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Patient iPSC-Derived Macrophages to Study Inborn Errors of the IFN-γ Responsive Pathway

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REBIRTH Cluster of Excellence, Institute of Experimental Hematology, Hannover Medical School (MHH), 30625 Hannover, Germany
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Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163, Necker Hospital for Sick Children, 75015 Paris, France
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Imagine Institute, Paris University, 75015 Paris, France
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Institute of Pathology, Hannover Medical School (MHH), 30625 Hannover, Germany
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Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), German Center for Lung Research, 30625 Hannover, Germany
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Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between The Helmholtz Centre for Infection Research, Braunschweig, and The Hannover Medical School, 30625 Hannover, Germany
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Department of Pediatrics, University Medical Center Ulm, 89081 Ulm, Germany
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Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
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Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA
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Institute for Microbiology, University of Veterinary Medicine Hannover, 30625 Hannover, Germany
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St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA
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Howard Hughes Medical Institute, New York, NY 10065, USA
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Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, 75015 Paris, France
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Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, 75015 Paris, France
*
Author to whom correspondence should be addressed.
Cells 2020, 9(2), 483; https://doi.org/10.3390/cells9020483
Received: 13 January 2020 / Revised: 13 February 2020 / Accepted: 17 February 2020 / Published: 19 February 2020
(This article belongs to the Section Stem Cells)
Interferon γ (IFN-γ) was shown to be a macrophage activating factor already in 1984. Consistently, inborn errors of IFN-γ immunity underlie Mendelian Susceptibility to Mycobacterial Disease (MSMD). MSMD is characterized by genetic predisposition to disease caused by weakly virulent mycobacterial species. Paradoxically, macrophages from patients with MSMD were little tested. Here, we report a disease modeling platform for studying IFN-γ related pathologies using macrophages derived from patient specific induced pluripotent stem cells (iPSCs). We used iPSCs from patients with autosomal recessive complete- and partial IFN-γR2 deficiency, partial IFN-γR1 deficiency and complete STAT1 deficiency. Macrophages from all patient iPSCs showed normal morphology and IFN-γ-independent functionality like phagocytic uptake of bioparticles and internalization of cytokines. For the IFN-γ-dependent functionalities, we observed that the deficiencies played out at various stages of the IFN-γ pathway, with the complete IFN-γR2 and complete STAT1 deficient cells showing the most severe phenotypes, in terms of upregulation of surface markers and induction of downstream targets. Although iPSC-derived macrophages with partial IFN-γR1 and IFN-γR2 deficiency still showed residual induction of downstream targets, they did not reduce the mycobacterial growth when challenged with Bacillus Calmette–Guérin. Taken together, we report a disease modeling platform to study the role of macrophages in patients with inborn errors of IFN-γ immunity. View Full-Text
Keywords: hematopoiesis; induced pluripotent stem cells; macrophages; MSMD; mycobacteria; interferon γ hematopoiesis; induced pluripotent stem cells; macrophages; MSMD; mycobacteria; interferon γ
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MDPI and ACS Style

Haake, K.; Neehus, A.-L.; Buchegger, T.; Kühnel, M.P.; Blank, P.; Philipp, F.; Oleaga-Quintas, C.; Schulz, A.; Grimley, M.; Goethe, R.; Jonigk, D.; Kalinke, U.; Boisson-Dupuis, S.; Casanova, J.-L.; Bustamante, J.; Lachmann, N. Patient iPSC-Derived Macrophages to Study Inborn Errors of the IFN-γ Responsive Pathway. Cells 2020, 9, 483. https://doi.org/10.3390/cells9020483

AMA Style

Haake K, Neehus A-L, Buchegger T, Kühnel MP, Blank P, Philipp F, Oleaga-Quintas C, Schulz A, Grimley M, Goethe R, Jonigk D, Kalinke U, Boisson-Dupuis S, Casanova J-L, Bustamante J, Lachmann N. Patient iPSC-Derived Macrophages to Study Inborn Errors of the IFN-γ Responsive Pathway. Cells. 2020; 9(2):483. https://doi.org/10.3390/cells9020483

Chicago/Turabian Style

Haake, Kathrin, Anna-Lena Neehus, Theresa Buchegger, Mark P. Kühnel, Patrick Blank, Friederike Philipp, Carmen Oleaga-Quintas, Ansgar Schulz, Michael Grimley, Ralph Goethe, Danny Jonigk, Ulrich Kalinke, Stéphanie Boisson-Dupuis, Jean-Laurent Casanova, Jacinta Bustamante, and Nico Lachmann. 2020. "Patient iPSC-Derived Macrophages to Study Inborn Errors of the IFN-γ Responsive Pathway" Cells 9, no. 2: 483. https://doi.org/10.3390/cells9020483

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