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Holmgren, G., Ulfenborg, B., Asplund, A., Toet, K., Andersson, C. X., Hammarstedt, A., . . . Synnergren, J. (2020). Characterization of Human Induced Pluripotent Stem Cell-Derived Hepatocytes with Mature Features and Potential for Modeling Metabolic Diseases. International Journal of Molecular Sciences, 21(2), Article ID E469.
Open this publication in new window or tab >>Characterization of Human Induced Pluripotent Stem Cell-Derived Hepatocytes with Mature Features and Potential for Modeling Metabolic Diseases
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2020 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 21, no 2, article id E469Article in journal (Refereed) Published
Abstract [en]

There is a strong anticipated future for human induced pluripotent stem cell-derived hepatocytes (hiPS-HEP), but so far, their use has been limited due to insufficient functionality. We investigated the potential of hiPS-HEP as an in vitro model for metabolic diseases by combining transcriptomics with multiple functional assays. The transcriptomics analysis revealed that 86% of the genes were expressed at similar levels in hiPS-HEP as in human primary hepatocytes (hphep). Adult characteristics of the hiPS-HEP were confirmed by the presence of important hepatocyte features, e.g., Albumin secretion and expression of major drug metabolizing genes. Normal energy metabolism is crucial for modeling metabolic diseases, and both transcriptomics data and functional assays showed that hiPS-HEP were similar to hphep regarding uptake of glucose, low-density lipoproteins (LDL), and fatty acids. Importantly, the inflammatory state of the hiPS-HEP was low under standard conditions, but in response to lipid accumulation and ER stress the inflammation marker tumor necrosis factor α (TNFα) was upregulated. Furthermore, hiPS-HEP could be co-cultured with primary hepatic stellate cells both in 2D and in 3D spheroids, paving the way for using these co-cultures for modeling non-alcoholic steatohepatitis (NASH). Taken together, hiPS-HEP have the potential to serve as an in vitro model for metabolic diseases. Furthermore, differently expressed genes identified in this study can serve as targets for future improvements of the hiPS-HEP.

Keywords
characterization, human induced pluripotent stem cells, human stem cell-derived hepatocytes, in vitro, maturation, metabolic diseases, transcriptomics
National Category
Cell Biology
Identifiers
urn:nbn:se:his:diva-18158 (URN)10.3390/ijms21020469 (DOI)31940797 (PubMedID)2-s2.0-85077941486 (Scopus ID)
Available from: 2020-01-23 Created: 2020-01-23 Last updated: 2020-01-31Bibliographically approved
Synnergren, J., Vukusic, K., Dönnes, P., Jonsson, M., Lindahl, A., Dellgren, G., . . . Asp, J. (2020). Transcriptional sex and regional differences in paired human atrial and ventricular cardiac biopsies collected in vivo. Physiological Genomics, 52(2), 110-120
Open this publication in new window or tab >>Transcriptional sex and regional differences in paired human atrial and ventricular cardiac biopsies collected in vivo
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2020 (English)In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 52, no 2, p. 110-120Article in journal (Refereed) Published
Abstract [en]

Transcriptional studies of the human heart provide insight into physiological and pathophysiological mechanisms, essential for understanding the fundamental mechanisms of normal cardiac function and how they are altered by disease. To improve the understanding of why men and women may respond differently to the same therapeutic treatment it is crucial to learn more about sex-specific transcriptional differences. In this study the transcriptome of right atrium and left ventricle was compared across sex and regional location. Paired biopsies from five male and five female patients undergoing aortic valve replacement or coronary artery bypass grafting were included. Gene expression analysis identified 620 differentially expressed transcripts in atrial and ventricular tissue in men and 471 differentially expressed transcripts in women. In total 339 of these transcripts overlapped across sex but notably, 281 were unique in the male tissue and 162 in the female tissue, displaying marked sex differences in the transcriptional machinery. The transcriptional activity was significantly higher in atrias than in ventricles as 70% of the differentially expressed genes were upregulated in the atrial tissue. Furthermore, pathway- and functional annotation analyses performed on the differentially expressed genes showed enrichment for a more heterogeneous composition of biological processes in atrial compared with the ventricular tissue, and a dominance of differentially expressed genes associated with infection disease was observed. The results reported here provide increased insights about transcriptional differences between the cardiac atrium and ventricle but also reveal transcriptional differences in the human heart that can be attributed to sex.

