Altered Oxygen Metabolism Associated to Neurogenesis of Induced Pluripotent Stem Cells Derived from a Schizophrenic Patient

Paulsen, Bruna; Maciel, Roseli Martins Tristão; Galina, Antônio; Silveira, Mariana S.; Souza, Cleide dos Santos; Drummond, Hannah; Pozzatto, Ernesto Nascimento; Silva, Hamilton; Chicaybam, Leonardo; Massuda, Raffael; Setti-Perdigão, Pedro; Bonamino, Martín; Belmonte-de-Abreu, Paulo; Castro, Newton G.; Brentani, Helena; Rehen, Stevens K.

doi:10.3727/096368911x600957

Cited by 135 publications

(55 citation statements)

References 53 publications

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“…To induce embryonic stem cells to direct neural differentiation, we performed an adaptation of Baharvand et al (2007) protocol (Paulsen et al, 2012). Briefly, 70% confluent BR1 culture was differentiated to the neural lineage in defined adherent culture by retinoic acid and basic fibroblast growth factor (bFGF) within 18 days of culture.…”

Section: Methodsmentioning

confidence: 99%

Harmine stimulates proliferation of human neural progenitors

Dakic

Maciel

Drummond

et al. 2016

PeerJ

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Harmine is the β-carboline alkaloid with the highest concentration in the psychotropic plant decoction Ayahuasca. In rodents, classical antidepressants reverse the symptoms of depression by stimulating neuronal proliferation. It has been shown that Ayahuasca presents antidepressant effects in patients with depressive disorder. In the present study, we investigated the effects of harmine in cell cultures containing human neural progenitor cells (hNPCs, 97% nestin-positive) derived from pluripotent stem cells. After 4 days of treatment, the pool of proliferating hNPCs increased by 71.5%. Harmine has been reported as a potent inhibitor of the dual specificity tyrosine-phosphorylation-regulated kinase (DYRK1A), which regulates cell proliferation and brain development. We tested the effect of analogs of harmine, an inhibitor of DYRK1A (INDY), and an irreversible selective inhibitor of monoamine oxidase (MAO) but not DYRK1A (pargyline). INDY but not pargyline induced proliferation of hNPCs similarly to harmine, suggesting that inhibition of DYRK1A is a possible mechanism to explain harmine effects upon the proliferation of hNPCs. Our findings show that harmine enhances proliferation of hNPCs and suggest that inhibition of DYRK1A may explain its effects upon proliferation in vitro and antidepressant effects in vivo.

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Section: Methodsmentioning

confidence: 99%

Harmine stimulates proliferation of human neural progenitors

Dakic

Maciel

Drummond

et al. 2016

PeerJ

Self Cite

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“…As far as we are aware, only a few studies utilized iPS cells in schizophrenia research. Nonetheless, two exploratory studies have already suggested involvement of oxidative stress: one case report indicated an increase in reactive oxygen species in SZ [26]. Another group showed that SZ-derived iPS cells had difficulty of differentiating to neurons and exhibited substantial mitochondrial deficits [16**].…”

Section: Biochemical Evidence In Human Biospecimensmentioning

confidence: 99%

Oxidative stress and schizophrenia

Emiliani

Sedlak

Sawa

2014

Current Opinion in Psychiatry

152

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Purpose of review Oxidative stress has become an exciting area of schizophrenia research, and provides ample opportunities and hope for a better understanding of its pathophysiology, which may lead to novel treatment strategies. This review describes how recent methodological advances have allowed the study of oxidative stress to tackle fundamental questions and have provided several conceptual breakthroughs to the field. Recent findings Recent human studies support the notion that intrinsic susceptibility to oxidative stress may underlie the pathophysiology of schizophrenia. More than one animal model that may be relevant to study biology of schizophrenia also shows sign of oxidative stress in the brain. Summary These advances have made this topic of paramount importance to the understanding of schizophrenia, and will play a role in advancing treatment options. This review covers topics from classic biochemical studies of human biospecimens to the use of magnetic resonance spectroscopy and novel mouse models, and focuses on highlighting promising areas of research.

