Conference 2021 Live Talk


Talk title

TIMD4 and CCR2 mark resident tissue macrophage subsets with conserved lifecycles across organs


Authors and Affiliations

Anthony Wong1,2,3, Sarah Dick2,3, Homaira Hamidzada1,2,3, Sara Nejat2,3, Robert Nechanitzky2, Shabana Vohra2,3, Rysa Zaman1,2,3, Crystal Kantores2,3, Laura Aronoff2,3, Abdul Momen2, Slava Epelman1,2,3,4

1. Department of Immunology, University of Toronto, Canada
2. University Health Network, Toronto, Canada
3. Ted Rogers Centre for Heart Research, Toronto, Canada
4. Peter Munk Cardiac Centre, Toronto Canada




Resident macrophages are present in all tissues of the body from the earliest stages of development and orchestrate homeostatic, inflammatory, and reparative activities. Macrophages are highly adapted to their tissue of residence, and recent work in the field has shown that several subpopulations can also coexist within a single tissue, suggesting additional heterogeneity. Although the functional differences between resident macrophages of various tissues have been well defined, what has been overlooked is whether by investigating transcriptionally and biologically relevant similarities, an underlying macrophage framework can be revealed across organs.


Single-cell RNA-sequencing was performed in conjunction with parabiosis and genetic fate mapping to examine the gene expression profiles and lifecycle properties of macrophage subpopulations from the mouse heart, brain, liver, lung, and kidney throughout life.


Bioinformatics analysis of single-cell RNA-Seq of macrophages from the mouse heart, brain, liver, lung, and kidney revealed the presence of three macrophage subpopulations that were distinguishable in each tissue by a common repertoire of core genes. Sequential long-term parabiosis experiments revealed that these core markers tracked with distinct populations of macrophages with unique lifecycles. TIMD4+ (CCR2-) macrophages persisted via self-renewal with negligible monocyte input. TIMD4-CCR2- macrophages, while receiving modest monocyte contribution, were not continually replaced, as monocyte-derived macrophages contributed until a defined limit in the tissue after which they did not outcompete pre-existing resident TIMD4-CCR2- macrophages. In contrast, CCR2+ (TIMD4-) macrophages in each tissue were almost exclusively monocyte-dependent. TIMD4+ macrophages were the earliest single-cell transcriptional state observed in the yolk sac and early fetal organs, an observation that was confirmed by fate mapping studies in embryonic development. Inducible genetic fate mapping revealed a dual yolk sac and fetal monocyte origin of TIMD4+ and TIMD4-CCR2- macrophages in development, while CCR2+ macrophages were entirely derived from fetal monocytes – findings that were consistent across all organs examined.


The existence of three macrophage subpopulations across five mouse organs can be organized into a common framework of heterogeneity based on common patterns of ontogeny, lifecycle, and core gene signatures.