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Sökning: LAR1:gu > Högskolan i Skövde > Lindahl Anders 1954

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1.
  • Holmgren, Gustav, 1983-, et al. (författare)
  • Expression Profiling of Human Pluripotent Stem Cell-Derived Cardiomyocytes Exposed to Doxorubicin-Integration and Visualization of Multi-Omics Data
  • 2018
  • Ingår i: Toxicological Sciences. - : Oxford University Press (OUP). - 1096-6080 .- 1096-0929. ; 163:1, s. 182-195
  • Tidskriftsartikel (refereegranskat)abstract
    • 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 this 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 2 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.
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2.
  • Holmgren, Gustav, 1983-, et al. (författare)
  • MicroRNAs as potential biomarkers for doxorubicin-induced cardiotoxicity
  • 2016
  • Ingår i: Toxicology in Vitro. - : Elsevier BV. - 0887-2333 .- 1879-3177. ; 34, s. 26-34
  • Tidskriftsartikel (refereegranskat)abstract
    • Anthracyclines, such as doxorubicin, are well-established, highly efficient anti-neoplastic drugs used for treatment of a variety of cancers, including solid tumors, leukemia, lymphomas, and breast cancer. The successful use of doxorubicin has, however, been hampered by severe cardiotoxic side-effects. In order to prevent or reverse negative side-effects of doxorubicin, it is important to find early biomarkers of heart injury and drug-induced cardiotoxicity. The high stability under extreme conditions, presence in various body fluids, and tissue specificity, makes,microRNAs very suitable as clinical.biomarkers. The present study aimed towards evaluating the early and late effects of doxorubicin on the microRNA expression in cardiomyocytes derived from human pluripotent stem cells. We report on several microRNAs, including miR-34a, miR-34b, miR-187, miR-199a, miR-199b, miR-146a, miR-15b, miR-130a, miR-214, and miR-424, that are differentially expressed upon, and after, treatment with doxorubicin. Investigation of the biological relevance of the identified microRNAs revealed connections to cardiomyocyte function and cardiotoxicity, thus supporting the findings of these microRNAs as potential biomarkers for drug-induced cardiotoxicity.
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3.
  • Sandstedt, Mikael, 1990, et al. (författare)
  • Regional transcriptomic profiling reveals immune system enrichment in nonfailing atria as well as all chambers of the failing human heart
  • 2023
  • Ingår i: American Journal of Physiology. Heart and Circulatory Physiology. - : American Physiological Society. - 0363-6135 .- 1522-1539. ; 325:6, s. H1430-H1445
  • Tidskriftsartikel (refereegranskat)abstract
    • The different chambers of the human heart demonstrate regional physiological traits and may be differentially affected during pathologic remodeling, resulting in heart failure. Few previous studies have, however, characterized the different chambers at a transcriptomic level. We therefore conducted whole-tissue RNA sequencing and gene set enrichment analysis of biopsies collected from the four chambers of adult failing (n = 8) and nonfailing (n = 11) human hearts. Atria and ventricles demonstrated distinct transcriptional patterns. Compared to nonfailing ventricles, the transcriptional pattern of nonfailing atria was enriched for a large number of gene sets associated with cardiogenesis, the immune system and bone morphogenetic protein (BMP), transforming growth factor beta (TGF beta), MAPK/JNK and Wnt signaling. Differences between failing and nonfailing hearts were also determined. The transcriptional pattern of failing atria was distinct compared to that of nonfailing atria and enriched for gene sets associated with the innate and adaptive immune system, TGF beta/SMAD signaling, and changes in endothelial, smooth muscle cell and cardiomyocyte physiology. Failing ventricles were also enriched for gene sets associated with the immune system. Based on the transcriptomic patterns, upstream regulators associated with heart failure were identified. These included many immune response factors predicted to be similarly activated for all chambers of failing hearts. In summary, the heart chambers demonstrate distinct transcriptional patterns that differ between failing and nonfailing hearts. Immune system signaling may be a hallmark of all four heart chambers in failing hearts, and could constitute a novel therapeutic target.