Place, publisher, year, edition, pages
NLM (Medline), 2020
Keywords
cardiac tissue, differentially expressed genes, gender, gene expression, left ventricle, microarray, right atrium, sex, transcription
Identifiers
urn:nbn:se:his:diva-18213 (URN)10.1152/physiolgenomics.00036.2019 (DOI)31869284 (PubMedID)2-s2.0-85079250310 (Scopus ID)
Available from: 2020-02-20 Created: 2020-02-20 Last updated: 2020-02-20
Granéli, C., Hicks, R., Brolén, G., Synnergren, J. & Sartipy, P. (2019). Diabetic Cardiomyopathy Modelling Using Induced Pluripotent Stem Cell Derived Cardiomyocytes: Recent Advances and Emerging Models. Stem Cell Reviews, 15(1), 13-22
Open this publication in new window or tab >>Diabetic Cardiomyopathy Modelling Using Induced Pluripotent Stem Cell Derived Cardiomyocytes: Recent Advances and Emerging Models
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2019 (English)In: Stem Cell Reviews, ISSN 1550-8943, E-ISSN 1558-6804, Vol. 15, no 1, p. 13-22Article in journal (Refereed) Published
Abstract [en]

The global burden of diabetes has drastically increased over the past decades and in 2017 approximately 4 million deaths were caused by diabetes and cardiovascular complications. Diabetic cardiomyopathy is a common complication of diabetes with early manifestations of diastolic dysfunction and left ventricular hypertrophy with subsequent progression to systolic dysfunction and ultimately heart failure. An in vitro model accurately recapitulating key processes of diabetic cardiomyopathy would provide a useful tool for investigations of underlying disease mechanisms to further our understanding of the disease and thereby potentially advance treatment strategies for patients. With their proliferative capacity and differentiation potential, human induced pluripotent stem cells (iPSCs) represent an appealing cell source for such a model system and cardiomyocytes derived from induced pluripotent stem cells have been used to establish other cardiovascular related disease models. Here we review recently made advances and discuss challenges still to be overcome with regard to diabetic cardiomyopathy models, with a special focus on iPSC-based systems. Recent publications as well as preliminary data presented here demonstrate the feasibility of generating cardiomyocytes with a diabetic phenotype, displaying insulin resistance, impaired calcium handling and hypertrophy. However, capturing the full metabolic- and functional phenotype of the diabetic cardiomyocyte remains to be accomplished. 

Place, publisher, year, edition, pages
Springer, 2019
Keywords
Cardiomyocytes, Diabetic cardiomyopathy, Disease modeling, Induced pluripotent stem cells, Insulin resistance
National Category
Cell Biology
Research subject
Bioinformatics; INF502 Biomarkers
Identifiers
urn:nbn:se:his:diva-16413 (URN)10.1007/s12015-018-9858-1 (DOI)000457386100003 ()30343468 (PubMedID)2-s2.0-85055676513 (Scopus ID)
Available from: 2018-11-20 Created: 2018-11-20 Last updated: 2019-02-15Bibliographically approved
Delsing, L., Kallur, T., Zetterberg, H., Hicks, R. & Synnergren, J. (2019). Enhanced xeno-free differentiation of hiPSC-derived astroglia applied in a blood-brain barrier model. Fluids and Barriers of the CNS, 16(1), Article ID 27.
Open this publication in new window or tab >>Enhanced xeno-free differentiation of hiPSC-derived astroglia applied in a blood-brain barrier model
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2019 (English)In: Fluids and Barriers of the CNS, ISSN 2045-8118, E-ISSN 2045-8118, Vol. 16, no 1, article id 27Article in journal (Refereed) Published
Abstract [en]

