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,Steffen Jung +15 more
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TLDR
It is established 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 microglial.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. 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.read more
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