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Publications (5 of 5) Show all publications
Synnergren, J., Ghosheh, N. & Dönnes, P. (2018). Integration of Biomedical Big Data Requires Efficient Batch Effect Reduction. In: Hisham Al-Mubaid, Qin Ding, Oliver Eulenstein (Ed.), 10th International Conference on Bioinformatics and Computational Biology (BICOB): Las Vegas, Nevada, USA 19 – 21 March 2018. Paper presented at 10th International Conference on Bioinformatics and Computational Biology (BICOB) March 19 - 21, 2018, Las Vegas, NV, USA (pp. 76-82).
Open this publication in new window or tab >>Integration of Biomedical Big Data Requires Efficient Batch Effect Reduction
2018 (English)In: 10th International Conference on Bioinformatics and Computational Biology (BICOB): Las Vegas, Nevada, USA 19 – 21 March 2018 / [ed] Hisham Al-Mubaid, Qin Ding, Oliver Eulenstein, 2018, p. 76-82Conference paper, Published paper (Refereed)
Abstract [en]

 Efficiency in dealing with batch effects will be the next frontier in large-scale biological data analysis, particularly when involving the integration of different types of datasets. Large-scale omics techniques have quickly developed during the last decade and huge amounts of data are now generated, which has started to revolutionize the area of medical research. With the increase in the volume of data across the whole spectrum of biology, problems related to data analytics are continuously increasing as analysis and interpretation of these large volumes of molecular data has become a real challenge. Tremendous efforts have been made to obtain data from various molecular levels and the most recent trends show that more and more researchers now are trying to integrate data of various molecular types to inform hypotheses and biological questions. Tightly connected to this work are the batch-related biases that commonly are apparent between different datasets, but these problems are often not tackled. In present study the ComBat algorithm was applied and evaluated on two different data integration problems. Results show that the batch effects present in the integrated datasets efficiently could be removed by applying the ComBat algorithm.

National Category
Bioinformatics (Computational Biology)
Research subject
Bioinformatics; INF501 Integration of -omics Data
Identifiers
urn:nbn:se:his:diva-15850 (URN)2-s2.0-85048592521 (Scopus ID)978-1-943436-11-8 (ISBN)978-1-5108-5866-4 (ISBN)
Conference
10th International Conference on Bioinformatics and Computational Biology (BICOB) March 19 - 21, 2018, Las Vegas, NV, USA
Available from: 2018-06-28 Created: 2018-06-28 Last updated: 2019-09-04Bibliographically approved
Ghosheh, N., Küppers-Munther, B., Asplund, A., Edsbagge, J., Ulfenborg, B., Andersson, T. B., . . . Synnergren, J. (2017). Comparative transcriptomics of hepatic differentiation of human pluripotent stem cells and adult human liver tissue. Physiological Genomics, 49(8), 430-446
Open this publication in new window or tab >>Comparative transcriptomics of hepatic differentiation of human pluripotent stem cells and adult human liver tissue
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2017 (English)In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 49, no 8, p. 430-446Article in journal (Refereed) Published
Abstract [en]

Hepatocytes derived from human pluripotent stem cells (hPSC-HEP) have the potential to replace presently used hepatocyte sources applied in liver disease treatment and models of drug discovery and development. Established hepatocyte differentiation protocols are effective and generate hepatocytes, which recapitulate some key features of their in vivo counterparts. However, generating mature hPSC-HEP remains a challenge. In this study, we applied transcriptomics to investigate the progress of in vitro hepatic differentiation of hPSCs at the developmental stages, definitive endoderm, hepatoblasts, early hPSC-HEP, and mature hPSC-HEP, to identify functional targets that enhance efficient hepatocyte differentiation. Using functional annotation, pathway and protein interaction network analyses, we observed the grouping of differentially expressed genes in specific clusters representing typical developmental stages of hepatic differentiation. In addition, we identified hub proteins and modules that were involved in the cell cycle process at early differentiation stages. We also identified hub proteins that differed in expression levels between hPSC-HEP and the liver tissue controls. Moreover, we identified a module of genes that were expressed at higher levels in the liver tissue samples than in the hPSC-HEP. Considering that hub proteins and modules generally are essential and have important roles in the protein-protein interactions, further investigation of these genes and their regulators may contribute to a better understanding of the differentiation process. This may suggest novel target pathways and molecules for improvement of hPSC-HEP functionality, having the potential to finally bring this technology to a wider use.

