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1.
Stem Cell Res ; 43: 101713, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32000109

RESUMEN

Chronic mucocutaneous candidiasis (CMC) is a disease that is characterized by susceptibility to chronic or recurrent infections with Candida spp. due to mutations affecting mainly the IL-17 signaling of T-Cells. The most common etiologies of CMC are gain-of-function (GOF) mutations in the STAT1 gene. In this paper we report the generation of a hiPSC line from a patient suffering from CMC due to a heterozygous GOF STAT1 p.R274Q mutation which can be used for disease modeling purposes.


Asunto(s)
Candidiasis Mucocutánea Crónica/genética , Mutación con Ganancia de Función/genética , Células Madre Pluripotentes Inducidas/metabolismo , Factor de Transcripción STAT1/genética , Adolescente , Animales , Humanos , Masculino
2.
Stem Cell Reports ; 4(2): 282-96, 2015 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-25680479

RESUMEN

Interleukin-3 (IL-3) is capable of supporting the proliferation of a broad range of hematopoietic cell types, whereas granulocyte colony-stimulating factor (G-CSF) and macrophage CSF (M-CSF) represent critical cytokines in myeloid differentiation. When this was investigated in a pluripotent-stem-cell-based hematopoietic differentiation model, IL-3/G-CSF or IL-3/M-CSF exposure resulted in the continuous generation of myeloid cells from an intermediate myeloid-cell-forming complex containing CD34(+) clonogenic progenitor cells for more than 2 months. Whereas IL-3/G-CSF directed differentiation toward CD45(+)CD11b(+)CD15(+)CD16(+)CD66b(+) granulocytic cells of various differentiation stages up to a segmented morphology displaying the capacity of cytokine-directed migration, respiratory burst response, and neutrophil-extracellular-trap formation, exposure to IL-3/M-CSF resulted in CD45(+)CD11b(+)CD14(+)CD163(+)CD68(+) monocyte/macrophage-type cells capable of phagocytosis and cytokine secretion. Hence, we show here that myeloid specification of human pluripotent stem cells by IL-3/G-CSF or IL-3/M-CSF allows for prolonged and large-scale production of myeloid cells, and thus is suited for cell-fate and disease-modeling studies as well as gene- and cell-therapy applications.


Asunto(s)
Técnicas de Cultivo de Célula , Diferenciación Celular , Granulocitos/citología , Células Madre Pluripotentes Inducidas/citología , Macrófagos/citología , Diferenciación Celular/efectos de los fármacos , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Factor Estimulante de Colonias de Granulocitos/farmacología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Granulocitos/metabolismo , Humanos , Inmunohistoquímica , Inmunofenotipificación , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Pluripotentes Inducidas/metabolismo , Interleucina-3/farmacología , Macrófagos/metabolismo , Fenotipo
3.
Am J Respir Crit Care Med ; 189(2): 167-82, 2014 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-24279725

RESUMEN

RATIONALE: Hereditary pulmonary alveolar proteinosis (hPAP) caused by granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor α-chain (CSF2RA) deficiency is a rare, life-threatening lung disease characterized by accumulation of proteins and phospholipids in the alveolar spaces. The disease is caused by a functional insufficiency of alveolar macrophages, which require GM-CSF signaling for terminal differentiation and effective degradation of alveolar proteins and phospholipids. Therapeutic options are extremely limited, and the pathophysiology underlying the defective protein degradation in hPAP alveolar macrophages remains poorly understood. OBJECTIVES: To further elucidate the cellular mechanisms underlying hPAP and evaluate novel therapeutic strategies, we here investigated the potential of hPAP patient-derived induced pluripotent stem cell (PAP-iPSCs) derived monocytes and macrophages. METHODS: Patient-specific PAP-iPSCs were generated from CD34(+) bone marrow cells of a CSF2RA-deficient patient with PAP. We assessed pluripotency, chromosomal integrity, and genetic correction of established iPSC lines. On hematopoietic differentiation, genetically corrected or noncorrected monocytes and macrophages were investigated in GM-CSF-dependent assays. MEASUREMENTS AND MAIN RESULTS: Although monocytes and macrophages differentiated from noncorrected PAP-iPSCs exhibited distinct defects in GM-CSF-dependent functions, such as perturbed CD11b activation, phagocytic activity, and STAT5 phosphorylation after GM-CSF exposure and lack of GM-CSF uptake, these defects were fully repaired on lentiviral gene transfer of a codon-optimized CSF2RA-cDNA. CONCLUSIONS: These data establish PAP-iPSC-derived monocytes and macrophages as a valid in vitro disease model of CSF2RA-deficient PAP, and introduce gene-corrected iPSC-derived monocytes and macrophages as a potential autologous cell source for innovative therapeutic strategies. Transplantation of such cells to patients with hPAP could serve as a paradigmatic proof for the potential of iPSC-derived cells in clinical gene therapy.


Asunto(s)
Enfermedades Genéticas Ligadas al Cromosoma X/terapia , Terapia Genética , Células Madre Pluripotentes Inducidas , Proteinosis Alveolar Pulmonar/terapia , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/deficiencia , Técnicas de Cultivo de Célula , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Preescolar , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/metabolismo , Humanos , Macrófagos Alveolares/metabolismo , Modelos Biológicos , Monocitos/metabolismo , Proteinosis Alveolar Pulmonar/genética , Proteinosis Alveolar Pulmonar/metabolismo , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética
4.
Traffic ; 9(6): 924-35, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18363777

RESUMEN

Members of the tetraspanin family including CD9 contribute to the structural organization and plasticity of the plasma membrane. K41, a CD9-specific monoclonal antibody, inhibits the release of HIV-1 and canine distemper virus (CDV)- but not measles virus (MV)-induced cell-cell fusion. We now report that K41, which recognizes a conformational epitope on the large extracellular loop of CD9, induces rapid relocation and clustering of CD9 in net-like structures at cell-cell contact areas. High-resolution analyses revealed that CD9 clustering is accompanied by the formation of microvilli that protrude from either side of adjacent cell surfaces, thus forming structures like microvilli zippers. While the cellular CD9-associated proteins beta(1)-integrin and EWI-F were co-clustered with CD9 at cell-cell interfaces, viral proteins in infected cells were differentially affected. MV envelope proteins were detected within CD9 clusters, whereas CDV proteins were excluded from CD9 clusters. Thus, the tetraspanin CD9 can regulate cell-cell fusion by controlling the access of the fusion machinery to cell contact areas.


Asunto(s)
Antígenos CD/inmunología , Fusión Celular , Virus del Moquillo Canino/patogenicidad , Virus del Sarampión/patogenicidad , Glicoproteínas de Membrana/inmunología , Microvellosidades/metabolismo , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/metabolismo , Anticuerpos Monoclonales/ultraestructura , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/ultraestructura , Antígenos CD/metabolismo , Antígenos CD/ultraestructura , Células CHO , Comunicación Celular , Células Cultivadas , Chlorocebus aethiops , Cricetinae , Cricetulus , Virus del Moquillo Canino/genética , Perros , Células Endoteliales/inmunología , Células Endoteliales/ultraestructura , Células Endoteliales/virología , Endotelio Vascular/citología , Técnica del Anticuerpo Fluorescente Indirecta , Células HeLa , Humanos , Cinética , Virus del Sarampión/genética , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/ultraestructura , Microvellosidades/ultraestructura , Tetraspanina 29 , Transfección , Venas Umbilicales/citología , Células Vero
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