Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge (RNA-Seq)

Microglia are yolk sac-derived macrophages residing in the parenchyma of brain and spinal cord, where they interact with neurons and other glial cells by constantly probing their surroundings with dynamic extensions. 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. Overall design: overall there are 28 samples, from total of 2 experiments. in each experiment there were at least 3 biological repeats (3 individual mice). Sorting of the CD45.1 and CD45.2 populations were performed from the same animal. Animals were either injected with LPS (2.5 mg/kg) or untreated.

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Shemer A, Grozovski J, Tay TL, Tao J, Volaski A, Süß P, Ardura-Fabregat A, Gross-Vered M, Kim JS, David E, Chappell-Maor L, Thielecke L, Glass CK, Cornils K, Prinz M, Jung S