Use of induced pluripotent stem cells to recapitulate pulmonary alveolar proteinosis pathogenesis.
Am J Respir Crit Care Med
; 189(2): 183-93, 2014 Jan 15.
Article
em En
| MEDLINE
| ID: mdl-24279752
ABSTRACT
RATIONALE In patients with pulmonary alveolar proteinosis (PAP) syndrome, disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling is associated with pathogenic surfactant accumulation from impaired clearance in alveolar macrophages. OBJECTIVES:
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.METHODS:
We created iPS cells from two children with hereditary PAP (hPAP) caused by recessive CSF2RA(R217X) mutations and three normal people, differentiated them into macrophages (hPAP-iPS-Mφs and NL-iPS-Mφs, respectively), and evaluated macrophage functions with and without gene-correction to restore GM-CSF signaling in hPAP-iPS-Mφs. MEASUREMENTS AND MAINRESULTS:
Both hPAP and normal iPS cells had human embryonic stem cell-like 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-Mφs had impaired GM-CSF receptor signaling and reduced GM-CSF-dependent gene expression, GM-CSF- but not M-CSF-dependent cell proliferation, surfactant clearance, and proinflammatory cytokine secretion. Restoration of GM-CSF receptor signaling corrected the surfactant clearance abnormality in hPAP-iPS-Mφs.CONCLUSIONS:
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteinose Alveolar Pulmonar
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Surfactantes Pulmonares
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Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos
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Doenças Genéticas Ligadas ao Cromossomo X
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Células-Tronco Pluripotentes Induzidas
Tipo de estudo:
Etiology_studies
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Observational_studies
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Risk_factors_studies
Limite:
Child
/
Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article