br Experimental Procedures br Author Contributions br

Experimental Procedures
Author Contributions
Acknowledgments We thank Ms. Y. Ogata for technical assistance. Financial support for this research was provided by the Uehara Memorial Foundation, Takeda Science Foundation, the Naito Foundation, the Ministry of Education, Culture, Sports, Science, and Technology of Japan (15K08153), and the Japan Science and Technology Agency (PRESTO), Grants-in-aid for Scientific Research on Innovative Areas “Epigenome Dynamics and Regulation in Germ Cells” (25112003) and “Stem Cell Aging and Disease” (15H01510).
Introduction Following the groundbreaking work of Takahashi and Yamanaka in 2006 (Takahashi et al., 2007; Takahashi and Yamanaka, 2006), induced pluripotent stem 69 9 (iPSCs) and their in vitro differentiation into appropriate cell types or tissues have become a powerful tool to model defined disease entities as well as to study pathophysiology and new therapeutic options. With regard to rare diseases, this approach also allows us to overcome the limited availability of primary patient cells, a problem still hampering research in this area to a considerable extent. In this respect, iPSCs and derived progeny thereof constitute a valuable and potentially highly standardized source for the derivation of patient- and disease-specific cells for medical research. This also applies to diseases caused by defects in progenitor or mature effector cells of the hematopoietic system, such as lymphocytes (ADA-SCID, X-SCID) (Menon et al., 2015; Park et al., 2008), granulocytes and myeloid progenitors (chronic granulomatous disease, juvenile myelomonocytic leukemia) (Gandre-Babbe et al., 2013; Jiang et al., 2012; Ye et al., 2009), erythrocytes (thalassemias, sickle cell disease) (Ma et al., 2013; Tubsuwan et al., 2013; Zou et al., 2011), or megakaryocytes (congenital amegakaryocytic thrombocytopenia) (Hirata et al., 2013), which all have been successfully recapitulated in vitro utilizing iPSC-based models. Macrophages (Mφ) constitute another highly interesting cell population in this context. In the past years, our understanding of Mφ biology has been considerably extended, especially with regard to tissue-resident populations, such as osteoclasts, Langerhans\' and Kupffer cells, microglia, or peritoneal and alveolar Mφ (Davies et al., 2013). While traditionally tissue-resident Mφ (TRM) have been regarded as being continuously replenished from the hematopoietic stem cells via the intermediate step of peripheral blood monocytes, this concept now has been challenged for many tissues. Thus, it has recently been demonstrated that substantial populations of TRMs are already seeded prenatally, exhibit considerable longevity (months to years), and have, at least in part, self-renewal potential (Gomez Perdiguero et al., 2015; Hashimoto et al., 2013). Furthermore, a high degree of plasticity has been demonstrated for Mφ and TRMs, allowing them to adjust to the specific functional requirements of the surrounding tissues, e.g., following organ-specific transplantation (Lavin et al., 2014). For several of these Mφ and TRM populations, a direct and causative role has been identified in the pathophysiology of distinct congenital diseases, including heme oxygenase 1 deficiency (Kovtunovych et al., 2014), adrenoleukodystrophy (Biffi et al., 2011; Cartier et al., 2014), autosomal recessive osteopetrosis (Neri et al., 2015), Gaucher disease (Sgambato et al., 2015), and mucopolysaccharidosis type I (Viana et al., 2016). Another example in this context is hereditary pulmonary alveolar proteinosis (herPAP), a life-threatening, rare pulmonary disease caused by mutations in CSF2RA or CSF2RB encoding the α or β chain of the granulocyte macrophage colony-stimulating factor (GM-CSF) receptor, respectively (Suzuki et al., 2008, 2011). These mutations lead to receptor dysfunction and altered GM-CSF response. As GM-CSF signaling is especially important for alveolar Mφ differentiation, maturation, and function, the corresponding signaling defect leads to an impaired capacity of alveolar Mφ to clear the alveolar spaces from proteins and phospholipids (Hansen et al., 2008; Trapnell and Whitsett, 2002). Clinically this deficiency leads to progressive, life-threatening respiratory insufficiency and an increased susceptibility to pulmonary infections. Current treatment options of herPAP are purely symptomatic and comprise vigorous treatment of infections and repetitive bilateral whole lung lavage, an invasive procedure requiring general anesthesia and associated with significant cardiovascular risks (Trapnell et al., 2003, 2009).