Distinct developmental pathways from blood monocytes generate human lung macrophage diversity

• Published in: Immunity (Cambridge, Mass.) Vol. 54; no. 2; pp. 259 - 275.e7
• Main Authors: Evren, Elza, Ringqvist, Emma, Tripathi, Kumar Parijat, Sleiers, Natalie, Rives, Inés Có, Alisjahbana, Arlisa, Gao, Yu, Sarhan, Dhifaf, Halle, Tor, Sorini, Chiara, Lepzien, Rico, Marquardt, Nicole, Michaëlsson, Jakob, Smed-Sörensen, Anna, Botling, Johan, Karlsson, Mikael C.I., Villablanca, Eduardo J., Willinger, Tim
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.02.2021; Elsevier Limited
• Subjects: Alveoli; Blood; Blood circulation; blood monocytes; CD14 antigen; CD16 antigen; CD34 antigen; Cell differentiation; Cell fate; Cells (biology); Cytokines; fate mapping; Fate maps; Gene sequencing; Hematopoiesis; Hematopoietic stem cells; human macrophages; humanized mice; intravascular macrophages; Localization; lung; Lungs; Macrophages; Medicin och hälsovetenskap; Monocytes; Ontogeny; origin; Pathology; Patologi; Population; Progenitor cells; Ribonucleic acid; RNA; single-cell RNA sequencing; Stem cells; Surfactants; Transplantation; lung; blood monocytes; single-cell RNA sequencing; fate mapping; origin; humanized mice; human macrophages; ontogeny; intravascular macrophages
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2020.12.003

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. [Display omitted] •A developmental map of human lung macrophages from blood monocytes in vivo•Extravasating CD14+ monocytes give rise to alveolar and interstitial macrophages•Identification of CD14+HLA-DRhi lung monocytes as intermediate differentiation stage•Pulmonary intravascular macrophages originate from CD16+ blood monocytes Tissue-resident macrophages maintain healthy organ function, but the ontogeny of human macrophages is largely unknown. Using humanized mice and single-cell RNA sequencing, Evren et al. uncover the migration and differentiation of blood monocytes into distinct populations of human lung macrophages in vivo.