Abstract
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 invivo. 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 invivo.
Highlights
The lung is a vital organ exposed to airborne challenges that are first encountered by tissue-resident macrophages
The main cell population found in the bronchoalveolar lavage (BAL) fluid of engrafted MISTRG mice (Figure 1B), were large autofluorescent human CD45+HLA-DR+CD11b+ cells that expressed cell-surface proteins characteristic of human alveolar macrophages (Bharat et al, 2016; Yu et al, 2016), such as CD206, CD169 (Siglec-1), and macrophage receptor with collagenous structure (MARCO)
Human alveolar macrophages derived from CD34+ hematopoietic stem and progenitor cells (HSPCs) in MISTRG mice had a similar phenotype to their counterparts found in the BAL fluid of healthy human donors (Figure 1B)
Summary
The lung is a vital organ exposed to airborne challenges that are first encountered by tissue-resident macrophages. Alveolar macrophages catabolize lung surfactant, phagocytose-inhaled material, and orchestrate immune responses against airborne microbes. Interstitial macrophages located within the space between the lung epithelium and the vasculature perform tissue remodeling and contribute to barrier immunity through antigen presentation. Macrophages originate from either embryonic precursors or from blood monocytes arising from hematopoietic stem cells in the bone marrow (Epelman et al, 2014; Ginhoux and Guilliams, 2016; Perdiguero and Geissmann, 2016; Varol et al, 2015). Blood monocytes derived from hematopoietic stem cells increasingly contribute to the alveolar macrophage compartment in older mice (Gomez Perdiguero et al, 2015; Liu et al, 2019). Mouse interstitial macrophages originate mainly from adult hematopoiesis (Sabatel et al, 2017; Tan and Krasnow, 2016) and are slowly replaced by circulating monocytes (Chakarov et al, 2019; Gibbings et al, 2017; Schyns et al, 2019)
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