Repopulated microglia are solely derived from the proliferation of residual microglia after acute depletion

Huang, Yubin; Xu, Zhen; Xiong, Sidong; Sun, Fangfang; Qin, Guangrong; Hu, Guanglei; Wang, Jingjing; Zhao, Lei; Liang, Yu‐Xiang; Wu, Tianzhun; Lu, Zhonghua; Humayun, Mark S.; So, Kwok-Fai; Pan, Yihang; Li, Ningning; Yuan, Ti‐Fei; Rao, Yu; Peng, Bo

doi:10.1038/s41593-018-0090-8

Cited by 440 publications

(487 citation statements)

References 41 publications

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“…Here, we show that repopulated microglia display high expression of both TMEM119 and P2RY12 (Figure 2k–n), demonstrating that repopulated microglia are indeed resident microglia and do not originate from peripherally‐derived myeloid cells. These findings are in line with previous studies from our laboratory (Elmore et al, 2014) and others (Cronk et al, 2018; Huang et al, 2018) showing that repopulating microglia are CNS‐derived and not from peripheral infiltrates. Thus, CSF1R inhibitor‐directed replacement of microglia in the aged brain restores age‐induced changes in microglial numbers, morphologies, and CD68 puncta, reverting the microglial phenotype to that observed in the young brain, at least out to 28 days.…”

Section: Resultssupporting

confidence: 92%

“…Measurements of the chow‐administered PLX5622 in both plasma and brain tissue revealed a comparable reduction in inhibitor levels in aged mice, reflecting either reduced chow‐intake with aging, an increased metabolism and excretion of the compound, or an altered sensitivity of microglia with age. Recent data indicate that repopulating microglia with PLX5622 mainly derive from proliferation of surviving microglia (Huang et al, 2018), suggesting that regardless of the comparative extent of microglial depletion, the source of the resultant tissue is the same. Moreover, cell proliferation can reset (Bufalino & van der Kooy, 2014; Unruh, Slaughter, & Li, 2013) and rejuvenate (Chishti et al, 2013; Pattabiraman & Kaganovich, 2014) cellular phenotypes.…”

Section: Discussionmentioning

confidence: 99%

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Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

et al. 2018

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Microglia, the resident immune cell of the brain, can be eliminated via pharmacological inhibition of the colony‐stimulating factor 1 receptor (CSF1R). Withdrawal of CSF1R inhibition then stimulates microglial repopulation, effectively replacing the microglial compartment. In the aged brain, microglia take on a “primed” phenotype and studies indicate that this coincides with age‐related cognitive decline. Here, we investigated the effects of replacing the aged microglial compartment with new microglia using CSF1R inhibitor‐induced microglial repopulation. With 28 days of repopulation, replacement of resident microglia in aged mice (24 months) improved spatial memory and restored physical microglial tissue characteristics (cell densities and morphologies) to those found in young adult animals (4 months). However, inflammation‐related gene expression was not broadly altered with repopulation nor the response to immune challenges. Instead, microglial repopulation resulted in a reversal of age‐related changes in neuronal gene expression, including expression of genes associated with actin cytoskeleton remodeling and synaptogenesis. Age‐related changes in hippocampal neuronal complexity were reversed with both microglial elimination and repopulation, while microglial elimination increased both neurogenesis and dendritic spine densities. These changes were accompanied by a full rescue of age‐induced deficits in long‐term potentiation with microglial repopulation. Thus, several key aspects of the aged brain can be reversed by acute noninvasive replacement of microglia.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

et al. 2018

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“…However, Bruttger et al demonstrated that following partial depletion (80%) in the CX3CR1 CreER iDTR mouse, microglia proliferate by themselves rather than from nestin + microglial progenitor cells to finally refill the niche (Figure d) (Bruttger et al, ; Jakel & Dimou, ). This mechanism has received further support (Askew et al, ) including using elegant fate‐mapping approaches, single‐cell RNA sequencing and parabiosis (Huang, Xu, Xiong, Sun, et al, ).…”

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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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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“…Maturation and development of microglia requires colony stimulating factor‐1 receptor (CSF1R) Ginhoux et al, ) and the transcription factors Pu.1 and Irf8 (Kierdorf et al, ). The existence of a microglia progenitor cell (Elmore et al, ) versus proliferation of existing or residual microglia (depending on experimental context; Huang et al, ) is an ongoing debate. However, it is clear from multiple studies that microglia proliferate in response to injury (Tay et al, ) including prolonged cerebral ischemia (Denes et al, ; Moraga et al, ).…”

Section: Introductionmentioning

confidence: 99%

Ischemic preconditioning induces cortical microglial proliferation and a transcriptomic program of robust cell cycle activation

McDonough

Noor

Lee

et al. 2019

Glia

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Ischemic preconditioning (IPC) is an experimental phenomenon in which a subthreshold ischemic insult applied to the brain reduces damage caused by a subsequent more severe ischemic episode. Identifying key molecular and cellular mediators of IPC will provide critical information needed to develop novel therapies for stroke. Here we report that the transcriptomic response of acutely isolated preconditioned cortical microglia is dominated by marked upregulation of genes involved in cell cycle activation and cellular proliferation. Notably, this transcriptional response occurs in the absence of cortical infarction. We employed ex vivo flow cytometry, immunofluorescent microscopy, and quantitative stereology methods on brain tissue to evaluate microglia proliferation following IPC. Using cellular colocalization of microglial (Iba1) and proliferation (Ki67 and BrdU) markers, we observed a localized increase in the number of microglia and proliferating microglia within the preconditioned hemicortex at 72, but not 24, hours post‐IPC. Our quantification demonstrated that the IPC‐induced increase in total microglia was due entirely to proliferation. Furthermore, microglia in the preconditioned hemisphere had altered morphology and increased soma volumes, indicative of an activated phenotype. Using transgenic mouse models with either fractalkine receptor (CX3CR1)‐haploinsufficiency or systemic type I interferon signaling loss, we determined that microglial proliferation after IPC is dependent on fractalkine signaling but independent of type I interferon signaling. These findings suggest there are multiple distinct targetable signaling pathways in microglia, including CX3CR1‐dependent proliferation that may be involved in IPC‐mediated protection.

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Repopulated microglia are solely derived from the proliferation of residual microglia after acute depletion

Cited by 440 publications

References 41 publications

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

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

Ischemic preconditioning induces cortical microglial proliferation and a transcriptomic program of robust cell cycle activation

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