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

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.

The lymphoid-associated interleukin 7 receptor (IL7R) regulates tissue-resident macrophage development

“…6C). Together, these data suggest that although IL7R expression labels a multipotent fetal liver progenitor, expression of IL7R on developing tissues macrophages later in gestation regulates their development during later waves of macrophage seeding (De et al, 2018;Ferrero et al, 2018;Tan and Krasnow, 2016).…”

Resident Immunity in Tissue Repair and Maintenance: The Zebrafish Model Coming of Age

“…Unfortunately, though, this is where the problem starts. In the mouse, the most commonly used vertebrate immunology model, the origin of tissue resident or associated immune cells is generally well described, exemplified in (Bain et al, 2014; Ginhoux and Guilliams, 2016; Ferrero et al, 2018), whereas in the zebrafish, our knowledge is still largely incomplete.…”

Zebrafish cardiac regeneration—looking beyond cardiomyocytes to a complex microenvironment

“…This M1/M2 nomenclature is now largely seen as an oversimplification, with macrophages more likely to have a spectrum of activation states that inform their function. This plasticity of macrophage phenotype and function is largely controlled by the tissue microenvironment, but is also determined by cellular origin, with tissue resident and monocyte-derived populations shown to be distinct populations (He et al 2018 ; Ferrero et al 2018 ), which, in turn, is likely to affect their contribution to regeneration and scarring (Lavine et al 2014 ).…”