Johannes Meisig's research while affiliated with Humboldt-Universität zu Berlin and other places

Publications (28)

Article
Despite the progress made in developmental toxicology, there is a great need for in vitro tests that identify developmental toxicants in relation to human oral doses and blood concentrations. In the present study, we established the hiPSC-based UKK2 in vitro test and analyzed genome-wide expression profiles of 23 known teratogens and 16 non-teratog...
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Thousands of transcriptome data sets are available, but approaches for their use in dynamic cell response modelling are few, especially for processes affected simultaneously by two orthogonal influencing variables. We approached this problem for neuroepithelial development of human pluripotent stem cells (differentiation variable), in the presence...
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The first in vitro tests for developmental toxicity made use of rodent cells. Newer teratology tests, e.g. developed during the ESNATS project, use human cells and measure mechanistic endpoints (such as transcriptome changes). However, the toxicological implications of mechanistic parameters are hard to judge, without functional/morphological endpo...
Article
A large body of data have accumulated that characterize the gene regulatory network of stem cells. Yet, a comprehensive and integrative understanding of this complex network is lacking. Network reverse engineering methods that use transcriptome data to derive these networks may help to uncover the topology in an unbiased way. Many methods exist tha...
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The RAF-MEK-ERK signalling pathway controls fundamental, often opposing cellular processes such as proliferation and apoptosis. Signal duration has been identified to play a decisive role in these cell fate decisions. However, it remains unclear how the different early and late responding gene expression modules can discriminate short and long sign...
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The RAF‐MEK‐ERK signalling pathway controls fundamental, often opposing cellular processes such as proliferation and apoptosis. Signal duration has been identified to play a decisive role in these cell fate decisions. However, it remains unclear how the different early and late responding gene expression modules can discriminate short and long sign...
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Stem cell-based in vitro test systems can recapitulate specific phases of human development. In the UKK test system, human pluripotent stem cells (hPSCs) randomly differentiate into cells of the three germ layers and their derivatives. In the UKN1 test system, hPSCs differentiate into early neural precursor cells. During the normal differentiation...
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Stem cell-based in vitro test systems can recapitulate specific phases of human development. In the UKK test system, human pluripotent stem cells (hPSCs) randomly differentiate into cells of the three germ layers and their derivatives. In the UKN1 test system, hPSCs differentiate into early neural precursor cells. During the normal differentiation...
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Background Human embryonic stem cells (hESCs) partially recapitulate early embryonic three germ layer development, allowing testing of potential teratogenic hazards. Because use of hESCs is ethically debated, we investigated the potential for human induced pluripotent stem cells (hiPSCs) to replace hESCs in such tests. Methods Three cell lines, co...
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Significance: The generation of human cells from pluripotent stem cells has aroused great hopes in biomedical research and safety sciences. Neurotoxicity testing is a particularly important application for stem cell-derived somatic cells, as human neurons are hardly available otherwise. Also, peripheral neurotoxicity has become of major concern in...
Article
Background Human embryonic stem cells (hESCs) partially recapitulate early embryonic three germ layer development, allowing testing of potential teratogenic hazards. Because use of hESCs is ethically debated, we investigated the potential for human induced pluripotent stem cells (hiPSCs) to replace hESCs in such tests. Methods Three cell lines, co...
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Full-text available
Test systems to identify developmental toxicants are urgently needed. A combination of human stem cell technology and transcriptome analysis was to provide a proof of concept that toxicants with a related mode of action can be identified and grouped for read-across. We chose a test system of developmental toxicity, related to the generation of neur...
Article
Haploidentical stem cell transplantation (haploSCT) offers an alternative treatment option for advanced leukemia patients lacking a HLA-compatible donor. Transfer of NK cells represents a promising therapeutic option in combination with SCT, as NK cells can promote graft versus leukemia with low risk of graft versus host disease. In this study, we...
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Cellular signaling systems show astonishing precision in their response to external stimuli despite strong fluctuations in the molecular components that determine pathway activity. To control the effects of noise on signaling most efficiently, living cells employ compensatory mechanisms that reach from simple negative feedback loops to robustly des...
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During early development of female mouse embryos, both X chromosomes are transiently active. X gene dosage is then equalized between the sexes through the process of X chromosome inactivation (XCI). Whether the double dose of X-linked genes in females compared with males leads to sex-specific developmental differences has remained unclear. Using em...
Article
RORγt(+) innate lymphoid cells (ILCs) are crucial players of innate immune responses and represent a major source of interleukin-22 (IL-22), which has an important role in mucosal homeostasis. The signals required by RORγt(+) ILCs to express IL-22 and other cytokines have been elucidated only partially. Here we showed that RORγt(+) ILCs can directl...
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Full-text available
In eukaryotes transcriptional regulation often involves multiple long-range elements and is influenced by the genomic environment. A prime example of this concerns the mouse X-inactivation centre (Xic), which orchestrates the initiation of X-chromosome inactivation (XCI) by controlling the expression of the non-protein-coding Xist transcript. The e...

