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

Nature Neuroscience volume 21, pages 530–540 (2018)Cite this article

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Abstract

Newborn microglia rapidly replenish the whole brain after selective elimination of most microglia (>99%) in adult mice. Previous studies reported that repopulated microglia were largely derived from microglial progenitor cells expressing nestin in the brain. However, the origin of these repopulated microglia has been hotly debated. In this study, we investigated the origin of repopulated microglia by a series of fate-mapping approaches. We first excluded the blood origin of repopulated microglia via parabiosis. With different transgenic mouse lines, we then demonstrated that all repopulated microglia were derived from the proliferation of the few surviving microglia (<1%). Despite a transient pattern of nestin expression in newly forming microglia, none of repopulated microglia were derived from nestin-positive non-microglial cells. In summary, we conclude that repopulated microglia are solely derived from residual microglia rather than de novo progenitors, suggesting the absence of microglial progenitor cells in the adult brain.

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Fig. 1: Repopulated microglia rapidly replenish the whole brain after removal of CSF1R inhibition.
Fig. 2: Repopulated microglia do not originate from blood cells.
Fig. 3: Repopulated microglia are not derived from nestin-expressing cells.
Fig. 4: Nestin is transiently expressed in repopulated microglia.
Fig. 5: Repopulated microglia are solely derived from residual microglia.
Fig. 6: Repopulated microglia are derived from the proliferation of residual microglia.
Fig. 7: Transcriptomes of repopulated microglia are distinct from resident microglia and transcriptomes of the brain are little influenced by repopulated microglia.

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Acknowledgements

The authors wish to thank C. Ren, K. Wang and L. Huang (Jinan University), J. Chang, P. Ren, J. Zhang, Z. Yao and W. Zhan (Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences), and Q. Gao, L. Yang, H. Zhong, C. Zhang, W. Zhao, Z. Dong, B. Chen, W. Wu, F. Fan, Z. Liu and M. Xie (BGI) for technical support. They thank C. Liu (Zhejiang University) for donating NG2-CreER mice. They also thank H. Zheng for supporting the establishment of Bo Peng's laboratory. The authors thank P. Lin, B. West, P. Singh and A. Rymar (Plexxikon Inc.) for kindly providing the PLX5622 compound and formulated chow diet. Last but not least, the authors show their gratitude and respect to all animals sacrificed in this study. This study was supported by National Key R&D Program of China (2017YFC0111202; B.P.), National Natural Science Foundation of China (31600839; B.P.), Shenzhen Science and Technology Research Program (JCYJ20170307171222692 and JCYJ20170818163320865 to B.P.; JCYJ20170818161734072 to Y.H.), Guangdong Innovative and Entrepreneurial Research Team Program (2013S046; B.P.) and Shenzhen Peacock Plan (B.P.). This study was also supported by NSFC Grants (31771215, 81501164 and 81611130224; T.-F.Y.) and Young Elite Scientists Sponsorship Program by CAST (YESS; T.Y.).

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Author notes

  1. These authors contributed equally: Yubin Huang, Zhen Xu.

Authors and Affiliations

  1. Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China

    Yubin Huang, Zhen Xu, Shanshan Xiong, Fangfang Sun, Guanglei Hu, Jingjing Wang, Lei Zhao, Tianzhun Wu, Zhonghua Lu & Bo Peng

