Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge.
Anat ShemerJonathan GrozovskiTuan Leng TayJenhan TaoAlon VolaskiPatrick SüßAlberto Ardura-FabregatMor Gross-VeredJung-Seok KimEyal DavidLouise Chappell-MaorLars ThieleckeChristopher K GlassKerstin CornilsMarco PrinzSteffen JungPublished in: Nature communications (2018)
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.
Keyphrases
- neuropathic pain
- inflammatory response
- spinal cord
- induced apoptosis
- resting state
- white matter
- cell cycle arrest
- bone marrow
- gene expression
- genome wide
- functional connectivity
- cerebral ischemia
- endothelial cells
- dna damage
- mesenchymal stem cells
- spinal cord injury
- transcription factor
- multiple sclerosis
- blood brain barrier
- endoplasmic reticulum stress
- adipose tissue
- big data
- climate change
- cell therapy
- human health
- single molecule