Signaling Via PI3K/FOXO1A Pathway Modulates Formation and Survival of Human Embryonic Stem Cell-Derived Endothelial Cells

Merkely, Béla; Gara, Edit; Lendvai, Zsuzsanna; Skopál, Judit; Leja, Thomas; Zhou, Wenhua; Kosztin, Annamária; Várady, György; Mioulane, Maxime; Bagyura, Zsolt; Németh, Tamás; Harding, Siân E.; Földes, Gábor

doi:10.1089/scd.2014.0247

Cited by 18 publications

(12 citation statements)

References 36 publications

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“…Next, we further differentiated WT, patient-derived, and inversion-corrected iPSCs into mature endothelial cells (Merkely et al, 2015) and checked the expression of the F8 protein by immunocytochemistry. As expected, the endothelial cells differentiated from the WT and the three inversion-corrected Pa1-iPSC clones (termed Pa1 Co-1 to Pa1 Co-3) expressed the F8 protein ( Figures 3A and S3).…”

Section: Resultsmentioning

confidence: 99%

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Functional Correction of Large Factor VIII Gene Chromosomal Inversions in Hemophilia A Patient-Derived iPSCs Using CRISPR-Cas9

et al. 2015

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Hemophilia A is an X-linked genetic disorder caused by mutations in the F8 gene, which encodes the blood coagulation factor VIII. Almost half of all severe hemophilia A cases result from two gross (140-kbp or 600-kbp) chromosomal inversions that involve introns 1 and 22 of the F8 gene, respectively. We derived induced pluripotent stem cells (iPSCs) from patients with these inversion genotypes and used CRISPR-Cas9 nucleases to revert these chromosomal segments back to the WT situation. We isolated inversion-corrected iPSCs with frequencies of up to 6.7% without detectable off-target mutations based on whole-genome sequencing or targeted deep sequencing. Endothelial cells differentiated from corrected iPSCs expressed the F8 gene and functionally rescued factor VIII deficiency in an otherwise lethal mouse model of hemophilia. Our results therefore provide a proof of principle for functional correction of large chromosomal rearrangements in patient-derived iPSCs and suggest potential therapeutic applications.

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Section: Resultsmentioning

confidence: 99%

“…Differentiation into Endothelial Cells and In Vivo Study iPSCs were induced to differentiate into mature endothelial cells as described (Merkely et al, 2015). Hemophilia A mice (Jackson Laboratory, strain: B6; 129S4-F8 tm1Kaz /J) were used for the in vivo functional assay.…”

Section: Analysis Of Genome Modificationsmentioning

confidence: 99%

Functional Correction of Large Factor VIII Gene Chromosomal Inversions in Hemophilia A Patient-Derived iPSCs Using CRISPR-Cas9

et al. 2015

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“…FoxO6 may oversee memory consolidation and emotion [ 35 ], since it is present in several regions of the brain, such as the hippocampus, the amygdala, and the nucleus accumbens [ 36 , 37 ]. FoxO1 may have a vital role in a number of functions given its broad expression that may relate to astrocyte survival [ 38 ], modulation of embryonic endothelial stem cell survival [ 39 ], regulation of ischemic brain injury [ 10 ], vascular disease [ 40 ], and motor and memory pathways in the striatum and subregions of the hippocampus [ 36 ]. FoxO3 may have a more critical role in auditory synaptic transmission [ 41 ], cerebral endothelial vascular cell survival [ 42 , 43 ], oxidative stress injury in mouse cerebellar granule neurons [ 44 ], neonatal hypoxic-ischemic encephalopathy [ 45 ], erythroid cell growth [ 46 ], and hippocampal neuronal injury [ 47 , 48 ].…”

Section: Targeting Forkhead Transcription Factorsmentioning

confidence: 99%

FoxO Proteins in the Nervous System

Maiese¹

2015

Analytical Cellular Pathology

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Acute as well as chronic disorders of the nervous system lead to significant morbidity and mortality for millions of individuals globally. Given the ability to govern stem cell proliferation and differentiated cell survival, mammalian forkhead transcription factors of the forkhead box class O (FoxO) are increasingly being identified as potential targets for disorders of the nervous system, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and auditory neuronal disease. FoxO proteins are present throughout the body, but they are selectively expressed in the nervous system and have diverse biological functions. The forkhead O class transcription factors interface with an array of signal transduction pathways that include protein kinase B (Akt), serum- and glucocorticoid-inducible protein kinase (SgK), IκB kinase (IKK), silent mating type information regulation 2 homolog 1 (S. cerevisiae) (SIRT1), growth factors, and Wnt signaling that can determine the activity and integrity of FoxO proteins. Ultimately, there exists a complex interplay between FoxO proteins and their signal transduction pathways that can significantly impact programmed cell death pathways of apoptosis and autophagy as well as the development of clinical strategies for the treatment of neurodegenerative disorders.

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“…FoxO3 may be involved in a number of pathways that involve in auditory synaptic transmission (39), cerebral endothelial vascular cell survival (40, 41), oxidative stress injury in mouse cerebellar granule neurons (42), erythroid cell growth (43), hippocampal neuronal injury (44, 45), and neonatal hypoxic-ischemic encephalopathy (46). In relation to FoxO1, this transcription factor may impact astrocyte survival (47), embryonic endothelial stem cell survival (48), ischemic brain injury (49), vascular disease (50), and memory pathways in the striatum and sub-regions of the hippocampus (35). …”

Section: Foxo Transcription Factors In the Nervous Systemmentioning

confidence: 99%