Alveolar-like Stem Cell-derived Myb- Macrophages Promote Recovery and Survival in Airway Disease

Rationale: Abnormal alveolar macrophages (AM) are found in chronic obstructive pulmonary disease, asthma, cystic fibrosis, and adenosine deaminase deficiency (ADA(-/-)). There is no specific treatment strategy to compensate for these innate immune abnormalities. Recent findings suggest AMs are of early embryonic or fetal origin. Pluripotent stem cells (PSCs) as a source of embryonic derived AMs for therapeutic use in acute and chronic airway diseases has yet to be investigated. Objectives: To determine if embryonic Myb(-/-) alveolar-like macrophages have therapeutic value on pulmonary transplantation in acute and chronic airway diseases. Methods: Directed differentiation of murine PSCs was used in factor-defined media to produce expandable embryonic macrophages conditioned to an alveolar-like phenotype with granulocyte macrophage colony stimulating factor. AMs were partially depleted in mice to create an acute lung injury. To model a chronic lung disease, ADA(-/-) mice were used. Alveolar-like macrophages were intratracheally transplanted to the injured animals and therapeutic potential was determined. Measurements and Main Results: The differentiation protocol is highly efficient and adaptable to human PSCs. The PSC macrophages are phenotypically like AMs both functionally and by ligand marker characterization. They engulf bacteria and apoptotic cells and are better phagocytes than bone marrow derived macrophages. In vivo, these macrophages remain in healthy airways for at least 4 weeks, can engulf neutrophils during acute lung injury, enhance pulmonary tissue repair, and promote survival in ADA(-/-) mice. Animals receiving the macrophages do not develop abnormal pathology or teratomas. Conclusions: PSCs are a reliable source to produce therapeutically active alveolar-like macrophages to treat airway disease.