cell, and that newly born microglia do not recapitulate a slow developmental maturation but instead quickly take on mature roles in the nervous system.

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Dual extra-retinal origins of microglia in the model of retinal microglia repopulation

Cited by 87 publications

References 48 publications

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

Modulation of three key innate immune pathways for the most common retinal degenerative diseases

In vivoimaging of the kinetics of microglial self-renewal and maturation in the adult visual cortex

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