Molecular Cardiology Identification of a Monocyte-Predisposed Hierarchy of Hematopoietic Progenitor Cells in the Adventitia of Postnatal Murine Aorta

Background—Hematopoiesis originates from the dorsal aorta during embryogenesis. Although adult blood vessels harbor progenitor populations for endothelial and smooth muscle cells, it is not known if they contain hematopoietic progenitor or stem cells. Here, we hypothesized that the arterial wall is a source of hematopoietic progenitor and stem cells in postnatal life. Methods and Results—Single-cell aortic disaggregates were prepared from adult chow-fed C57BL/6 and apolipoprotein E–null (ApoE Ϫ/Ϫ) mice. In short-and long-term methylcellulose-based culture, aortic cells generated a broad spectrum of multipotent and lineage-specific hematopoietic colony-forming units, with a preponderance of macrophage colony-forming units. This clonogenicity was higher in lesion-free ApoE Ϫ/Ϫ mice and localized primarily to stem cell antigen-1–positive cells in the adventitia. Expression of stem cell antigen-1 in the aorta colocalized with canonical hematopoietic stem cell markers, as well as CD45 and mature leukocyte antigens. Adoptive transfer of labeled aortic cells from green fluorescent protein transgenic donors to irradiated C57BL/6 recipients confirmed the content of rare hematopoietic stem cells (1 per 4 000 000 cells) capable of self-renewal and durable, low-level reconstitution of leukocytes. Moreover, the predominance of long-term macrophage precursors was evident by late recovery of green fluorescent protein–positive colonies from recipient bone marrow and spleen that were exclusively macrophage colony-forming units. Although trafficking from bone marrow was shown to replenish some of the hematopoietic potential of the aorta after irradiation, the majority of macrophage precursors appeared to arise locally, suggesting long-term residence in the vessel wall. Conclusions—The postnatal murine aorta contains rare multipotent hematopoietic progenitor/stem cells and is selectively enriched with stem cell antigen-1–positive monocyte/macrophage precursors. These populations may represent novel, local vascular sources of inflammatory cells. C ells of hematopoietic lineage play key regulatory roles in a diverse spectrum of vascular diseases, most notably atherosclerosis. 1,2 Defining the tissue origins of these cells is crucial to understanding vascular physiology and pathological remodeling. Historically, the longstanding dogma of atherosclerosis has been that mature inflammatory cells are recruited from the peripheral circulation to the expanding plaque. 1 However, several lines of evidence prompt consideration of an alternative view that the vasculature itself may harbor resident progenitor cells that act as a source of locally derived hematopoietic cells throughout adult life. During embryogenesis, definitive hematopoiesis has a conserved origin across various species within the developing aorta-gonad-mesonephros region and specifically the hemogenic endothelium of the ventral floor of the dorsal aorta. 3– 6 Although the hematopoietic potential of the …