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4.
  • Stenberg, Johan, et al. (författare)
  • Clinical Outcome 3 Years After Autologous Chondrocyte Implantation Does Not Correlate With the Expression of a Predefined Gene Marker Set in Chondrocytes Prior to Implantation but Is Associated With Critical Signaling Pathways
  • 2014
  • Ingår i: The Orthopaedic Journal of Sports Medicine. - : Sage Publications. - 2325-9671. ; 2:9, s. 1-14
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: There is a need for tools to predict the chondrogenic potency of autologous cells for cartilage repair.PURPOSE: To evaluate previously proposed chondrogenic biomarkers and to identify new biomarkers in the chondrocyte transcriptome capable of predicting clinical success or failure after autologous chondrocyte implantation.STUDY DESIGN: Controlled laboratory study and case-control study; Level of evidence, 3.METHODS: Five patients with clinical improvement after autologous chondrocyte implantation and 5 patients with graft failures 3 years after implantation were included. Surplus chondrocytes from the transplantation were frozen for each patient. Each chondrocyte sample was subsequently thawed at the same time point and cultured for 1 cell doubling, prior to RNA purification and global microarray analysis. The expression profiles of a set of predefined marker genes (ie, collagen type II α1 [COL2A1], bone morphogenic protein 2 [BMP2], fibroblast growth factor receptor 3 [FGFR3], aggrecan [ACAN], CD44, and activin receptor-like kinase receptor 1 [ACVRL1]) were also evaluated.RESULTS: No significant difference in expression of the predefined marker set was observed between the success and failure groups. Thirty-nine genes were found to be induced, and 38 genes were found to be repressed between the 2 groups prior to autologous chondrocyte implantation, which have implications for cell-regulating pathways (eg, apoptosis, interleukin signaling, and β-catenin regulation).CONCLUSION: No expressional differences that predict clinical outcome could be found in the present study, which may have implications for quality control assessments of autologous chondrocyte implantation. The subtle difference in gene expression regulation found between the 2 groups may strengthen the basis for further research, aiming at reliable biomarkers and quality control for tissue engineering in cartilage repair.CLINICAL RELEVANCE: The present study shows the possible limitations of using gene expression before transplantation to predict the chondrogenic and thus clinical potency of the cells. This result is especially important as the chondrogenic potential of the chondrocytes is currently part of quality control measures according to European and American legislations regarding advanced therapies.
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5.
  • Synnergren, Jane, 1967, et al. (författare)
  • Cardiomyogenic gene expression profiling of differentiating human embryonic stem cells.
  • 2008
  • Ingår i: Journal of biotechnology. - : Elsevier BV. - 0168-1656 .- 1873-4863. ; 134:1-2, s. 162-70
  • Tidskriftsartikel (refereegranskat)abstract
    • Human embryonic stem cells (hESCs) can differentiate into a variety of specialized cell types. Thus, they provide a model system for embryonic development to investigate the molecular processes of cell differentiation and lineage commitment. The development of the cardiac lineage is easily detected in mixed cultures by the appearance of spontaneously contracting areas of cells. We performed gene expression profiling of undifferentiated and differentiating hESCs and monitored 468 genes expressed during cardiac development and/or in cardiac tissue. Their transcription during early differentiation of hESCs through embryoid bodies (EBs) was investigated and compared with spontaneously differentiating hESCs maintained on feeders in culture without passaging (high-density (HD) protocol). We observed a larger variation in the gene expression between cells from a single cell line that were differentiated using two different protocols than in cells from different cell lines that were cultured according to the same protocol. Notably, the EB protocol resulted in more reproducible transcription profiles than the HD protocol. The results presented here provide new information about gene regulation during early differentiation of hESCs with emphasis on the cardiomyogenic program. In addition, we also identified regulatory elements that could prove critical for the development of the cardiomyocyte lineage.
