The study of human macrophages and their ontogeny is an important unresolved issue. Here, we use a humanized mouse model expressing human cytokines to dissect the development of lung macrophages from human hematopoiesis in vivo. Human CD34⁺ hematopoietic stem and progenitor cells (HSPCs) generated three macrophage populations, occupying separate anatomical niches in the lung. Intravascular cell labeling, cell transplantation, and fate-mapping studies established that classical CD14⁺ blood monocytes derived from HSPCs migrated into lung tissue and gave rise to human interstitial and alveolar macrophages. In contrast, non-classical CD16⁺ blood monocytes preferentially generated macrophages resident in the lung vasculature (pulmonary intravascular macrophages). Finally, single-cell RNA sequencing defined intermediate differentiation stages in human lung macrophage development from blood monocytes. This study identifies distinct developmental pathways from circulating monocytes to lung macrophages and reveals how cellular origin contributes to human macrophage identity, diversity, and localization in vivo.

人类巨噬细胞及其个体发育的研究是一个重要的悬而未决的问题。在这里，我们使用表达人类细胞因子的人源化小鼠模型来剖析体内人类造血过程中肺巨噬细胞的发育。人类 CD34 ⁺造血干细胞和祖细胞 (HSPC) 产生了三个巨噬细胞群，占据了肺中不同的解剖位置。血管内细胞标记、细胞移植和命运图谱研究表明，源自 HSPC 的经典 CD14 ⁺血液单核细胞迁移到肺组织并产生人间质和肺泡巨噬细胞。相比之下，非经典 CD16 ⁺血液单核细胞优先产生驻留在肺血管系统中的巨噬细胞（肺血管内巨噬细胞）。最后，单细胞 RNA 测序确定了从血液单核细胞发展到人肺巨噬细胞的中间分化阶段。这项研究确定了从循环单核细胞到肺巨噬细胞的不同发育途径，并揭示了细胞起源如何促进人类巨噬细胞的身份、多样性和体内定位。