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Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge

Author

Listed:
  • Anat Shemer

    (Weizmann Institute of Science)

  • Jonathan Grozovski

    (Weizmann Institute of Science)

  • Tuan Leng Tay

    (University of Freiburg
    University of Freiburg
    University of Freiburg)

  • Jenhan Tao

    (University of California, San Diego)

  • Alon Volaski

    (Weizmann Institute of Science)

  • Patrick Süß

    (University of Freiburg)

  • Alberto Ardura-Fabregat

    (University of Freiburg)

  • Mor Gross-Vered

    (Weizmann Institute of Science)

  • Jung-Seok Kim

    (Weizmann Institute of Science)

  • Eyal David

    (Weizmann Institute of Science)

  • Louise Chappell-Maor

    (Weizmann Institute of Science)

  • Lars Thielecke

    (Technische Universität Dresden)

  • Christopher K. Glass

    (University of California, San Diego)

  • Kerstin Cornils

    (University Medical Center Hamburg-Eppendorf, Department of Pediatric Hematology and Oncology, Division of Pediatric Stem Cell Transplantation and Immunology and Research Institute, Children’s Cancer Center Hamburg)

  • Marco Prinz

    (University of Freiburg
    University of Freiburg
    University of Freiburg)

  • Steffen Jung

    (Weizmann Institute of Science)

Abstract

Microglia are yolk sac-derived macrophages residing in the parenchyma of brain and spinal cord, where they interact with neurons and other glial. After different conditioning paradigms and bone marrow (BM) or hematopoietic stem cell (HSC) transplantation, graft-derived cells seed the brain and persistently contribute to the parenchymal brain macrophage compartment. Here we establish that graft-derived macrophages acquire, over time, microglia characteristics, including ramified morphology, longevity, radio-resistance and clonal expansion. However, even after prolonged CNS residence, transcriptomes and chromatin accessibility landscapes of engrafted, BM-derived macrophages remain distinct from yolk sac-derived host microglia. Furthermore, engrafted BM-derived cells display discrete responses to peripheral endotoxin challenge, as compared to host microglia. In human HSC transplant recipients, engrafted cells also remain distinct from host microglia, extending our finding to clinical settings. Collectively, our data emphasize the molecular and functional heterogeneity of parenchymal brain macrophages and highlight potential clinical implications for HSC gene therapies aimed to ameliorate lysosomal storage disorders, microgliopathies or general monogenic immuno-deficiencies.

Suggested Citation

  • Anat Shemer & Jonathan Grozovski & Tuan Leng Tay & Jenhan Tao & Alon Volaski & Patrick Süß & Alberto Ardura-Fabregat & Mor Gross-Vered & Jung-Seok Kim & Eyal David & Louise Chappell-Maor & Lars Thiele, 2018. "Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07548-5
    DOI: 10.1038/s41467-018-07548-5
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    Cited by:

    1. Pasqualina Colella & Ruhi Sayana & Maria Valentina Suarez-Nieto & Jolanda Sarno & Kwamina Nyame & Jian Xiong & Luisa Natalia Pimentel Vera & Jessica Arozqueta Basurto & Marco Corbo & Anay Limaye & Kar, 2024. "CNS-wide repopulation by hematopoietic-derived microglia-like cells corrects progranulin deficiency in mice," Nature Communications, Nature, vol. 15(1), pages 1-26, December.
    2. Jingbo Qie & Yang Liu & Yunzhi Wang & Fan Zhang & Zhaoyu Qin & Sha Tian & Mingwei Liu & Kai Li & Wenhao Shi & Lei Song & Mingjun Sun & Yexin Tong & Ping Hu & Tao Gong & Xiaqiong Wang & Yi Huang & Bolo, 2022. "Integrated proteomic and transcriptomic landscape of macrophages in mouse tissues," Nature Communications, Nature, vol. 13(1), pages 1-23, December.
    3. Rita Milazzo & Annita Montepeloso & Rajesh Kumar & Francesca Ferro & Eleonora Cavalca & Pietro Rigoni & Paolo Cabras & Yuri Ciervo & Sabyasachi Das & Alessia Capotondo & Danilo Pellin & Marco Peviani , 2024. "Therapeutic efficacy of intracerebral hematopoietic stem cell gene therapy in an Alzheimer’s disease mouse model," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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