Zsuzsa Erdei

HUN-REN Research Centre for Natural Sciences

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ÀA

Àgota Apàti

HUN-REN Research Centre for Natural Sciences

Balázs Sarkadi

HUN-REN Research Centre for Natural Sciences

Tamás I. Orbán

Eötvös Loránd University

György Várady

HUN-REN Research Centre for Natural Sciences

Kornélia Szebényi

University of Cambridge

László Homolya

HUN-REN Research Centre for Natural Sciences

Nóra Varga

HUN-REN Research Centre for Natural Sciences

Adrienn Péntek

Hungarian Academy of Sciences

János Réthelyi

Semmelweis University

Eszter Szabó

Institute of Molecular Life Sciences

Cooperative Institutions

Semmelweis University

Hungarian Academy of Sciences

HUN-REN Research Centre for Natural Sciences

Institute of Molecular Life Sciences

Hungarian Research Network

Spanish National Cancer Research Centre

Centro de Investigación del Cáncer

Eötvös Loránd University

Nagoya University

Harvard University

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Tyrosine kinase inhibitors as modulators of ATP binding cassette multidrug transporters: substrates, chemosensitizers or inducers of acquired multidrug resistance?

Expert Opinion on Drug Metabolism & Toxicology (2011)

Anna Brózik Csilla Hegedüs Zsuzsa Erdei Tamás Hegedűs Csilla Özvegy‐Laczka

Anticancer tyrosine kinase inhibitors (TKIs) are small molecule hydrophobic compounds designed to arrest aberrant signaling pathways in malignant cells. Multidrug resistance (MDR) ATP binding cassette (ABC) transporters have recently been recognized as important determinants of the general ADME-Tox (absorption, distribution, metabolism, excretion, toxicity) properties of small molecule TKIs, as well as key factors of resistance against targeted anticancer therapeutics.The article summarizes MDR-related ABC transporter interactions with imatinib, nilotinib, dasatinib, gefitinib, erlotinib, lapatinib, sunitinib and sorafenib, including in vitro and in vivo observations. An array of methods developed to study such interactions is presented. Transporter-TKI interactions relevant to the ADME-Tox properties of TKI drugs, primary or acquired cancer TKI resistance, and drug-drug interactions are also reviewed.Based on the concept presented in this review, TKI anticancer drugs are considered as compounds recognized by the cellular mechanisms handling xenobiotics. Accordingly, novel anticancer therapies should equally focus on the effectiveness of target inhibition and exploration of potential interactions of the designed molecules by membrane transporters. Thus, targeted hydrophobic small molecule compounds should also be screened to evade xenobiotic-sensing cellular mechanisms.

Lapatinib

ADME

Abcg2

ABCC1

10.1517/17425255.2011.562892

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Citations (116)

The importance of drug transporters in human pluripotent stem cells and in early tissue differentiation

Expert Opinion on Drug Metabolism & Toxicology (2015)

Àgota Apàti Kornélia Szebényi Zsuzsa Erdei György Várady Tamás I. Orbán

Drug transporters are large transmembrane proteins which catalyse the movement of a wide variety of chemicals, including drugs as well as xeno- and endobiotics through cellular membranes. The major groups of these proteins include the ATP-binding cassette transporters which in eukaryotes work as ATP-fuelled drug 'exporters' and the Solute Carrier transporters, with various transport directions and mechanisms.In this review, we discuss the key ATP-binding cassette and Solute Carrier drug transporters which have been reported to contribute to the function and/or protection of undifferentiated human stem cells and during tissue differentiation. We review the various techniques for studying transporter expression and function in stem cells, and the role of drug transporters in foetal and placental tissues is also discussed. We especially focus on the regulation of transporter expression by factors modulating cell differentiation properties and on the function of the transporters in adjustment to environmental challenges.The relatively new and as yet unexplored territory of transporters in stem cell biology may rapidly expand and bring important new information regarding the metabolic and epigenetic regulation of 'stemness' and the early differentiation properties. Drug transporters are clearly important protective and regulatory components in stem cells and differentiation.

