Engrafted parenchymal brain macrophages differ from host microglia in transcriptome, epigenome and response to challenge

Abstract

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. Following different conditioning paradigms and bone marrow (BM) / hematopoietic stem cell (HSC) transplantation, graft-derived cells seed the brain and persistently contribute to the parenchymal brain macrophage compartment. Here we establish that these cells acquire over time microglia characteristics, including ramified morphology, longevity, radioresistance and clonal expansion. However, even following prolonged CNS residence, transcriptomes and epigenomes of engrafted HSC-derived macrophages remain distinct from yolk sac-derived host microglia. Furthermore, BM graft-derived cells display discrete responses to peripheral endotoxin challenge, as compared to host microglia. Also in human HSC transplant recipients, engrafted cells 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 patients treated by HSC gene therapy.

Hematopoietic stem cell requirement for macrophage regeneration is tissue-specific

“…Only when there is a great need to increase MΦ numbers, due to an infection or inflammatory insult in the CNS (e.g., experimental autoimmune encephalitis), will the microglia pool be supplemented with MDMΦ (Ajami et al, 2007;Ajami et al, 2011;Huang et al, 2018). However, infiltrating MDMΦ are unable to differentiate into bona fide microglia and remain distinct from the resident microglia population, further supporting the notion that ontogeny, in addition to local microenvironment, influence MΦ heterogeneity (Cronk et al, 2018;Gosselin et al, 2014;Lavin et al, 2014;Shemer et al, 2018;Van Hove et al, 2019).…”