From the Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (P.J.P., A.S.P., D.B.S., C.D.C., S.J.H., T.A.W., S.D., L.S.K., C.S.M., S.P., R.G., R.D.S.); Monash Cardiovascular Research Centre, Monash University, Clayton, Victoria, Australia (P.J.P.); Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia (P.J.P., S.D.); and Kansas University Medical Center, The University of Kansas, Kansas City (R.D.S).
Circ Res. 2014 Jul 18;115(3):364-75. doi: 10.1161/CIRCRESAHA.115.303299. Epub 2014 Jun 6.
Macrophages regulate blood vessel structure and function in health and disease. The origins of tissue macrophages are diverse, with evidence for local production and circulatory renewal.
We identified a vascular adventitial population containing macrophage progenitor cells and investigated their origins and fate.
Single-cell disaggregates from adult C57BL/6 mice were prepared from different tissues and tested for their capacity to form hematopoietic colony-forming units. Aorta showed a unique predilection for generating macrophage colony-forming units. Aortic macrophage colony-forming unit progenitors coexpressed stem cell antigen-1 and CD45 and were adventitially located, where they were the predominant source of proliferating cells in the aortic wall. Aortic Sca-1(+)CD45(+) cells were transcriptionally and phenotypically distinct from neighboring cells lacking stem cell antigen-1 or CD45 and contained a proliferative (Ki67(+)) Lin(-)c-Kit(+)CD135(-)CD115(+)CX3CR1(+)Ly6C(+)CD11b(-) subpopulation, consistent with the immunophenotypic profile of macrophage progenitors. Adoptive transfer studies revealed that Sca-1(+)CD45(+) adventitial macrophage progenitor cells were not replenished via the circulation from bone marrow or spleen, nor was their prevalence diminished by depletion of monocytes or macrophages by liposomal clodronate treatment or genetic deficiency of macrophage colony-stimulating factor. Rather adventitial macrophage progenitor cells were upregulated in hyperlipidemic ApoE(-/-) and LDL-R(-/-) mice, with adventitial transfer experiments demonstrating their durable contribution to macrophage progeny particularly in the adventitia, and to a lesser extent the atheroma, of atherosclerotic carotid arteries.
The discovery and characterization of resident vascular adventitial macrophage progenitor cells provides new insight into adventitial biology and its participation in atherosclerosis and provokes consideration of the broader existence of local macrophage progenitors in other tissues.
巨噬细胞在健康和疾病中调节血管结构和功能。组织巨噬细胞的起源多种多样，有证据表明其来源于局部产生和循环更新。
我们鉴定了一种含有巨噬细胞祖细胞的血管外膜群体，并研究了其起源和命运。
从成年 C57BL/6 小鼠的不同组织中分离出单细胞，检测其形成造血集落形成单位的能力。主动脉显示出独特的生成巨噬细胞集落形成单位的倾向。主动脉巨噬细胞集落形成单位祖细胞共同表达干细胞抗原-1 和 CD45，位于外膜，是主动脉壁中增殖细胞的主要来源。主动脉 Sca-1(+)CD45(+)细胞在转录和表型上与缺乏干细胞抗原-1 或 CD45 的邻近细胞不同，并且包含一个增殖（Ki67(+)）Lin(-)c-Kit(+)CD135(-)CD115(+)CX3CR1(+)Ly6C(+)CD11b(-)亚群，与巨噬细胞祖细胞的免疫表型特征一致。过继转移研究表明，Sca-1(+)CD45(+)外膜巨噬细胞祖细胞不是通过循环从骨髓或脾脏补充的，也不是通过脂质体氯膦酸盐处理或巨噬细胞集落刺激因子基因缺失耗尽单核细胞或巨噬细胞而减少其患病率。相反，高脂血症 ApoE(-/-)和 LDL-R(-/-)小鼠中外膜巨噬细胞祖细胞上调，外膜转移实验表明它们对巨噬细胞后代，特别是在动脉粥样硬化颈动脉的外膜中的持久贡献，以及在动脉粥样硬化中的贡献较小。
驻留血管外膜巨噬细胞祖细胞的发现和特征为外膜生物学及其在动脉粥样硬化中的参与提供了新的见解，并引发了对其他组织中局部巨噬细胞祖细胞更广泛存在的考虑。
