Embryo-derived macrophages are more proliferative and resistant to cell death than monocyte-derived macrophages even after ex vivo expansion [ATAC-seq]

Tissue macrophages have been thought to be maintained by the differentiation of bone marrow-derived monocytes. However, recent studies have revealed that embryo-derived macrophages persist in many adult tissues, presumably due to their high self-renewing capacity. Here, we show that yolk sac-derived macrophages are more proliferative and resistant to cell death than monocyte-derived macrophages even after ex vivo expansion. The self-renewing macrophages were expanded from mouse bone marrow (BM), fetal liver (FL), or yolk sac (YS), by the long-term culture. Their phenotypes were overlapped but not identical. All of them stably proliferated in unlimited numbers, in the presence of the cytokine M-CSF. However, the proliferation speed of YS lines was the fastest and that of BM lines was the slowest. Moreover, YS and FL lines were more resistant to cell death caused by M-CSF-depletion or two apoptosis-inducers than BM lines. In line with these phenotypic similarity and difference, YS and FL lines were relatively similar in gene expression and chromatin accessibility whereas YS and BM lines showed the most distinct profiles. Furthermore, after transfer into mice, the YS line restores the high expression level of the core cell surface markers of embryonic macrophages that was lost during the long-term culture. These results suggest that ex vivo-expanded self-renewing macrophages are convenient and useful models, and provide a new opportunity for mechanistic analysis of macrophage self-renewal.