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

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.