Keywords
human pluripotent stem cell, stem cell-derived hepatocytes, liver tissue, differentiation, transcriptomics
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Bioinformatics; INF501 Integration of -omics Data; INF502 Biomarkers
Identifiers
urn:nbn:se:his:diva-14112 (URN)10.1152/physiolgenomics.00007.2017 (DOI)000407487100004 ()28698227 (PubMedID)2-s2.0-85027420517 (Scopus ID)
Available from: 2017-09-14 Created: 2017-09-14 Last updated: 2018-11-16
Ghosheh, N., Olsson, B., Edsbagge, J., Küppers-Munther, B., Van Giezen, M., Asplund, A., . . . Synnergren, J. (2016). Highly Synchronized Expression of Lineage-Specific Genes during In Vitro Hepatic Differentiation of Human Pluripotent Stem Cell Lines. Stem Cells International, 2016, Article ID 8648356.
Open this publication in new window or tab >>Highly Synchronized Expression of Lineage-Specific Genes during In Vitro Hepatic Differentiation of Human Pluripotent Stem Cell Lines
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2016 (English)In: Stem Cells International, ISSN 1687-9678, Vol. 2016, article id 8648356Article in journal (Refereed) Published
Abstract [en]

Human pluripotent stem cells- (hPSCs-) derived hepatocytes have the potential to replace many hepatic models in drug discovery and provide a cell source for regenerative medicine applications. However, the generation of fully functional hPSC-derived hepatocytes is still a challenge. Towards gaining better understanding of the differentiation and maturation process, we employed a standardized protocol to differentiate six hPSC lines into hepatocytes and investigated the synchronicity of the hPSC lines by applying RT-qPCR to assess the expression of lineage-specific genes (OCT4, NANOG, T, SOX17, CXCR4, CER1, HHEX, TBX3, PROX1, HNF6, AFP, HNF4a, KRT18, ALB, AAT, and CYP3A4) which serve as markers for different stages during liver development. The data was evaluated using correlation and clustering analysis, demonstrating that the expression of these markers is highly synchronized and correlated well across all cell lines. The analysis also revealed a distribution of the markers in groups reflecting the developmental stages of hepatocytes. Functional analysis of the differentiated cells further confirmed their hepatic phenotype. Taken together, these results demonstrate, on the molecular level, the highly synchronized differentiation pattern across multiple hPSC lines. Moreover, this study provides additional understanding for future efforts to improve the functionality of hPSC-derived hepatocytes and thereby increase the value of related models.

National Category
Cell Biology
Research subject
Bioinformatics
Identifiers
urn:nbn:se:his:diva-12033 (URN)10.1155/2016/8648356 (DOI)000373503900001 ()26949401 (PubMedID)2-s2.0-84959330405 (Scopus ID)
Available from: 2016-03-14 Created: 2016-03-14 Last updated: 2018-07-31Bibliographically approved
Asplund, A., Pradip, A., van Giezen, M., Aspegren, A., Choukair, H., Rehnström, M., . . . Küppers-Munther, B. (2016). One Standardized Differentiation Procedure Robustly Generates Homogenous Hepatocyte Cultures Displaying Metabolic Diversity from a Large Panel of Human Pluripotent Stem Cells. Stem Cell Reviews, 12(1), 90-104
Open this publication in new window or tab >>One Standardized Differentiation Procedure Robustly Generates Homogenous Hepatocyte Cultures Displaying Metabolic Diversity from a Large Panel of Human Pluripotent Stem Cells
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2016 (English)In: Stem Cell Reviews, ISSN 1550-8943, E-ISSN 1558-6804, Vol. 12, no 1, p. 90-104Article in journal (Refereed) Published
Abstract [en]

