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

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 Thielecke, Christopher K. Glass, Kerstin Cornils, Marco Prinz and Steffen Jung ()
Additional contact information
Anat Shemer: Weizmann Institute of Science
Jonathan Grozovski: Weizmann Institute of Science
Tuan Leng Tay: 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
Steffen Jung: Weizmann Institute of Science

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07548-5

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