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Induced pluripotent stem cells: A novel frontier in the study of human primary immunodeficiencies

2010; Elsevier BV; Volume: 127; Issue: 6 Linguagem: Inglês

10.1016/j.jaci.2010.11.008

1097-6825

Itai M. Pessach, José Ordovás-Montañés, Shen‐Ying Zhang, Jean‐Laurent Casanova, Silvia Giliani, Andrew R. Gennery, Waleed Al‐Herz, Philip D. Manos, Thorsten M. Schlaeger, In‐Hyun Park, Francesca Rucci, Suneet Agarwal, Gustavo Mostoslavsky, George Q. Daley, Luigi D. Notarangelo,

Renal and related cancers

BackgroundThe novel ability to epigenetically reprogram somatic cells into induced pluripotent stem cells (iPSCs) through the exogenous expression of transcription promises to revolutionize the study of human diseases.ObjectiveHere we report on the generation of 25 iPSC lines from 6 patients with various forms of primary immunodeficiencies (PIDs) affecting adaptive immunity, innate immunity, or both.MethodsPatients' dermal fibroblasts were reprogrammed by expression of 4 transcription factors, octamer-binding transcription factor 4 (OCT4), sex determining region Y-box 2 (SOX2), Krueppel-like factor 4 (KLF4), and cellular myelomonocytosis proto-oncogene (cMYC), by using a single excisable polycistronic lentiviral vector.ResultsiPSCs derived from patients with PIDs show a stemness profile that is comparable with that observed in human embryonic stem cells. After in vitro differentiation into embryoid bodies, pluripotency of the patient-derived iPSC lines was demonstrated by expression of genes characteristic of each of the 3 embryonic layers. We have confirmed the patient-specific origin of the iPSC lines and ascertained maintenance of karyotypic integrity.ConclusionBy providing a limitless source of diseased stem cells that can be differentiated into various cell types in vitro, the repository of iPSC lines from patients with PIDs represents a unique resource to investigate the pathophysiology of hematopoietic and extrahematopoietic manifestations of these diseases and might assist in the development of novel therapeutic approaches based on gene correction. The novel ability to epigenetically reprogram somatic cells into induced pluripotent stem cells (iPSCs) through the exogenous expression of transcription promises to revolutionize the study of human diseases. Here we report on the generation of 25 iPSC lines from 6 patients with various forms of primary immunodeficiencies (PIDs) affecting adaptive immunity, innate immunity, or both. Patients' dermal fibroblasts were reprogrammed by expression of 4 transcription factors, octamer-binding transcription factor 4 (OCT4), sex determining region Y-box 2 (SOX2), Krueppel-like factor 4 (KLF4), and cellular myelomonocytosis proto-oncogene (cMYC), by using a single excisable polycistronic lentiviral vector. iPSCs derived from patients with PIDs show a stemness profile that is comparable with that observed in human embryonic stem cells. After in vitro differentiation into embryoid bodies, pluripotency of the patient-derived iPSC lines was demonstrated by expression of genes characteristic of each of the 3 embryonic layers. We have confirmed the patient-specific origin of the iPSC lines and ascertained maintenance of karyotypic integrity. By providing a limitless source of diseased stem cells that can be differentiated into various cell types in vitro, the repository of iPSC lines from patients with PIDs represents a unique resource to investigate the pathophysiology of hematopoietic and extrahematopoietic manifestations of these diseases and might assist in the development of novel therapeutic approaches based on gene correction.