Solute carrier family

10.1517/17425255.2016.1121382

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Establishing a human embryonic stem cell clone with a heterozygous mutation in the DGCR8 gene

Stem Cell Research (2020)

Dóra Reé Adrienn Borsy Ábel Fóthi Tamás I. Orbán György Várady

DiGeorge Syndrome (DGS) Critical Region 8 (DGCR8) is a primary candidate gene in they DGS. The DGCR8 microprocessor complex subunit is an essential cofactor in the canonical miRNA biogenesis which is involved in diverse cellular functions such as cell fate decisions, apoptosis and different signaling pathways. However, the role of DGCR8 in these processes or development of DGS is not fully understood. Here we present a heterozygous DGCR8 mutant human embryonic stem cell line (HuES9DGCR8+/−) created by the CRISPR/Cas9 system. The generated HuES9DGCR8+/− cells maintain normal karyotype, morphology, pluripotency and differentiation capacity into all three germ layers.

clone (Java method)

Germ layer

10.1016/j.scr.2020.102134

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Citations (2)

Tissue-specific and transcription-dependent mechanisms regulate primary microRNA processing efficiency of the human Chromosome 19 MicroRNA Cluster

Figshare (2020)

Ábel Fóthi Orsolya Bíró Zsuzsa Erdei Àgota Apàti Tamás I. Orbán

One of the longest human microRNA (miRNA) clusters is located on chromosome 19 (C19MC), containing 46 miRNA genes, which were considered to be expressed simultaneously and at similar levels from a common long noncoding transcript. Investigating the two tissue types where C19MC is exclusively expressed, we could show that there is a tissue-specific and chromosomal position-dependent decrease in mature miRNA levels towards the 3ʹ end of the cluster in embryonic stem cells but not in placenta. Although C19MC transcription level is significantly lower in stem cells, this gradual decrease is not present at the primary miRNA levels, indicating that difference in posttranscriptional processing could explain this observation. By depleting Drosha, the nuclease component of the Microprocessor complex, we could further enhance the positional decrease in stem cells, demonstrating that a tissue-specific, local availability of the Microprocessor complex could lie behind the phenomenon. Moreover, we could describe a tissue-specific promoter being exclusively active in placenta, and the epigenetic mark analysis suggested the presence of several putative enhancer sequences in this region. Performing specific chromatin immunoprecipitation followed by quantitative real-time PCR experiments we could show a strong association of Drosha with selected enhancer regions in placenta, but not in embryonic stem cells. These enhancers could provide explanation for a more efficient co-transcriptional recruitment of the Microprocessor, and therefore a more efficient processing of pri-miRNAs throughout the cluster in placenta. Our results point towards a new model where tissue-specific, posttranscriptional “fine-tuning” can differentiate among miRNAs that are expressed simultaneously from a common precursor.

Transcription

10.6084/m9.figshare.13092846.v1

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Excision Efficiency Is Not Strongly Coupled to Transgenic Rate: Cell Type-Dependent Transposition Efficiency ofSleeping BeautyandpiggyBacDNA Transposons

Human Gene Therapy Methods (2014)

Orsolya Kolacsek Zsuzsa Erdei Àgota Apàti Sára Sándor Zsuzsanna Izsvák

The Sleeping Beauty (SB) and piggyBac (PB) DNA transposons represent an emerging new gene delivery technology, potentially suitable for human gene therapy applications. Previous studies pointed to important differences between these transposon systems, depending on the cell types examined and the methodologies applied. However, efficiencies cannot always be compared because of differences in applications. In addition, "overproduction inhibition," a phenomenon believed to be a characteristic of DNA transposons, can remarkably reduce the overall transgenic rate, emphasizing the importance of transposase dose applied. Therefore, because of lack of comprehensive analysis, researchers are forced to optimize the technology for their own "in-house" platforms. In this study, we investigated the transposition of several SB (SB11, SB32, SB100X) and PB (mPB and hyPB) variants in various cell types at three levels: comparing the excision efficiency of the reaction by real-time PCR, testing the overall transgenic rate by detecting cells with stable integrations, and determining the average copy number when using different transposon systems and conditions. We concluded that high excision activity is not always followed by a higher transgenic rate, as exemplified by the hyperactive transposases, indicating that the excision and the integration steps of transposition are not strongly coupled as previously thought. In general, all levels of transposition show remarkable differences depending on the transposase used and cell lines examined, being the least efficient in human embryonic stem cells (hESCs). In spite of the comparably low activity in those special cell types, the hyperactive SB100X and hyPB systems could be used in hESCs with similar transgenic efficiency and with reasonably low (2-3) transgene copy numbers, indicating their potential applicability for gene therapy purposes in the future.