  2. Shanghai Center for Bioinformation Technology, Shanghai, China

    Guangrong Qin

  3. School of Psychology, Nanjing Normal University, Nanjing, China

    Jingjing Wang

  4. State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong, China

    Yu-Xiang Liang, Kwok-Fai So & Yanxia Rao

  5. Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Mark S. Humayun

  6. Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China

    Kwok-Fai So

  7. The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China

    Yihang Pan & Ningning Li

  8. Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Ti-Fei Yuan

  9. Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China

    Ti-Fei Yuan

  10. School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

    Yanxia Rao

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Contributions

B.P. and Y.R. designed and initiated this study. B.P. conducted quality control on the data and conceptualized the research. B.P. supervised this study. B.P. wrote the manuscript with inputs from T.-F.Y., Y.R., Y.H., S.X. and F.S. B.P., Y.H., S.X., J.W., F.S., Z.X., L.Z., Y.-X.L., Z.L., K.-F.S., T.W., Y.P., N.L., M.S.H. and G.H. performed experiments. Y.H., J.W. Y.R. and B.P. performed most neuroanatomy experiments. S.X. maintained the transgenic animals and performed flow cytometry. Z.X. performed single-cell RT-PCR and FACS-ELISA with the assistance of S.X. and F.S. F.S. and Y.-X.L. performed parabiosis surgery. Z.X., S.X., Y.H., and F.S. performed RNA-seq experiments. G.Q. and B.P. analyzed the RNA-seq results. Y.H., T.Y., S.X. and B.P. performed statistical analysis of results. B.P., Y.H., T.-F.Y. and Y.R. contributed to the interpretation of results. B.P. assembled the figures. All authors discussed results and commented on the manuscript.

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Correspondence to Ti-Fei Yuan, Yanxia Rao or Bo Peng.

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Integrated supplementary information

Supplementary Figure 1 Inhibition of CSF1R by PLX5622 rapidly depletes brain microglia.

(a) Scheme of PLX5622 administration and time points for observation. (b) Representative images show microglial numbers are reduced in the brain after PLX5622 administration. Each white dot represents a microglial cell. (c) Zoom-in images of microglia in somatosensory cortex. (d) Quantification of microglial density in somatosensory cortex of normal brains and the brains on PLX5622 treatment. N (mouse number) = 8, 4, 4, 4, 3, 4, 7 and 7, respectively. PLX5622: PLX5622 formulated diet. Green: GFP; blue: DAPI. The data are presented as mean ± SD; NS: not significant; *: p < 0.05; **: p < 0.01; ***: p < 0.001. One tailed one-way ANOVA with Tukey’s post hoc. p = 0.011, p < 0.001, p < 0.001, p < 0.001, p < 0.001, p < 0.001 and p < 0.001, respectively.

Supplementary Figure 2 Inhibition of CSF1R by PLX5622 rapidly depletes microglia in hippocampus.

(a) Representative confocal images show microglial numbers are reduced in the hippocampus after PLX5622 administration. (b) Quantification of microglial density in hippocampus of normal brains and the brains on PLX5622 treatment. N (mouse number) = 8, 4, 4, 4, 3, 4, 7 and 7, respectively. Green: GFP; blue: DAPI. The data are presented as mean ± SD; NS: not significant; *: p < 0.05; **: p < 0.01; ***: p < 0.001. One tailed one-way ANOVA with Tukey’s post hoc. p < 0.001, p < 0.001, p < 0.001, p < 0.001, p < 0.001, p < 0.001 and p < 0.001, respectively.

Supplementary Figure 3 Repopulated microglia rapidly replenish the hippocampus after removal of CSF1R inhibition.

(a) Representative images show microglia are repopulated in hippocampus after removal of PLX5622. Each white dot indicates a microglial cell. (b) Quantification of microglial density in hippocampus during microglial repopulation. The red line and red area indicate the mean and SD of microglial density in normal brain, respectively. N (mouse number) = 7, 3, 3, 4, 4, 4, 3, 3, 3 and 8, respectively. NS: not significant; *: p < 0.05 to D0; **: p < 0.01 to D0; ***: p < 0.001 to D0; p = 0.983, p = 0.531, p = 0.002, p < 0.001, p < 0.001, p < 0.001, p < 0.001 and p < 0.001, respectively. #: p < 0.05 to normal brain; ##: p < 0.01 to normal brain; ###: p < 0.001 to normal brain; p < 0.001, p < 0.001, p < 0.001, p < 0.001, p > 0.999, p = 0.754, p = 0.995, p > 0.999 and p = 0.988, respectively. (c) Quantification of BrdU-positive microglia among all microglia in S1 during repopulation. N (mouse number) = 4, 3, 3, 4, 3, 3, 3, 3 and 3, respectively. NS: not significant; *: p < 0.05; **: p < 0.01; ***: p < 0.001; p = 0.001, p = 0.001, p = 0.080, p = 0.012, p > 0.999, 0.997, p > 0.999 and p > 0.999, respectively. Green: GFP; blue: DAPI; magenta: BrdU. The data are presented as mean ± SD. One tailed one-way ANOVA with Tukey’s post hoc.

Supplementary Figure 4

Representative gating strategy for blood cell analyses.

Supplementary Figure 5 Circulating progenitors in parabiotic mice can give rise to macrophages in peripheral organs.

