IRF8
生物
干细胞
造血
细胞生物学
细胞分化
诱导多能干细胞
祖细胞
免疫学
髓样
胚胎干细胞
转录因子
遗传学
基因
作者
Stephanie Sontag,Malrun Förster,Jie Qin,Paul Wanek,Saskia Mitzka,Herdit M. Schüler,Steffen Koschmieder,Stefan Rose‐John,Kristin Seré,Martin Zenke
出处
期刊:Stem Cells
[Wiley]
日期:2017-01-16
卷期号:35 (4): 898-908
被引量:56
摘要
Abstract Human induced pluripotent stem (iPS) cells can differentiate into cells of all three germ layers, including hematopoietic stem cells and their progeny. Interferon regulatory factor 8 (IRF8) is a transcription factor, which acts in hematopoiesis as lineage determining factor for myeloid cells, including dendritic cells (DC). Autosomal recessive or dominant IRF8 mutations occurring in patients cause severe monocytic and DC immunodeficiency. To study IRF8 in human hematopoiesis we generated human IRF8−/− iPS cells and IRF8−/− embryonic stem (ES) cells using RNA guided CRISPR/Cas9n genome editing. Upon induction of hematopoietic differentiation, we demonstrate that IRF8 is dispensable for iPS cell and ES cell differentiation into hemogenic endothelium and for endothelial-to-hematopoietic transition, and thus development of hematopoietic progenitors. We differentiated iPS cell and ES cell derived progenitors into CD141+ cross-presenting cDC1 and CD1c+ classical cDC2 and CD303+ plasmacytoid DC (pDC). We found that IRF8 deficiency compromised cDC1 and pDC development, while cDC2 development was largely unaffected. Additionally, in an unrestricted differentiation regimen, IRF8−/− iPS cells and ES cells exhibited a clear bias toward granulocytes at the expense of monocytes. IRF8−/− DC showed reduced MHC class II expression and were impaired in cytokine responses, migration, and antigen presentation. Taken together, we engineered a human IRF8 knockout model that allows studying molecular mechanisms of human immunodeficiencies in vitro, including the pathophysiology of IRF8 deficient DC.
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