A Combination of Ontogeny and CNS Environment Establishes Microglial Identity

• Published in: Neuron (Cambridge, Mass.) Mass.), 2018-06, Vol.98 (6), p.1170-1183.e8
• Main Authors: Bennett, F. Chris, Bennett, Mariko L., Yaqoob, Fazeela, Mulinyawe, Sara B., Grant, Gerald A., Hayden Gephart, Melanie, Plowey, Edward D., Barres, Ben A.
• Format: Article
• Language: English
• Subjects: Animals; Brain - cytology; Brain - metabolism; brain macrophage; Brain research; Cell culture; Cell Lineage; Central Nervous System; Csf1r; Embryos; Gene expression; glial biology; Hematopoietic Stem Cells - cytology; Humans; Macrophages; Macrophages - cytology; Macrophages - metabolism; Mice; Mice, Knockout; Microglia; Microglia - cytology; Microglia - metabolism; neuroimmunity; Ontogeny; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; Tmem119; Transplantation; Transplants & implants; Yolk; Yolk sac
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2018.05.014

Microglia, the brain’s resident macrophages, are dynamic CNS custodians with surprising origins in the extra-embryonic yolk sac. The consequences of their distinct ontogeny are unknown but critical to understanding and treating brain diseases. We created a brain macrophage transplantation system to disentangle how environment and ontogeny specify microglial identity. We find that donor cells extensively engraft in the CNS of microglia-deficient mice, and even after exposure to a cell culture environment, microglia fully regain their identity when returned to the CNS. Though transplanted macrophages from multiple tissues can express microglial genes in the brain, only those of yolk-sac origin fully attain microglial identity. Transplanted macrophages of inappropriate origin, including primary human cells in a humanized host, express disease-associated genes and specific ontogeny markers. Through brain macrophage transplantation, we discover new principles of microglial identity that have broad applications to the study of disease and development of myeloid cell therapies. [Display omitted] •Brain signals induce and sustain homeostatic gene expression in microglia•Hematopoietic stem cell (HSC)-derived macrophages attain a microglia-like identity•Stable markers and gene signatures betray HSC origin•Macrophages with HSC origin markers are found in human neurodegeneration Bennett et al. create a macrophage transplantation system to measure how origin and brain environment contribute to microglial identity. Although diverse macrophage types survive in the brain, only those sharing developmental origins with microglia express microglial genes normally.