Fate‐mapping studies in inbred mice: A model for understanding macrophage development and homeostasis?

Abstract

The mononuclear phagocyte system (MPS) was defined in the early 1970s as a family of cells including progenitors, monocytes in the circulation, and resident tissue macrophages. They arise during development in three waves, in the yolk sac, fetal liver, and bone marrow. Fate-mapping studies using conditional reporter genes and regulated expression of cre recombinase have led to the view that most resident tissue macrophage populations are established during embryonic development and maintained in the adult by self-renewal with minimal input from bone marrow progenitors or blood monocytes. The interpretation of fate-mapping studies depends upon multiple assumptions: (i) that expression of cre recombinase has no effect on monocyte-macrophage homeostasis, (ii) that tamoxifen is a neutral agonist, (iii) that life in an SPF animal facility reflects the normal life course of a mouse, and (iv) that the C57Bl/6J inbred mouse is a generalizable model and the biology of the MPS is unaffected by mouse genetic background or species. This review summarizes evidence that questions each of these assumptions and concludes that fate-mapping studies may over-estimate the longevity and relative contribution of fetal-derived cells to resident tissue macrophage populations. In the opinion of the author, the original concept of the MPS does not require revision.

The effect of a dominant kinase-deadCsf1rmutation associated with adult-onset leukoencephalopathy on brain development and neuropathology

“…One argument against that suggestion is that microgliosis and neuropathology was also observed in a conditional heterozygous mutation ( Csf1r fl/+; Cx3cr1 Cre/+ ) (Arreola et al, 2021; Biundo et al, 2020). However, that model is actually a double heterozygote for Csf1r and Cx3cr1 mutations (see below) and complicated further by the known genotoxic effects of expression of Cre recombinase (Faust et al, 2023; Hume, 2023). Chitu et al .…”

“…The Csf1r +/- model of neuropathology depends upon the C57Bl/6J inbred mouse genetic background. Compared to other strains, C57BL/6J mice have a wide range of genetic variants that impact macrophage function including a coding variant in the Csf1r gene (Hume, 2023). The Csf1r +/- brain phenotype includes ventricular enlargement (Chitu et al, 2015).…”

“…The Csf1r +/- brain phenotype includes ventricular enlargement (Chitu et al, 2015). C57BL/6J mice exhibit strain-specific susceptibility to development of hydrocephalus in response to a diverse array of mutations affecting ependymal cells (Hume, 2023). Microglial activation could potentially be a downstream consequence of hydrocephalus (Brown et al, 2023).…”

Genetic models of fibrillinopathies

“…Genome editing techniques using clustered regularly interspaced short palindromic repeats (CRISPR) with the Cas9 enzyme, zinc finger nucleases, and transcription activator-like effector nucleases (TALENs) ( Gaj et al 2016 ) have opened the possibility of precisely engineering genetic changes in both laboratory animals and other less conventional model species ( Whitelaw et al 2016 ). However, most models are still created in the mouse, usually in the C57BL/6 strain, which has characteristics atypical of other mouse strains ( Orozco et al 2009 ; Keane et al 2011 ; Lilue et al 2018 ; Hume 2023 ) and other mammals. Mice are very different from humans, in size, metabolism, physiology, anatomy, and life history ( Perlman 2016 ).…”