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

• Published in: Nature communications Vol. 9; no. 1; pp. 5206 - 16
• Main Authors: Shemer, Anat, Grozovski, Jonathan, Tay, Tuan Leng, Tao, Jenhan, Volaski, Alon, Süß, Patrick, Ardura-Fabregat, Alberto, Gross-Vered, Mor, Kim, Jung-Seok, David, Eyal, Chappell-Maor, Louise, Thielecke, Lars, Glass, Christopher K., Cornils, Kerstin, Prinz, Marco, Jung, Steffen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.12.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/31; 45; 45/91; 631/250/1904; 631/250/2502; 631/250/2504; 631/250/371; Animals; Bone marrow; Bone marrow transplantation; Brain; Brain - cytology; Brain - metabolism; Cell Proliferation - genetics; Chromatin; Chromatin - genetics; Chromatin - metabolism; Endotoxins; Female; Gene expression; Gene therapy; Hematopoietic Stem Cell Transplantation - methods; Hematopoietic stem cells; Heterogeneity; Humanities and Social Sciences; Humans; Lipopolysaccharides - pharmacology; Lysosomal storage diseases; Macrophages; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Male; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Microglia - cytology; Microglia - drug effects; Microglia - metabolism; Morphology; multidisciplinary; Neuronal-glial interactions; Parenchyma; Physical characteristics; Science; Science (multidisciplinary); Spinal cord; Stem cells; Transcriptome; Transplantation; Transplants & implants; Yolk; Yolk sac
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-07548-5

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. Irradiation depletes brain microglia cells and induces replenishment of the pool by bone marrow (BM)-derived macrophage. Here the authors show, using mouse BM chimera, that BM-derived macrophages establish long-term residency in the brain, but remain distinct from resident microglia in their transcriptome and gene accessibility landscape.