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“…Accordingly, altered oxygen metabolism has been associated to the neurogenesis of iPSCs derived from a schizophrenic patient [111]. Although future studies are warranted to address the connection between neural differentiation and mitochondrial function in schizophrenia, the studies so far conducted highlight the potential that iPSC-based studies may bring to the dissection of the molecular mechanisms underlying complex psychiatric disorders.…”

Section: Mitochondrial Impairment In Ipsc Models Of Brain Disordersmentioning

confidence: 99%

Energy metabolism in neuronal/glial induction and in iPSC models of brain disorders

Mlody

Lorenz

Inak

et al. 2016

Seminars in Cell & Developmental Biology

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The metabolic switch associated with the reprogramming of somatic cells to pluripotency has received increasing attention in recent years. However, the impact of mitochondrial and metabolic modulation on stem cell differentiation into neuronal/glial cells and related brain disease modeling still remains to be fully addressed. Here, we seek to focus on this aspect by first addressing brain energy metabolism and its inter-cellular metabolic compartmentalization. We then review the findings related to the mitochondrial and metabolic reconfiguration occurring upon neuronal/glial specification from pluripotent stem cells (PSCs). Finally, we provide an update of the PSC-based models of mitochondria-related brain disorders and discuss the challenges and opportunities that may exist on the road to develop a new era of brain disease modeling and therapy.3 Mitochondrial remodeling in cell fate specificationThe majority of cellular energy in form of ATP is provided through oxidative phosphorylation (OXPHOS) by mitochondria. Mitochondria are also involved in the metabolism of amino acids, fatty acids, and steroids, and contribute to cell signaling through the modulation of reactive oxygen species (ROS), calcium homeostasis, and apoptosis [1].Furthermore, intermediate metabolites can cross-talk to the nucleus acting as epigenetic regulators [2].In low oxygen environments, a typical conversion process of 1 molecule of glucose results into 2 molecules of ATP through glycolysis in the cytosol, which terminates with the secretion of lactate into the extracellular environment. Under normoxic conditions, the 2 molecules of pyruvate, generated through glycolysis, can enter the mitochondria and undergo further oxidation in the tricarboxylic acid (TCA) cycle, leading to the production of additional 34 molecules of ATP [3]. However, under conditions requiring high proliferative rates, this mitochondrial-based energy generation may be shut-down despite the presence of normal oxygen concentration [4]. This situation, known as aerobic glycolysis or Warburg effect, was first described by Otto Warburg in the context of cancer [5]. Recent studies demonstrated that a Warburg-like effect may also represent a defining feature of stem cells [6][7][8].Since distinct cell types have different energy demands, regulation of mitochondria may represent an essential process allowing the cells to meet their biological requirements.The metabolic identity of cells may in fact be influenced not only by changes in the expression of metabolic genes, but also by modulation of mitochondrial dynamics and mitochondrial DNA (mtDNA) copy number [9,10]. In particular, energy metabolism is shifted towards glycolysis in stem cells, whose mitochondria appear round-shaped with poorlydeveloped cristae [11,12]. This is in sharp contrast to cells with high energy demands, like muscle cells and neurons, where mitochondria are abundant in number and exhibit tubularlike morphology and cristae-rich structures [13]. 4As a consequence, acquisition of a distinct metabot...

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Altered Oxygen Metabolism Associated to Neurogenesis of Induced Pluripotent Stem Cells Derived from a Schizophrenic Patient

Cited by 135 publications

References 53 publications

Harmine stimulates proliferation of human neural progenitors

Harmine stimulates proliferation of human neural progenitors

Oxidative stress and schizophrenia

Energy metabolism in neuronal/glial induction and in iPSC models of brain disorders

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