Background Human induced pluripotent stem cells (hiPSC) hold great promise for use in cell therapy applications and for improved in vitro models of human disease. So far, most hiPSC differentiation protocols to astroglia use undefined, animal-containing culture matrices. Laminins, which play an essential role in the regulation of cell behavior, offer a source of defined, animal-free culture matrix. Methods In order to understand how laminins affect astroglia differentiation, recombinant human laminin-521 (LN521), was compared to a murine Engelbreth-Holm-Swarm sarcoma derived laminin (L2020). Astroglia expression of protein and mRNA together with glutamate uptake and protein secretion function, were evaluated. Finally, these astroglia were evaluated in a coculture model of the blood-brain barrier (BBB). Results Astroglia of good quality were generated from hiPSC on both LN521 and L2020. However, astroglia differentiated on human LN521 showed higher expression of several astroglia specific mRNAs and proteins such as GFAP, S100B, Angiopoietin-1, and EAAT1, compared to astroglia differentiated on murine L2020. In addition, glutamate uptake and ability to induce expression of junction proteins in endothelial cells were affected by the culture matrix for differentiation. Conclusion Our results suggest that astroglia differentiated on LN521 display an improved phenotype and are suitable for coculture in a hiPSC-derived BBB model. This provides a starting point for a more defined and robust derivation of astroglia for use in BBB coculture models.

Place, publisher, year, edition, pages
BioMed Central, 2019
Keywords
Astroglia, hiPSC, In vitro models, Diferentiation, Laminin-521, Blood–brain barrier
National Category
Pharmaceutical Sciences
Research subject
Bioinformatics
Identifiers
urn:nbn:se:his:diva-17672 (URN)10.1186/s12987-019-0147-4 (DOI)000483547700001 ()31462266 (PubMedID)2-s2.0-85071630761 (Scopus ID)
Available from: 2019-09-12 Created: 2019-09-12 Last updated: 2019-11-13Bibliographically approved
Delsing, L., Dönnes, P., Sánchez, J., Clausen, M., Voulgaris, D., Falk, A., . . . Synnergren, J. (2018). Barrier properties and transcriptome expression in human iPSC-derived models of the blood-brain barrier. Stem Cells, 36(12), 1816-1827
Open this publication in new window or tab >>Barrier properties and transcriptome expression in human iPSC-derived models of the blood-brain barrier
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2018 (English)In: Stem Cells, ISSN 1066-5099, E-ISSN 1549-4918, Vol. 36, no 12, p. 1816-1827Article in journal (Refereed) Published
Abstract [en]

Cell-based models of the blood-brain barrier (BBB) are important for increasing the knowledge of BBB formation, degradation and brain exposure of drug substances. Human models are preferred over animal models because of inter-species differences in BBB structure and function. However, access to human primary BBB tissue is limited and has shown degeneration of BBB functions in vitro. Human induced pluripotent stem cells (iPSCs) can be used to generate relevant cell types to model the BBB with human tissue. We generated a human iPSC-derived model of the BBB that includes endothelial cells in co-culture with pericytes, astrocytes and neurons. Evaluation of barrier properties showed that the endothelial cells in our co-culture model have high transendothelial electrical resistance, functional efflux and ability to discriminate between CNS permeable and non-permeable substances. Whole genome expression profiling revealed transcriptional changes that occur in co-culture, including upregulation of tight junction proteins such as claudins and neurotransmitter transporters. Pathway analysis implicated changes in the WNT, TNF and PI3K-Akt pathways upon co-culture. Our data suggests that co-culture of iPSC-derived endothelial cells promotes barrier formation on a functional and transcriptional level. The information about gene expression changes in co-culture can be used to further improve iPSC-derived BBB models through selective pathway manipulation.

