Heterogeneous Origins and Functions of Mouse Skeletal Muscle Resident Macrophages

Tissue resident macrophages can arise from either embryonic or adult hematopoiesis and play important roles in a wide range of biological processes, such as tissue remodeling during organogenesis, tissue homeostasis in the steady state, tissue repair following injury, and immune response to pathogens. Although the origins and tissue-specific functions of resident macrophages have been extensively studied in many other tissues, they are not well characterized in skeletal muscle. In the present study, we have characterized for the first time the ontogeny of skeletal muscle resident macrophages, showing evidence that they arise from both embryonic hematopoietic progenitors, including yolk sac primitive macrophages and fetal liver monocytes, and adult bone marrow hematopoietic stem cells. Single cell-based transcriptome analysis revealed that skeletal muscle resident macrophages were highly distinctive from resident macrophages in other tissues, expressing a specific set of transcription factors and containing functionally diverse subsets correlating to their origins. They appear more active in maintaining tissue homeostasis and promoting muscle growth and regeneration. Skeletal muscle resident macrophages from quadriceps and diaphragm, as well as peritoneal macrophages and lung alveolar macrophages, of 8 weeks old C57 BL/6J mice were sorted by flow cytometry and were then subjected to single cell-based RNA sequencing.