{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T23:55:13Z","timestamp":1791503713714,"version":"4.3.4"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2014,1,1]],"date-time":"2014-01-01T00:00:00Z","timestamp":1388534400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,1,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>In patients with pulmonary alveolar proteinosis (PAP) syndrome, disruption of granulocyte\/macrophage colony\u2013stimulating factor (GM-CSF) signaling is associated with pathogenic surfactant accumulation from impaired clearance in alveolar macrophages.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>The aim of this study was to overcome these barriers by using monocyte-derived induced pluripotent stem (iPS) cells to recapitulate disease-specific and normal macrophages.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We created iPS cells from two children with hereditary PAP (hPAP) caused by recessive CSF2RAR217X mutations and three normal people, differentiated them into macrophages (hPAP-iPS-M\u03c6s and NL-iPS-M\u03c6s, respectively), and evaluated macrophage functions with and without gene-correction to restore GM-CSF signaling in hPAP-iPS-M\u03c6s.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>Both hPAP and normal iPS cells had human embryonic stem cell\u2013like morphology, expressed pluripotency markers, formed teratomas in vivo, had a normal karyotype, retained and expressed mutant or normal CSF2RA genes, respectively, and could be differentiated into macrophages with the typical morphology and phenotypic markers. Compared with normal, hPAP-iPS-M\u03c6s had impaired GM-CSF receptor signaling and reduced GM-CSF\u2013dependent gene expression, GM-CSF\u2013 but not M-CSF\u2013dependent cell proliferation, surfactant clearance, and proinflammatory cytokine secretion. Restoration of GM-CSF receptor signaling corrected the surfactant clearance abnormality in hPAP-iPS-M\u03c6s.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We used patient-specific iPS cells to accurately reproduce the molecular and cellular defects of alveolar macrophages that drive the pathogenesis of PAP in more than 90% of patients. These results demonstrate the critical role of GM-CSF signaling in surfactant homeostasis and PAP pathogenesis in humans and have therapeutic implications for hPAP.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201306-1039oc","type":"journal-article","created":{"date-parts":[[2013,11,26]],"date-time":"2013-11-26T10:52:48Z","timestamp":1385463168000},"page":"183-193","source":"Crossref","is-referenced-by-count":55,"title":["Use of Induced Pluripotent Stem Cells to Recapitulate Pulmonary Alveolar Proteinosis Pathogenesis"],"prefix":"10.1093","volume":"189","author":[{"given":"Takuji","family":"Suzuki","sequence":"first","affiliation":[{"name":"Division of Pulmonary Biology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Mayhew","sequence":"additional","affiliation":[{"name":"Division of Developmental 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