NOX4 is the main NADPH oxidase involved in the early stages of hematopoietic differentiation from human induced pluripotent stem cells

Brault, Julie; Vigne, Bénédicte; Meunier, Mathieu; Beaumel, Sylvain; Mollin, Michelle; Park, Sophie; Stasia, Marie José

doi:10.1016/j.freeradbiomed.2019.10.005

Cited by 16 publications

(20 citation statements)

References 97 publications

(106 reference statements)

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“…In various organs including the central nervous system, the mitochondrial NADPH oxidase (Nox4) is a major source of ROS production 38 – 40 . Moreover, fine-tune regulation of the levels of Nox4-induced ROS is prime for efficient differentiation 41 – 43 . Thus, searching for a mechanism by which Parp3 regulates the redox balance, we analyzed the effect of Parp3 loss on the expression levels of Nox4 and Duox1 as control (Fig.…”

Section: Resultsmentioning

confidence: 99%

Parp3 promotes astrocytic differentiation through a tight regulation of Nox4-induced ROS and mTorc2 activation

et al. 2020

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Parp3 is a member of the Poly(ADP-ribose) polymerase (Parp) family that has been characterized for its functions in strand break repair, chromosomal rearrangements, mitotic segregation and tumor aggressiveness. Yet its physiological implications remain unknown. Here we report a central function of Parp3 in the regulation of redox homeostasis in continuous neurogenesis in mice. We show that the absence of Parp3 provokes Nox4-induced oxidative stress and defective mTorc2 activation leading to inefficient differentiation of post-natal neural stem/progenitor cells to astrocytes. The accumulation of ROS contributes to the decreased activity of mTorc2 as a result of an oxidation-induced and Fbxw7-mediated ubiquitination and degradation of Rictor. In vivo, mTorc2 signaling is compromised in the striatum of naïve post-natal Parp3-deficient mice and 6 h after acute hypoxia-ischemia. These findings reveal a physiological function of Parp3 in the tight regulation of striatal oxidative stress and mTorc2 during astrocytic differentiation and in the acute phase of hypoxia-ischemia.

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Section: Resultsmentioning

confidence: 99%

Parp3 promotes astrocytic differentiation through a tight regulation of Nox4-induced ROS and mTorc2 activation

et al. 2020

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“…In the early stage of hematopoietic differentiation, mitochondria and NADPH oxidases (NOX) are the main sources of ROS [90,91]. NOX4 as the major NOX enzyme have been shown to play a significant role in the early stages of hematopoietic differentiation from iPSCs [85]. UM171 is a potent small molecule (HSC self-renewal agonist) that increases the derivation of HSPCs from human iPSCs in vitro [84,92].…”

Section: In Vitro Culture Of Human Ipsc-derived Rbcsmentioning

confidence: 99%

Differentiation of human induced pluripotent stem cells into erythroid cells

et al. 2020

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During the last years, several strategies have been made to obtain mature erythrocytes or red blood cells (RBC) from the bone marrow or umbilical cord blood (UCB). However, UCB-derived hematopoietic stem cells (HSC) are a limited source and in vitro large-scale expansion of RBC from HSC remains problematic. One promising alternative can be human pluripotent stem cells (PSCs) that provide an unlimited source of cells. Human PSCs, including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), are self-renewing progenitors that can be differentiated to lineages of ectoderm, mesoderm, and endoderm. Several previous studies have revealed that human ESCs can differentiate into functional oxygen-carrying erythrocytes; however, the ex vivo expansion of human ESC-derived RBC is subjected to ethical concerns. Human iPSCs can be a suitable therapeutic choice for the in vitro/ex vivo manufacture of RBCs. Reprogramming of human somatic cells through the ectopic expression of the transcription factors (OCT4, SOX2, KLF4, c-MYC, LIN28, and NANOG) has provided a new avenue for disease modeling and regenerative medicine. Various techniques have been developed to generate enucleated RBCs from human iPSCs. The in vitro production of human iPSC-derived RBCs can be an alternative treatment option for patients with blood disorders. In this review, we focused on the generation of human iPSC-derived erythrocytes to present an overview of the current status and applications of this field.

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“…Even in this case, NOX4 is the major NOX enzyme involved in the early stages of hematopoietic differentiation from iPSCs and its activity can be involved in the production, the hematopoietic potential, and the phenotype of iPSC-derived CD34 + [ 120 ]. The presence of NOX in hematopoietic stem cells can have a functional role as O 2 sensors and/or as low-level ROS producers to be used as redox messengers for controlling cell growth and differentiation [ 121 ].…”

Section: Stem Cells and Progenitor Cells: Ros And Nox Functionsmentioning

confidence: 99%

“…These findings suggest a positive feedback mechanism of NOX activation and a potential fine tuning of the ROS level and consequently of redox-mediated signaling involved in HSC growth and differentiation [ 125 ]. Moreover, Brault and Colleagues recently reported that NOX4 is the major NOX enzyme involved in the early stages of hematopoietic differentiation from iPSCs and its activity can modulate the production, the hematopoietic potential, and the phenotype of iPSC-derived CD34 + [ 120 ].…”

Section: Noxs In Hematopoietic Stem Cells: Regulators or Effectors?mentioning

confidence: 99%

NADPH Oxidases: Redox Regulators of Stem Cell Fate and Function

et al. 2021

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One of the major sources of reactive oxygen species (ROS) generated within stem cells is the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes (NOXs), which are critical determinants of the redox state beside antioxidant defense mechanisms. This balance is involved in another one that regulates stem cell fate: indeed, self-renewal, proliferation, and differentiation are decisive steps for stem cells during embryo development, adult tissue renovation, and cell therapy application. Ex vivo culture-expanded stem cells are being investigated for tissue repair and immune modulation, but events such as aging, senescence, and oxidative stress reduce their ex vivo proliferation, which is crucial for their clinical applications. Here, we review the role of NOX-derived ROS in stem cell biology and functions, focusing on positive and negative effects triggered by the activity of different NOX isoforms. We report recent findings on downstream molecular targets of NOX-ROS signaling that can modulate stem cell homeostasis and lineage commitment and discuss the implications in ex vivo expansion and in vivo engraftment, function, and longevity. This review highlights the role of NOX as a pivotal regulator of several stem cell populations, and we conclude that these aspects have important implications in the clinical utility of stem cells, but further studies on the effects of pharmacological modulation of NOX in human stem cells are imperative.

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NOX4 is the main NADPH oxidase involved in the early stages of hematopoietic differentiation from human induced pluripotent stem cells

Cited by 16 publications

References 97 publications

Parp3 promotes astrocytic differentiation through a tight regulation of Nox4-induced ROS and mTorc2 activation

Parp3 promotes astrocytic differentiation through a tight regulation of Nox4-induced ROS and mTorc2 activation

Differentiation of human induced pluripotent stem cells into erythroid cells

NADPH Oxidases: Redox Regulators of Stem Cell Fate and Function

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