Vascular Adventitia is an Enriched Source of Postnatal Tissue Macrophage Precursor Cells (#68)
Macrophages are present in all tissues and are critical effectors and regulators of immune responses, also playing key roles during fibrosis and angiogenesis. Thus far, the cellular origins of tissue macrophages have remained uncertain, with evidence for both circulatory renewal and local production. Given the intricate relationship between haematopoiesis and the vasculature during embryogenesis, we have investigated whether postnatal blood vessels may also harbor haematopoietic stem (HSC) and progenitor cells (HPC). Aortic and arterial cell disaggregates from adult mice are capable of generating the full spectrum of haematopoietic colony forming units in vitro, demonstrating both spatial and temporal heterogeneity. While multipotent HPC and HSC are rare within the vessel wall, adult arteries have marked predilection and enrichment for macrophage colony forming units (CFU-M), compared to traditional haematopoietic and non-haematopoietic tissues. These macrophage precursor cells are contained within the vascular adventitia, where they co-express Sca-1 and CD45. Adventitial Sca-1+CD45+ precursors are the predominant source of proliferating cells in the aorta and are phenotypically and genotypically distinct from cells lacking the Sca-1 or CD45 antigens, with upregulation of macrophage/dendritic cell markers, chemokine receptors and transcription factors implicated in matrix remodeling, angiogenesis and atherosclerosis. As revealed by tracking studies, adventitial macrophage precursors are predominantly of local origin rather than arising from BM or spleen, unlike multipotent HPC/HSC which survey the vessel wall via peripheral circulation. Although macrophage-colony stimulating factor (M-CSF) is not required for the presence of vascular CFU-M, it does mediate phenotypic transformation of precursor cells to mature macrophage and dendritic cell progeny and may partly account for an increase of Sca-1+CD45+ cells and CFU-M in aortas of pro-atherogenic and atherosclerotic mice. In addition, adventitial Sca-1+CD45+ precursors have striking pro-angiogenic capacity and can participate directly in the formation of endothelial-containing vascular and lymphatic structures. The new discovery of an enriched source of macrophage precursor cells in postnatal vascular adventitia has important implications for our understanding of the local production and regulation of tissue macrophages in health and disease.