Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge

Anat Shemer,Patrick Süß,Alberto Ardura-Fabregat,Tuan Leng Tay,Jonathan Grozovski,Jung-Seok Kim,Steffen Jung,Louise Chappell-Maor,Marco Prinz,Kerstin Cornils,Lars Thielecke,Alon Volaski,Christopher K Glass,Jenhan Tao,Mor Gross-Vered,Eyal David

doi:10.1038/s41467-018-07548-5

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.

Highlights

Microglia are yolk sac-derived macrophages residing in the parenchyma of brain and spinal cord, where they interact with neurons and other glial
Analysis of the central nervous system (CNS) compartment of the chimeras revealed the presence of three distinct macrophage populations: host microglia (CD45.1/2+), cells derived from the first graft (CD45.1+ GFP+), and cells derived from the second bone marrow (BM) graft (CD45.2+ RFP+) (Fig. 1c, d, Supplementary Fig. 1f)
Here we established that BM-derived brain macrophages that persistently seed the CNS of recipient organisms following irradiation or myeloablation remain distinct from host microglia with respect to their transcriptomes, chromatin accessibility landscapes, and response to challenge

Summary

Introduction

Microglia are yolk sac-derived macrophages residing in the parenchyma of brain and spinal cord, where they interact with neurons and other glial. Even after prolonged CNS residence, transcriptomes and chromatin accessibility landscapes of engrafted, BM-derived macrophages remain distinct from yolk sac-derived host microglia. In human HSC transplant recipients, engrafted cells remain distinct from host microglia, extending our finding to clinical settings. Deficiencies affecting intrinsic microglia fitness can result in neuropsychiatric or neurologic disorders[23] Therapeutic approaches to these “microgliopathies” could include microglia replacement by wild-type (WT) cells. Replacement of YS-derived microglia by HSC-derived cells is a by-product of therapeutic stem cell transplantations that are routinely used to treat monogenic immune disorders, such as Wiskott–Aldrich syndrome (WAS) and IL-10 receptor deficiencies. Understanding how engrafted cells perform in the host, in particular following challenge, is of considerable clinical importance, in HSC transplantation and in HSC gene therapy approaches of disorders with a neurological phenotype

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Results

Conclusion