Human hepatocytes display substantial functional inter-individual variation regarding drug metabolizing functions. In order to investigate if this diversity is mirrored in hepatocytes derived from different human pluripotent stem cell (hPSC) lines, we evaluated 25 hPSC lines originating from 24 different donors for hepatic differentiation and functionality. Homogenous hepatocyte cultures could be derived from all hPSC lines using onestandardized differentiation procedure. To the best of our knowledge this is the first report of a standardized hepatic differentiation procedure that is generally applicable across a large panel of hPSC lines without any adaptations to individual lines. Importantly, with regard to functional aspects, such as Cytochrome P450 activities, we observed that hepatocytes derived from different hPSC lines displayed inter-individual variation characteristic for primary hepatocytes obtained from different donors, while these activities were highly reproducible between repeated experiments using the same line. Taken together, these data demonstrate the emerging possibility to compile panels of hPSC-derived hepatocytes of particular phenotypes/genotypes relevant for drug metabolism and toxicity studies. Moreover, these findings are of significance for applications within the regenerative medicine field, since our stringent differentiation procedure allows the derivation of homogenous hepatocyte cultures from multiple donors which is a prerequisite for the realization of future personalized stem cell based therapies.

Place, publisher, year, edition, pages
Springer, 2016
Keywords
Cellular therapy, Hepatocyte differentiation, Human embyronic stem cells, Human induced pluripotent stem cells, Liver, Toxicity
National Category
Cell and Molecular Biology
Research subject
Medical sciences; Bioinformatics
Identifiers
urn:nbn:se:his:diva-11781 (URN)10.1007/s12015-015-9621-9 (DOI)000374582000008 ()26385115 (PubMedID)2-s2.0-84955335024 (Scopus ID)
Available from: 2015-12-31 Created: 2015-12-31 Last updated: 2018-07-31Bibliographically approved
Holmgren, G., Ghosheh, N., Zeng, X., Bogestål, Y., Sartipy, P. & Synnergren, J. (2015). Identification of stable reference genes in differentiating human pluripotent stem cells. Physiological Genomics, 47(6), 232-239
Open this publication in new window or tab >>Identification of stable reference genes in differentiating human pluripotent stem cells
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2015 (English)In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 47, no 6, p. 232-239Article in journal (Refereed) Published
Abstract [en]

Reference genes, often referred to as housekeeping genes (HKGs), are frequently used to normalize gene expression data based on the assumption that they are expressed at a constant level in the cells. However, several studies have shown that there may be a large variability in the gene expression levels of HKGs in various cell types. In a previous study, employing human embryonic stem cells (hESCs) subjected to spontaneous differentiation, we observed that the expression of commonly used HKG varied to a degree that rendered them inappropriate to use as reference genes under those experimental settings. Here we present a substantially extended study of the HKG signature in human pluripotent stem cells (hPSC), including nine global gene expression datasets from both hESC and human induced pluripotent stem cells (hiPSCs), obtained during directed differentiation towards endoderm-, mesoderm-, and ectoderm derivatives. Sets of stably expressed genes were compiled and a handful of genes (e.g., EID2, ZNF324B, CAPN10, and RABEP2) were identified as generally applicable reference genes in hPSCs across all cell lines and experimental conditions. The stability in gene expression profiles was confirmed by quantitative PCR (RT-qPCR) analysis. Taken together, the current results suggest that differentiating hPSCs have a distinct HKG signature, which in some aspects is different from somatic cell types, and underscore the necessity to validate the stability of reference genes under the actual experimental setup used. In addition, the novel putative HKGs identified in this study can preferentially be used for normalization of gene expression data obtained from differentiating hPSCs.

Place, publisher, year, edition, pages
American Physiological Society, 2015
Keywords
Differentiation, Endogenous controls; Gene expression, Housekeeping genes, Human pluripotent stem cells, Normalization, Reference genes
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Bioinformatics
Identifiers
urn:nbn:se:his:diva-11419 (URN)10.1152/physiolgenomics.00130.2014 (DOI)000357489400005 ()25852171 (PubMedID)2-s2.0-84930975405 (Scopus ID)
Available from: 2015-08-25 Created: 2015-08-25 Last updated: 2018-07-31Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2942-6702

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