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

Anat Shemer1, Jonathan Grozovski1, Tuan Leng Tay2,3,4

  • 1Department of Immunology, Weizmann Institute of Science, Rehovot, 76100, Israel.

Nature Communications
|December 8, 2018
PubMed

Insights

Bone marrow or stem cell transplants can introduce cells into the brain that adopt microglia characteristics. However, these engrafted cells remain molecularly and functionally distinct from host microglia.

Area of Science:

  • Neuroscience
  • Immunology
  • Cell Biology

Background:

  • Microglia are the primary immune cells of the central nervous system (CNS), originating from yolk sac precursors.
  • Parenchymal brain macrophages play crucial roles in neuronal interaction and CNS homeostasis.
  • Hematopoietic stem cell (HSC) transplantation is a potential therapeutic strategy for various neurological and immunological disorders.

Purpose of the Study:

  • To investigate the long-term characteristics and functional identity of graft-derived macrophages within the brain parenchyma after transplantation.
  • To compare the molecular and functional profiles of engrafted bone marrow (BM)-derived macrophages with host microglia.
  • To assess the clinical relevance of these findings in human HSC transplant recipients.

Main Methods:

  • Bone marrow (BM) or hematopoietic stem cell (HSC) transplantation in preclinical models.
  • Analysis of graft-derived cell engraftment and phenotypic changes in the CNS.
  • Transcriptomic and chromatin accessibility profiling (ATAC-seq) of engrafted cells and host microglia.
  • Functional assessment using peripheral endotoxin challenge.
  • Analysis of engrafted cells in human HSC transplant recipients.

Main Results:

  • Engrafted macrophages acquire some microglia-like features, including morphology, longevity, radio-resistance, and clonal expansion.
  • Despite prolonged CNS residence, engrafted BM-derived macrophages maintain distinct transcriptomic and chromatin accessibility landscapes compared to host microglia.
  • Engrafted cells exhibit differential responses to endotoxin challenge compared to host microglia.
  • Engrafted cells in human HSC transplant recipients also remain distinct from host microglia.

Conclusions:

  • Parenchymal brain macrophages exhibit significant molecular and functional heterogeneity.
  • Graft-derived cells, while adopting some microglia characteristics, retain a distinct identity.
  • These findings have implications for the efficacy and safety of HSC gene therapies for CNS disorders, including lysosomal storage diseases and microgliopathies.

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