iPSC-Derived Macrophages Effectively Treat Pulmonary Alveolar Proteinosis in Csf2rb-Deficient Mice

• Published in: Stem cell reports 2018-09, Vol.11 (3), p.696-710
• Main Authors: Mucci, Adele, Lopez-Rodriguez, Elena, Hetzel, Miriam, Liu, Serena, Suzuki, Takuji, Happle, Christine, Ackermann, Mania, Kempf, Henning, Hillje, Roman, Kunkiel, Jessica, Janosz, Ewa, Brennig, Sebastian, Glage, Silke, Bankstahl, Jens P., Dettmer, Sabine, Rodt, Thomas, Gohring, Gudrun, Trapnell, Bruce, Hansen, Gesine, Trapnell, Cole, Knudsen, Lars, Lachmann, Nico, Moritz, Thomas
• Format: Article
• Language: English
• Subjects: cell therapy; hematopoiesis; iPSC; lung; macrophages
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2018.07.006

Induced pluripotent stem cell (iPSC)-derived hematopoietic cells represent a highly attractive source for cell and gene therapy. Given the longevity, plasticity, and self-renewal potential of distinct macrophage subpopulations, iPSC-derived macrophages (iPSC-Mφ) appear of particular interest in this context. We here evaluated the airway residence, plasticity, and therapeutic efficacy of iPSC-Mφ in a murine model of hereditary pulmonary alveolar proteinosis (herPAP). We demonstrate that single pulmonary macrophage transplantation (PMT) of 2.5–4 × 106 iPSC-Mφ yields efficient airway residence with conversion of iPSC-Mφ to an alveolar macrophage (AMφ) phenotype characterized by a distinct surface marker and gene expression profile within 2 months. Moreover, PMT significantly improves alveolar protein deposition and other critical herPAP disease parameters. Thus, our data indicate iPSC-Mφ as a source of functional macrophages displaying substantial plasticity and therapeutic potential that upon pulmonary transplantation will integrate into the lung microenvironment, adopt an AMφ phenotype and gene expression pattern, and profoundly ameliorate pulmonary disease phenotypes. [Display omitted] •iPSCs as a source of functional macrophages with substantial plasticity•iPSC-derived macrophages have therapeutic potential in hereditary PAP•Pulmonary-transplanted iPSC-Mφ integrate into the lung microenvironment•iPSC-Mφ can adopt an AMφ phenotype and gene expression pattern Mucci and colleagues demonstrate marked plasticity of iPSC-derived macrophages and rapid adoption of an alveolar macrophage phenotype upon pulmonary transplantation, as well as profound therapeutic efficacy of iPSC-derived macrophages in the context of the severe lung disease pulmonary alveolar proteinosis.