Progressive replacement of embryo-derived cardiac macrophages with age

Cardiac macrophages (cM ) are critical for early postnatal heart regeneration and fibrotic repair in the adult heart, but their origins and cellular dynamics during postnatal develop - ment have not been well characterized. Tissue macrophages can be derived from embryonic progenitors or from monocytes during inflammation. We report that within the first weeks after birth, the embryo-derived population of resident CX3CR1 + cM diversifies into MHCII + and MHCII cells. Genetic fate mapping demonstrated that cM derived from CX3CR1 + embryonic progenitors persisted into adulthood but the initially high contribution to resident cM declined after birth. Consistent with this, the early significant prolifera - tion rate of resident cM decreased with age upon diversification into subpopulations. Bone marrow (BM) reconstitution experiments showed monocyte-dependent quantitative replacement of all cM populations. Furthermore, parabiotic mice and BM chimeras of nonirradiated recipient mice revealed a slow but significant donor contribution to cM . Together, our observations indicate that in the heart, embryo-derived cM show declining self-renewal with age and are progressively substituted by monocyte-derived macrophages, even in the absence of inflammation