NF1 loss induces senescence during human melanocyte differentiation in an <scp>iPSC</scp>‐based model

Larribère, Lionel; Wu, Huizi; Novak, Daniel; Galach, Marta; Bernhardt, Mathias; Orouji, Elias; Weina, Kasia; Knappe, Nathalie; Sachpekidis, Christos; Umansky, Ludmila; Beckhove, Philipp; Umansky, Viktor; Schepper, Sofie De; Kaufmann, Dieter; Ballotti, Robert; Bertolotto, Corine; Utikal, Jochen

doi:10.1111/pcmr.12369

Cited by 53 publications

(51 citation statements)

References 44 publications

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“…The human iPS cells (hiPSCs) were generated from primary human fibroblasts derived from skin biopsies of a female healthy donor using lentiviral particles carrying the transactivator tTA and an inducible polycistronic cassette containing the reprogramming factors OCT4, SOX2, KLF4 and c-MYC as previously described 42, 43 . Generated hiPSCs were cultured under feeder free conditions.…”

Section: Methodsmentioning

confidence: 99%

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Lipopolysaccharides induced inflammatory responses and electrophysiological dysfunctions in human-induced pluripotent stem cell derived cardiomyocytes

Yücel

Zhao

El‐Battrawy

et al. 2017

Sci Rep

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126

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Severe infections like sepsis lead frequently to cardiomyopathy. The mechanisms are unclear and an optimal therapy for septic cardiomyopathy still lacks. The aim of this study is to establish an endotoxin-induced inflammatory model using human induced pluripotent stem cell (hiPSC) derived cardiomyocytes (hiPSC-CMs) for mechanistic and therapeutic studies. hiPSC-CMs were treated by lipopolysaccharide (LPS) in different concentrations for different times. ELISA, FACS, qPCR, and patch-clamp techniques were used for the study. TLR4 (Toll-like receptor 4) and its associated proteins, CD14, LBP (lipopolysaccharide binding protein), TIRAP (toll-interleukin 1 receptor domain containing adaptor protein), Ly96 (lymphocyte antigen 96) and nuclear factor kappa B as well as some pro-and anti-inflammatory factors are expressed in hiPSC-CMs. LPS-treatment for 6 hours increased the expression levels of pro-inflammatory and chemotactic cytokines (TNF-a, IL-1ß, IL-6, CCL2, CCL5, IL-8), whereas 48 hour-treatment elevated the expression of anti-inflammatory factors (IL-10 and IL-6). LPS led to cell injury resulting from exaggerated cell apoptosis and necrosis. Finally, LPS inhibited small conductance Ca2+-activated K+ channel currents, enhanced Na+/Ca2+-exchanger currents, prolonged action potential duration, suggesting cellular electrical dysfunctions. Our data demonstrate that hiPSC-CMs possess the functional reaction system involved in endotoxin-induced inflammation and can model some bacterium-induced inflammatory responses in cardiac myocytes.

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Section: Methodsmentioning

confidence: 99%

“…Generated hiPSCs were cultured under feeder free conditions. To investigate pluripotency, hiPSCs were subjected to a teratoma-formation assay 42 .…”

Section: Methodsmentioning

confidence: 99%

Lipopolysaccharides induced inflammatory responses and electrophysiological dysfunctions in human-induced pluripotent stem cell derived cardiomyocytes

Yücel

Zhao

El‐Battrawy

et al. 2017

Sci Rep

Self Cite

126

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“…Therefore, recent protocols for human embryonic stem cell (hESC)- and induced pluripotent stem cell (iPSC)-based derivation of melanocytes have been established 68–70 . Larribere and co-workers 69 reprogammed patient-derived NF1 +/ − fibroblasts into NF1 +/− iPSCs. The NF1 +/ − iPSCs showed an active RAS signaling and differential expression of genes associated with the RAS/MAPK signaling pathway compared with WT iPSCs.…”

Section: Nf1 In the Melanocyte Lineagementioning

confidence: 99%

The NF1 gene in tumor syndromes and melanoma

Kiuru

Busam

2017

Laboratory Investigation

162

133

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Activation of the RAS/MAPK pathway is critical in melanoma. Melanoma can be grouped into four molecular subtypes based on their main genetic driver: BRAF-mutant, NRAS-mutant, NF1-mutant, and triple wild-type tumors. The NF1 protein, neurofibromin 1, negatively regulates RAS proteins through GTPase activity. Germline mutations in NF1 cause neurofibromatosis type I, a common genetic tumor syndrome caused by dysregulation of the RAS/MAPK pathway, i.e. RASopathy. Melanomas with NF1 mutations typically occur on chronically sun-exposed skin or in older individuals, show a high mutation burden, and are wild-type for BRAF and NRAS. Additionally, NF1 mutations characterize certain clinicopathologic melanoma subtypes, specifically desmoplastic melanoma. This review discusses the current knowledge of the NF1 gene and neurofibromin 1 in neurofibromatosis type I and in melanoma.

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“…The human iPS cells (hiPSCs) were generated from primary human fibroblasts derived from skin biopsies of a healthy donor using lentiviral particles carrying the transactivator rtTA and an inducible polycistronic cassette containing the reprogramming factors OCT4, SOX2, KLF4 and c-MYC as previously described [24, 25]. Generated hiPSCs were cultured under feeder free conditions.…”

Section: Methodsmentioning

confidence: 99%

“…Generated hiPSCs were cultured under feeder free conditions. To investigate pluripotency, hiPSCs were subjected to a teratoma-formation assay [24]. …”

Section: Methodsmentioning

confidence: 99%

Hyperthermia Influences the Effects of Sodium Channel Blocking Drugs in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes

et al. 2016

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IntroductionFever can increase the susceptibility to supraventricular and ventricular arrhythmias, in which sodium channel dysfunction has been implicated. Whether fever influences the efficacy of sodium channel blocking drugs is unknown. The current study was designed to investigate the temperature dependent effects of distinct sodium channel blocking drugs on the sodium currents in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).Methods and ResultshiPSC-CMs were generated from human skin fibroblasts of a healthy donor. The peak and late sodium currents (INa), steady-state activation, inactivation and recovery from inactivation of INa in hiPSC-CMs were analyzed using the whole-cell patch clamp technique. The effects of different concentrations of the antiarrhythmic drugs flecainide, lidocaine, ajmaline and the antianginal drug ranolazine on INa were tested at 36°C and 40°C. Increasing the temperature of the bath solution from 36°C to 40°C enhanced the inhibition of peak INa but reduced the inhibition of late INa by flecainide and lidocaine. By contrast, increasing the temperature reduced the effect of ajmaline and ranolazine on the peak INa but not late INa. None of the tested drugs showed temperature-dependent effects on the steady-state activation and inactivation as well as on the recovery from inactivation of INa in hiPSC-CMs.ConclusionsTemperature variation from the physiological to the febrile range apparently influences the effects of sodium channel blockers on the sodium currents. This may influence their antiarrhythmic efficacy in patients suffering from fever.

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NF1 loss induces senescence during human melanocyte differentiation in an iPSC‐based model

Cited by 53 publications

References 44 publications

Lipopolysaccharides induced inflammatory responses and electrophysiological dysfunctions in human-induced pluripotent stem cell derived cardiomyocytes

Lipopolysaccharides induced inflammatory responses and electrophysiological dysfunctions in human-induced pluripotent stem cell derived cardiomyocytes

The NF1 gene in tumor syndromes and melanoma

Hyperthermia Influences the Effects of Sodium Channel Blocking Drugs in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes

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