Transposase

Transposition (logic)

P element

10.1089/hgtb.2013.149

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Citations (20)

Cdc42 Regulates Myocardin-Related Transcription Factor Nuclear Shuttling and α-Smooth Muscle Actin Promoter Activity during Renal Tubular Epithelial–Mesenchymal Transition

Nephron Experimental Nephrology (2009)

Attila Sebe Zsuzsa Erdei Karolina Varga Csaba Bödör István Mucsi

Background/Aims: Epithelial–mesenchymal transition of tubular cells into α-smooth muscle actin (SMA)-expressing myofibroblasts is a central mechanism in tubulointerstitial fibrosis. Previously, a ‘two-hit’ model was proposed for epithelial–mesenchymal transition wherein an initial injury of the intercellular contacts and TGF-β1 are both required for SMA protein expression in LLC-PK1 cells. The Rho-Rho kinase-myosin light chain-myocardin-related transcription factor (MRTF)-serum response factor (SRF) pathway and Rac1, p21-activated kinase (PAK) and p38 were described as important regulators of MRTF localization and SMA expression. Cdc42 is another small G protein situated upstream of PAK and p38, and is activated upon cell contact disassembly. Here, we investigated its potential role in the regulation of MRTF nuclear shuttling and in the regulation of the SMA promoter. Results: Transfection of a constitutive active (CA) Cdc42 construct alone induced the activation of the SMA promoter. The dominant negative (DN) Cdc42 construct prevented the activation of the promoter induced by cell contact disassembly, and reduced the combined effect of cell contact disruption and TGF-β1. SRF showed a marked nuclear accumulation in CA Cdc42-transfected cells. Cdc42 induced the nuclear translocation of MRTF, while DN Cdc42 inhibited its nuclear translocation induced by cell contact disassembly. Blocking PAK, MRTF and p38 by the corresponding DN constructs blunted the effects of CA Cdc42 on the SMA promoter. Conclusion: Cdc42 is involved in the regulation of SMA promoter activation through PAK, p38, MRTF and SRF. Cdc42 may be an important regulator of MRTF cellular localization.

Myocardin

CDC42

10.1159/000265550

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Citations (10)

Generation of multiple iPSC clones from a male schizophrenia patient carrying de novo mutations in genes KHSRP, LRRC7, and KIR2DL1, and his parents

Stem Cell Research (2020)

Edit Hathy Eszter Szabó Katalin Vincze Irén Haltrich Eszter Kiss

Here we describe the generation of induced pluripotent stem cell lines from each member - male proband, mother, father - of a schizophrenia case-parent trio that participated in an exome sequencing study, and 3 de novo mutations were identified in the proband. Peripheral blood mononuclear cells were obtained from all three individuals and reprogrammed using Sendai virus particles carrying the Yamanaka transgenes. These 3 iPSC lines (iPSC-SZ-HU-MO 1, iPSC-SZ-HU-FA 1, and iPSC-SZ-HU-PROB 1) represent a resource for examining the functional significance of the identified de novo mutations in the molecular pathophysiology of schizophrenia.