Place, publisher, year, edition, pages
AlphaMed Press, Inc., 2018
Keywords
blood–brain barrier, co-culture, hiPSC, in vitro models, transcriptome, endothelial cells
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Bioinformatics; INF502 Biomarkers
Identifiers
urn:nbn:se:his:diva-16283 (URN)10.1002/stem.2908 (DOI)000455838500004 ()30171748 (PubMedID)2-s2.0-85056115357 (Scopus ID)
Available from: 2018-10-08 Created: 2018-10-08 Last updated: 2019-11-19Bibliographically approved
Synnergren, J. & Dönnes, P. (2018). Current Perspectives on Multi-Omics Data Integration With Application on Toxicity Biomarkers Discovery. Open Access journal of Toxicology, 2(5), 1-2, Article ID OAJT.MS.ID.555597.
Open this publication in new window or tab >>Current Perspectives on Multi-Omics Data Integration With Application on Toxicity Biomarkers Discovery
2018 (English)In: Open Access journal of Toxicology, ISSN 2474-7599, Vol. 2, no 5, p. 1-2, article id OAJT.MS.ID.555597Article, review/survey (Refereed) Published
Place, publisher, year, edition, pages
Juniper publishers, 2018
National Category
Bioinformatics (Computational Biology)
Research subject
Bioinformatics; INF501 Integration of -omics Data
Identifiers
urn:nbn:se:his:diva-15851 (URN)10.19080/OAJT.2018.02.555597 (DOI)
Available from: 2018-06-28 Created: 2018-06-28 Last updated: 2019-09-04Bibliographically approved
Holmgren, G., Sartipy, P., Andersson, C. X., Lindahl, A. & Synnergren, J. (2018). Expression profiling of human pluripotent stem cell-derived cardiomyocytes exposed to doxorubicin - integration and visualization of multi omics data. Toxicological Sciences, 163(1), 182-195
Open this publication in new window or tab >>Expression profiling of human pluripotent stem cell-derived cardiomyocytes exposed to doxorubicin - integration and visualization of multi omics data
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2018 (English)In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 163, no 1, p. 182-195Article in journal (Refereed) Published
Abstract [en]

Anthracyclines, such as doxorubicin, are highly efficient chemotherapeutic agents against a variety of cancers. However, anthracyclines are also among the most cardiotoxic therapeutic drugs presently on the market. Chemotherapeutic-induced cardiomyopathy is one of the leading causes of disease and mortality in cancer survivors. The exact mechanisms responsible for doxorubicin-induced cardiomyopathy are not completely known, but the fact that the cardiotoxicity is dose-dependent and that there is a variation in time-to-onset of toxicity, and gender- and age differences suggests that several mechanisms may be involved.In the present study, we investigated doxorubicin-induced cardiotoxicity in human pluripotent stem cell-derived cardiomyocytes using proteomics. In addition, different sources of omics data (protein, mRNA, and microRNA) from the same experimental setup were further combined and analyzed using newly developed methods to identify differential expression in data of various origin and types. Subsequently, the results were integrated in order to generate a combined visualization of the findings.In our experimental model system, we exposed cardiomyocytes derived from human pluripotent stem cells to doxorubicin for up to two days, followed by a wash-out period of additionally 12 days. Besides an effect on the cell morphology and cardiomyocyte functionality, the data show a strong effect of doxorubicin on all molecular levels investigated. Differential expression patterns that show a linkage between the proteome, transcriptome, and the regulatory microRNA network, were identified. These findings help to increase the understanding of the mechanisms behind anthracycline-induced cardiotoxicity and suggest putative biomarkers for this condition.