GFP-positive macrophages are found in the kidney and spleen of WT parabionts. Arrows: GFP-positive macrophages. Green: GFP; red: Iba1. Each experiment has been independently repeated twice with similar results.

Supplementary Figure 6 Repopulated microglia do not originate from blood cells.

(a-b) Confocal images and quantificative results show there are no GFP-positive repopulated microglia in the hippocampus of WT parabionts. N (mouse number) = 6, 4 and 7, respectively. p < 0.001 (WT vs GFP), p > 0.999 (WT vs parabiotic-WT) and p < 0.001 (GFP vs parabiotic-WT), respectively. (c-d) Confocal images and quantificative results show there are no GFP-positive repopulated microglia in the median eminence of WT parabionts. N (mouse number) = 6, 4 and 7, respectively. p < 0.001 (WT vs GFP), p > 0.999 (WT vs parabiotic-WT) and p < 0.001 (GFP vs parabiotic-WT), respectively. Green: GFP; red: Iba1; blue: DAPI. The data are presented as mean ± SD. N: mouse number for each group; NS: not significant; *: p < 0.05; **: p < 0.01; ***: p < 0.001. One tailed one-way ANOVA with Tukey’s post hoc. Box plot elements: square for mean, box range for percentiles at 25 and 75, inside-box line for median and whisker for min and max. Each experiment in (g-h) has been independently repeated at least twice.

Supplementary Figure 7 Repopulated microglia are not derived from nestin-expressing cells.

(a) No tdTomato-positive microglia are found in hippocampus of treatment protocol Fig. 4a. (b) No tdTomato-positive microglia are found in hippocampus of treatment protocol Fig. 4e. Arrows: tdTomato-positive neurons. Green: GFP; red: tdTomato. Each experiment has been repeated 3 times independently with similar results.

Supplementary Figure 8 Uncropped gels for single-cell RT-PCR.

(a–g) Uncropped gels for single-cell RT-PCR in Fig. 4 of the normal brain (a), microglial depletion for 3 days (b), microglial repopulation for 3 (c), 5 (d) and 14 days (e), developmental P3 brain microglia (f) and microglia in the injured brain (g), respectively.

Supplementary Figure 9 Astrocytes, OPCs or neurons do not differentiate into microglia during repopulation.

(a) Scheme of fate mapping for the origin of repopulated microglia. (b-c) The rationale and hypotheses of tamoxifen triggered fate mapping. (d) Confocal images indicate no tdTomato-positive microglia in repopulated brains of GLAST-CreERT2::Ai14, NG2-CreER::Ai9, CaMK2a-CreERT2::Ai14, GAD2-CreER::Ai14 and TH-IRES-CreER::Ai14 mice, respectively. Each experiment has been independently repeated at least twice with similar results. PLX5622: PLX5622 formulated diet; CD: control diet; TAM: tamoxifen. Green: GFP; red: tdTomato.

Supplementary Figure 10 Repopulated microglia in the hippocampus are derived from residual microglia.

(a) Confocal images show all brain microglia in the hippocampus of tamoxifen administered mice at 2-month old are genetically labeled by tdTomato. (b) Confocal images indicate all repopulated microglia in the hippocampus are labeled with tdTomato in repopulating brain of tamoxifen-treated group. Green: GFP; red: Iba1. Each experiment has been independently repeated three times (7 mice) with similar results.

Supplementary Figure 11 CSF1R inhibition kills brain microglia instead of inducing microglial dedifferentiation.

The number of tdTomato-positive cells in microglia-labeled Cx3cr1-CreER::Ai14 mice is significantly reduced after PLX5622 administration for 10 days. All surviving tdTomato-positive cells are co-labeled with Iba1. Green: Iba1; red: tdTomato; blue: DAPI. The experiment has been independently repeated 3 times with similar results.

Supplementary Figure 12 Model of the origin of repopulated microglia.

(a) Repopulated microglia are not derived from blood cells. (b) Repopulated microglia are not derived from Nestin-positive progenitor cells. (c) Repopulated microglia are not derived from astrocytes, OPCs or neurons. (d) Repopulated microglia are derived from the direct proliferation of residual microglia.

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Huang, Y., Xu, Z., Xiong, S. et al. Repopulated microglia are solely derived from the proliferation of residual microglia after acute depletion. Nat Neurosci 21, 530–540 (2018). https://doi.org/10.1038/s41593-018-0090-8

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