Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge
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Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge. / 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.
in: NAT COMMUN, Jahrgang 9, Nr. 1, 06.12.2018, S. 5206.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge
AU - Shemer, Anat
AU - Grozovski, Jonathan
AU - Tay, Tuan Leng
AU - Tao, Jenhan
AU - Volaski, Alon
AU - Süß, Patrick
AU - Ardura-Fabregat, Alberto
AU - Gross-Vered, Mor
AU - Kim, Jung-Seok
AU - David, Eyal
AU - Chappell-Maor, Louise
AU - Thielecke, Lars
AU - Glass, Christopher K
AU - Cornils, Kerstin
AU - Prinz, Marco
AU - Jung, Steffen
PY - 2018/12/6
Y1 - 2018/12/6
N2 - 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.
AB - 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.
KW - Animals
KW - Brain
KW - Cell Proliferation
KW - Chromatin
KW - Female
KW - Hematopoietic Stem Cell Transplantation
KW - Humans
KW - Lipopolysaccharides
KW - Macrophages
KW - Male
KW - Mice, Inbred C57BL
KW - Mice, Transgenic
KW - Microglia
KW - Transcriptome
KW - Journal Article
KW - Research Support, N.I.H., Extramural
KW - Research Support, Non-U.S. Gov't
U2 - 10.1038/s41467-018-07548-5
DO - 10.1038/s41467-018-07548-5
M3 - SCORING: Journal article
C2 - 30523248
VL - 9
SP - 5206
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
ER -