Decreased neural precursor cell pool in NADPH oxidase 2-deficiency: From mouse brain to neural differentiation of patient derived iPSC
Zeynab Nayernia,
Marilena Colaianna,
Natalia Robledinos-Antón,
Eveline Gutzwiller,
Frédérique Sloan-Béna,
Elisavet Stathaki,
Yousef Hibaoui,
Antonio Cuadrado,
Jürgen Hescheler,
Marie-José Stasia,
Tomo Saric,
Vincent Jaquet,
Karl-Heinz Krause
Affiliations
Zeynab Nayernia
Department of Pathology and Immunology, University of Geneva Medical School, 1-rue Michel Servet, 1211 Geneva, Switzerland
Marilena Colaianna
Department of Pathology and Immunology, University of Geneva Medical School, 1-rue Michel Servet, 1211 Geneva, Switzerland
Natalia Robledinos-Antón
Instituto de Investigaciones Biomédicas “Alberto Sols", Faculty of Medicine, Autonomous University of Madrid (UAM), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Eveline Gutzwiller
Department of Pathology and Immunology, University of Geneva Medical School, 1-rue Michel Servet, 1211 Geneva, Switzerland
Frédérique Sloan-Béna
Hôpitaux Universitaires de Genève HUG, Laboratoires de Cytogénétique Constitutionnelle, Service de Médecine Génétique, Geneva, Switzerland
Elisavet Stathaki
Hôpitaux Universitaires de Genève HUG, Laboratoires de Cytogénétique Constitutionnelle, Service de Médecine Génétique, Geneva, Switzerland
Yousef Hibaoui
Department of Genetic Medicine and Development, University of Geneva Medical School, 1 rue Michel Servet, 1211 Geneva, Switzerland
Antonio Cuadrado
Instituto de Investigaciones Biomédicas “Alberto Sols", Faculty of Medicine, Autonomous University of Madrid (UAM), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
Jürgen Hescheler
Center for Physiology and Pathophysiology, Institute for Neurophysiology, Medical Faculty, University of Cologne, Cologne 50931, Germany
Marie-José Stasia
Université Grenoble Alpes, Techniques de l'Ingénierie Médicale et de la Complexité- Grenoble, F38000 Grenoble, France
Tomo Saric
Center for Physiology and Pathophysiology, Institute for Neurophysiology, Medical Faculty, University of Cologne, Cologne 50931, Germany
Vincent Jaquet
Department of Pathology and Immunology, University of Geneva Medical School, 1-rue Michel Servet, 1211 Geneva, Switzerland
Karl-Heinz Krause
Department of Pathology and Immunology, University of Geneva Medical School, 1-rue Michel Servet, 1211 Geneva, Switzerland
There is emerging evidence for the involvement of reactive oxygen species (ROS) in the regulation of stem cells and cellular differentiation. Absence of the ROS-generating NADPH oxidase NOX2 in chronic granulomatous disease (CGD) patients, predominantly manifests as immune deficiency, but has also been associated with decreased cognition. Here, we investigate the role of NOX enzymes in neuronal homeostasis in adult mouse brain and in neural cells derived from human induced pluripotent stem cells (iPSC). High levels of NOX2 were found in mouse adult neurogenic regions. In NOX2-deficient mice, neurogenic regions showed diminished redox modifications, as well as decrease in neuroprecursor numbers and in expression of genes involved in neural differentiation including NES, BDNF and OTX2. iPSC from healthy subjects and patients with CGD were used to study the role of NOX2 in human in vitro neuronal development. Expression of NOX2 was low in undifferentiated iPSC, upregulated upon neural induction, and disappeared during neuronal differentiation. In human neurospheres, NOX2 protein and ROS generation were polarized within the inner cell layer of rosette structures. NOX2 deficiency in CGD-iPSCs resulted in an abnormal neural induction in vitro, as revealed by a reduced expression of neuroprogenitor markers (NES, BDNF, OTX2, NRSF/REST), and a decreased generation of mature neurons. Vector-mediated NOX2 expression in NOX2-deficient iPSCs rescued neurogenesis. Taken together, our study provides novel evidence for a regulatory role of NOX2 during early stages of neurogenesis in mouse and human.