Citations

... Five expression datasets of VPA exposure in human embryonic stem cells (hESC) were selected ( SH Schulpen et al., 2015a ;Schulpen et al., 2015b ;Rempel et al., 2015 ;Pallocca et al., 2016 ;Meisig et al., 2020 ;de Leeuw et al., 2020 ). Further details of the studies are available in Supplemental Table 2. ...
... Well-established in vitro models for the detection of teratogenicity include the DevTox qp assay from Stemina and the mouse embryonic stem cell test (mEST). DevTox qp uses humaninduced pluripotent stem cells (hiPSCs) to predict teratogenicity based on the ratio of ornithine and cysteine in medium supernatants (Adler et al., 2008;Augustyniak et al., 2019;Burridge et al., 2011;Dreser et al., 2020;Palmer et al., 2013Palmer et al., , 2017Shinde et al., 2015;Worley et al., 2018). The mEST assay uses the beating of stem cell-derived cardiomyocytes as a functional readout for teratogenicity prediction (Genschow et al., 2000(Genschow et al., , 2004Scholz et al., 1999a,b;Whitlow et al., 2007). ...
... interaction discovery versus network property characterization versus perturbation response prediction) de la Fuente et al., 2004;Ghanbari et al., 2015;Kholodenko et al., 2002;Klamt et al., 2006;Natale et al., 2017). Not surprisingly, different methods produce radically different results on same datasets Meisig and Blü thgen, 2018). This makes for an intricate choice of method and guarantees a certain degree of arbitrariness in interpreting the inferred networks. ...
... The half-life of mRNA is important for the kinetics of gene expression, as mRNA expression is determined by the rates of both RNA synthesis and degradation. It has been reported that many transcription factors and regulatory proteins have short half-lives (Uhlitz et al., 2017;Yang et al., 2003). In a study that analyzed mRNA half-lives in human B-cells, the authors reported that genes involved in transcription factor activity, transcription, and transcription factor binding, are short-lived, with median half-lives ranging between 3.6 to 4.3 h, whereas genes involved in glucose and fatty acid metabolic process have longer median half-lives of 7.5 to 10.1 h (Friedel et al., 2009). ...
... To gain insights into the response of lung epithelial cells to P. aeruginosa at the early stage of infection, transcriptomic responses of human type II pneumocytes (A549 cells) were analyzed after 1 h infection with P. aeruginosa PA14. The length of incubation was selected to identify early changes in gene expression [16,17] without inducing cell death ( Figure S1). The gene expression analysis was performed and genes with a p-value ≤ 0.05, fold change > 2, and average FPKM difference > 7 were further analyzed. ...
... Thus, the BMCL provides a better estimation of non-cytotoxic concentrations than the BMC alone. Knowing this threshold is important for choosing test concentrations for functional assays or for gene expression studies (Krug et al., 2013;Rovida et al., 2014;Nyffeler et al., 2017a,b;Waldmann et al., 2014;Rempel et al., 2015;Shinde et al., 2017;House et al., 2017). As the BMC method uses the information of the whole dataset, including the data uncertainties (i.e., variability produced by experimental errors and fluctuations of experimental parameters), it is less influenced by concentration spacing than a NOAEL, and it provides an estimate of statistical uncertainty of a point of departure (PoD). ...
... Transcriptomics has proven to be a powerful tool for assessing disturbances of differentiation, also on a fully quantitative level (Shinde et al. 2016a;Waldmann et al. 2014Waldmann et al. , 2017. Extensive characterization has been performed on how to use transcriptomics data in toxicological hit definition (Dreser et al. 2015;Pallocca et al. 2016;Shinde et al. 2016b;Weng et al. 2012). However, chemicals may also trigger transcriptome changes that are not related to altered differentiation patterns Grinberg et al. 2014;Waldmann et al. 2017). ...
... This study characterizes the optimization of TeraTox and its application in the context of preclinical teratogenicity assessment of drugs. TeraTox extends and standardizes the previously published embryoid-body models and fully leverages the predictive potential of these models by adding a toxicological prediction model (Krug et al., 2013;Shinde et al., 2016). It exploits an explainable machine-learning approach to predict teratogenicity potential induced by drug-like molecules. ...
... The distinction shows that (1) teratogenicity of a compound is not a determinant for cytotoxicity, (2) a compound that shows cytotoxicity at a specific concentration can still be teratogenic at lower concentrations, and (3) genes and pathways associated with cytotoxicity and teratogenicity can be regulated independently from each other. This concurs with several previous findings (Krug et al., 2013;Rempel et al., 2015;Shinde et al., 2017). ...
... TeraTox informs predictions not only based on statistical data patterns but builds upon biological mechanisms and thus may reflect disturbed functionalities, similar to those leading to teratogenicity in vivo. These features put TeraTox conceptually in a group of other assays that use phenotypic changes or disturbed functionalities as readouts Hoelting et al., 2016;Meisig et al., 2020;Pallocca et al., 2016). The model consolidates our previous intention to "focus on germ layers" and corroborates recent work exploring gastruloid models that profiles morphological changes of germ-layers for teratogenicity prediction (Jaklin et al., 2020;Moris et al., 2020). ...