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Cell Rep. 2018 Jul 3;24(1):130-141. doi: 10.1016/j.celrep.2018.05.066.

Embryonic Microglia Derive from Primitive Macrophages and Are Replaced by cmyb-Dependent Definitive Microglia in Zebrafish.

Author information

1
Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium; ULB Institute of Neuroscience (UNI), ULB, Brussels, Belgium; WELBIO, ULB, Brussels, Belgium.
2
Department of Pathology and Immunology, University of Geneva, School of Medicine, Geneva, Switzerland.
3
Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium.
4
Hubrecht Institute-KNAW and University Medical Center, Utrecht, the Netherlands.
5
Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium; ULB Institute of Neuroscience (UNI), ULB, Brussels, Belgium.
6
Hubrecht Institute-KNAW and University Medical Center, Utrecht, the Netherlands; Regenerative Medicine Center, University Medical Center, Utrecht, the Netherlands.
7
Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0380, USA; Section of Cell and Developmental Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0380, USA. Electronic address: dtraver@ucsd.edu.
8
Department of Pathology and Immunology, University of Geneva, School of Medicine, Geneva, Switzerland. Electronic address: julien.bertrand@unige.ch.
9
Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium; ULB Institute of Neuroscience (UNI), ULB, Brussels, Belgium; WELBIO, ULB, Brussels, Belgium. Electronic address: vwittame@ulb.ac.be.

Abstract

Microglia, the tissue-resident macrophages of the CNS, represent major targets for therapeutic intervention in a wide variety of neurological disorders. Efficient reprogramming protocols to generate microglia-like cells in vitro using patient-derived induced pluripotent stem cells will, however, require a precise understanding of the cellular and molecular events that instruct microglial cell fates. This remains a challenge since the developmental origin of microglia during embryogenesis is controversial. Here, using genetic tracing in zebrafish, we uncover primitive macrophages as the unique source of embryonic microglia. We also demonstrate that this initial population is transient, with primitive microglia later replaced by definitive microglia that persist throughout adulthood. The adult wave originates from cmyb-dependent hematopoietic stem cells. Collectively, our work challenges the prevailing model establishing erythro-myeloid progenitors as the sole and direct microglial precursor and provides further support for the existence of multiple waves of microglia, which originate from distinct hematopoietic precursors.

KEYWORDS:

cmyb; developmental hematopoiesis; erythro-myeloid progenitors; fate mapping; hematopoietic stem cells; microglia; ontogeny; primitive macrophages

PMID:
29972775
DOI:
10.1016/j.celrep.2018.05.066
[Indexed for MEDLINE]
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