Place, publisher, year, edition, pages
Oxford University Press, 2018
Keywords
Human pluripotent stem cells, cardiomyocytes, doxorubicin, multi-omics data, proteomics, toxicity
National Category
Bioinformatics (Computational Biology)
Research subject
Bioinformatics; INF502 Biomarkers; INF501 Integration of -omics Data
Identifiers
urn:nbn:se:his:diva-14745 (URN)10.1093/toxsci/kfy012 (DOI)000432299900018 ()29385562 (PubMedID)2-s2.0-85046994085 (Scopus ID)
Available from: 2018-02-14 Created: 2018-02-14 Last updated: 2019-11-20Bibliographically approved
Lundin, A., Delsing, L., Clausen, M., Ricchiuto, P., Sanchez, J., Sabirsh, A., . . . Falk, A. (2018). Human iPS-Derived Astroglia from a Stable Neural Precursor State Show Improved Functionality Compared with Conventional Astrocytic Models. Stem Cell Reports, 10(3), 1030-1045
Open this publication in new window or tab >>Human iPS-Derived Astroglia from a Stable Neural Precursor State Show Improved Functionality Compared with Conventional Astrocytic Models
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2018 (English)In: Stem Cell Reports, ISSN 2213-6711, Vol. 10, no 3, p. 1030-1045Article in journal (Refereed) Published
Abstract [en]

In vivo studies of human brain cellular function face challenging ethical and practical difficulties. Animal models are typically used but display distinct cellular differences. One specific example is astrocytes, recently recognized for contribution to neurological diseases and a link to the genetic risk factor apolipoprotein E (APOE). Current astrocytic in vitro models are questioned for lack of biological characterization. Here, we report human induced pluripotent stem cell (hiPSC)-derived astroglia (NES-Astro) developed under defined conditions through long-term neuroepithelial-like stem (ltNES) cells. We characterized NES-Astro and astrocytic models from primary sources, astrocytoma (CCF-STTG1), and hiPSCs through transcriptomics, proteomics, glutamate uptake, inflammatory competence, calcium signaling response, and APOE secretion. Finally, we assess modulation of astrocyte biology using APOE-annotated compounds, confirming hits of the cholesterol biosynthesis pathway in adult and hiPSC-derived astrocytes. Our data show large diversity among astrocytic models and emphasize a cellular context when studying astrocyte biology.

Place, publisher, year, edition, pages
Cell Press, 2018
Keywords
apolipoproteins E, astrocytes, calcium signaling, cell differentiation, drug discovery, glutamate plasma membrane transport proteins, high-throughput screening assays, induced pluripotent stem cells, neurodegenerative diseases, neuroinflammation
National Category
Cell Biology
Research subject
Bioinformatics; INF502 Biomarkers
Identifiers
urn:nbn:se:his:diva-14757 (URN)10.1016/j.stemcr.2018.01.021 (DOI)000427349300028 ()29456185 (PubMedID)2-s2.0-85042043028 (Scopus ID)
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2019-11-20Bibliographically approved
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
Küppers-Munther, B., Asplund, A., Ulfenborg, B., Synnergren, J. & Abadie, A. (2018). Novel human iPSC-derived hepatocytes with advanced functionality and long-term 2D cultures of human primary hepatocytes for metabolic disease studies. Paper presented at Conference on Changing the Face of Modern Medicine - Stem Cell and Gene Therapy, OCT 16-19, 2018, Lausanne, SWITZERLAND. Human Gene Therapy, 29(12), A146-A146, Article ID P406.
Open this publication in new window or tab >>Novel human iPSC-derived hepatocytes with advanced functionality and long-term 2D cultures of human primary hepatocytes for metabolic disease studies
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2018 (English)In: Human Gene Therapy, ISSN 1043-0342, E-ISSN 1557-7422, Vol. 29, no 12, p. A146-A146, article id P406Article in journal, Meeting abstract (Refereed) Published
Place, publisher, year, edition, pages
USA: Mary Ann Liebert, 2018
National Category
Cell Biology
Research subject
Bioinformatics
Identifiers
urn:nbn:se:his:diva-16701 (URN)000453707700464 ()
Conference
Conference on Changing the Face of Modern Medicine - Stem Cell and Gene Therapy, OCT 16-19, 2018, Lausanne, SWITZERLAND
Available from: 2019-03-14 Created: 2019-03-14 Last updated: 2020-01-16Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-4697-0590

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