Proband

Sendai virus

10.1016/j.scr.2020.102140

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Citations (10)

Applying a “Double-Feature” Promoter to Identify Cardiomyocytes Differentiated from Human Embryonic Stem Cells Following Transposon-Based Gene Delivery

Stem Cells (2009)

Tamás I. Orbán Àgota Apàti Andrea H. Németh Nóra Varga Virág Krízsik

Abstract Human embryonic stem (HuES) cells represent a new potential tool for cell-therapy and gene-therapy applications. However, these approaches require the development of efficient, stable gene delivery, and proper progenitor cell and tissue separation methods. In HuES cell lines, we have generated stable, enhanced green fluorescent protein (EGFP)-expressing clones using a transposon-based (Sleeping Beauty) system. This method yielded high percentage of transgene integration and expression. Similarly to a lentiviral expression system, both the undifferentiated state and the differentiation pattern of the HuES cells were preserved. By using the CAG promoter, in contrast to several other constitutive promoter sequences (such as CMV, elongation factor 1α, or phosphoglycerate kinase), an exceptionally high EGFP expression was observed in differentiated cardiomyocytes. This phenomenon was independent of the transgene sequence, methods of gene delivery, copy number, and the integration sites. This “double-feature” promoter behavior, that is providing a selectable marker for transgene expressing undifferentiated stem cells, and also specifically labeling differentiated cardiomyocytes, was assessed by transcriptional profiling. We found a positive correlation between CAG promoter-driven EGFP transcription and expression of cardiomyocyte-specific genes. Our experiments indicate an efficient applicability of transposon-based gene delivery into HuES cells and provide a novel approach to identify differentiated tissues by exploiting a nontypical behavior of a constitutively active promoter, thereby avoiding invasive drug selection methods. Disclosure of potential conflicts of interest is found at the end of this article.

Marker gene

Stem cell marker

10.1002/stem.45

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Citations (59)

Human pluripotent stem cells in pharmacological and toxicological screening: new perspectives for personalized medicine

Personalized Medicine (2011)

Kornélia Szebényi Zsuzsa Erdei Adrienn Péntek Attila Sebe Tamás I. Orbán

Human stem cells provide an important novel tool for generating in vitro pharmacological and toxicological test systems. In the development of new targeted therapies, as well as in critical safety issues, including hepato-, neuro- and cardio-toxicity, animal-based tests are mostly unsatisfactory, whereas the use of in vitro model systems is limited by the unavailability of relevant human tissues. Human embryonic stem cell lines may fill this gap and offer an advantage over primary cultures as well as tissue-derived (adult) stem cells. Human embryonic stem cells represent an unlimited source for the production of differentiated somatic progenies and allow various stable genetic manipulations. As a new opening in personalized medicine test systems, the generation of induced pluripotent stem cell lines and their derivatives can provide patient- and disease-specific cellular assays for drug development and safety assessments. This article reviews promising human stem cell applications in pharmacological and toxicological screenings, focusing on the implications for personalized medicine.

Regenerative Medicine

Personalized Medicine

10.2217/pme.11.19

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Citations (7)

Efficient generation of human embryonic stem cell-derived cardiac progenitors based on tissue-specific EGFP expression

Kornélia Szebényi Adrienn Péntek Zsuzsa Erdei György Várady Tamás I. Orbán

Cardiac progenitor cells (CPCs) are committed to the cardiac lineage but retain their proliferative capacity before becoming quiescent mature cardiomyocytes. In medical therapy and research the use of human pluripotent stem cell-derived CPCs would have several advantages over mature cardiomyocytes, as the progenitors show better engraftment into existing heart tissues, and provide unique potential for cardiovascular developmental, as well as for pharmacological studies. Here we demonstrate that the CAG promoter-driven EGFP reporter system allows the identification and isolation of embryonic stem cell-derived CPCs. Tracing of CPCs during differentiation confirmed upregulation of surface markers, previously described to identify cardiac precursors and early cardiomyocytes. Isolated CPCs express cardiac lineage specific transcripts, still have proliferating capacity and can be re-aggregated into embryoid body-like structures (CAG-EGFPhigh rEBs). Expression of TROPONIN T and NKX2.5 mRNA are upregulated in long-term cultured CAG-EGFPhigh rEBs, in which more than 90% of the cells become Troponin I positive mature cardiomyocytes. Moreover, about one third of the CAG-EGFPhigh rEBs show spontaneous contractions. The method described here provides a powerful tool to generate expandable cultures of pure human CPCs which can be used to elucidate toxicological mechanisms during cardiac development, as well as to explore early markers of the cardiac lineage.

Embryoid body

Lineage markers

P19 cell

Heart development

Cardiac marker

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Citations (1)