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6.
  • Synnergren, Jane, 1967, et al. (författare)
  • Differentiating human embryonic stem cells express a unique housekeeping gene signature.
  • 2007
  • Ingår i: Stem cells (Dayton, Ohio). - : Oxford University Press (OUP). - 1066-5099 .- 1549-4918. ; 25:2, s. 473-80
  • Tidskriftsartikel (refereegranskat)abstract
    • Housekeeping genes (HKGs) are involved in basic functions needed for the sustenance of the cell and are assumed to be constitutively expressed at a constant level. Based on these features, HKGs are frequently used for normalization of gene expression data. In the present study, we used the CodeLink Gene Expression Bioarray system to interrogate changes in gene expression occurring during differentiation of human ESCs (hESCs). Notably, in the three hESC lines used for the study, we observed that the RNA levels of 56 frequently used HKGs varied to a degree that rendered them inappropriate as reference genes. Therefore, we defined a novel set of HKGs specifically for hESCs. Here we present a comprehensive list of 292 genes that are stably expressed (coefficient of variation <20%) in differentiating hESCs. These genes were further grouped into high-, medium-, and low-expressed genes. The expression patterns of these novel HKGs show very little overlap with results obtained from somatic cells and tissues. We further explored the stability of this novel set of HKGs in independent, publicly available gene expression data from hESCs and observed substantial similarities with our results. Gene expression was confirmed by real-time quantitative polymerase chain reaction analysis. Taken together, these results suggest that differentiating hESCs have a unique HKG signature and underscore the necessity to validate the expression profiles of putative HKGs. In addition, this novel set of HKGs can preferentially be used as controls in gene expression analyses of differentiating hESCs.
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7.
  • Synnergren, Jane, 1967, et al. (författare)
  • Expression of microRNAs and their target mRNAs in human stem cell-derived cardiomyocyte clusters and in heart tissue.
  • 2011
  • Ingår i: Physiological genomics. - : American Physiological Society. - 1531-2267 .- 1094-8341. ; 43:10, s. 581-94
  • Tidskriftsartikel (refereegranskat)abstract
    • Recent studies have shown that microRNAs (miRNAs) act as posttranscriptional regulators and that they play important roles during heart development and in cardiac function. Thus, they may provide new means of altering stem cell fate and differentiation processes. However, information about the correlation between global miRNA and mRNA expression in cardiomyocyte clusters (CMCs) derived from human embryonic stem cells (hESC) and in fetal and adult heart tissue is lacking. In the present study the global miRNA and mRNA expression in hESC-derived CMCs and in fetal and adult heart tissue was investigated in parallel using microarrays. Target genes for the differentially expressed miRNAs were predicted using computational methods, and the concordance in miRNA expression and mRNA levels of potential target genes was determined across the experimental samples. The biology of the predicted target genes was further explored regarding their molecular functions and involvement in known regulatory pathways. A clear correlation between the global miRNA expression and corresponding target mRNA expression was observed. Using three different sources of cardiac tissue-like samples, we defined the similarities between in vitro hESC-derived CMCs and their in vivo counterparts. The results are in line with previously reported observations that miRNAs repress mRNA expression and additionally identify a number of novel miRNAs with potential important roles in human cardiac tissue. The concordant miRNA expression pattern observed among all the cardiac tissue-like samples analyzed here provide a starting point for future ambitious studies aiming towards assessment of the functional roles of specific miRNAs during cardiomyocyte differentiation.
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8.
  • Synnergren, Jane, 1967, et al. (författare)
  • Molecular signature of cardiomyocyte clusters derived from human embryonic stem cells.
  • 2008
  • Ingår i: Stem cells (Dayton, Ohio). - : Oxford University Press (OUP). - 1549-4918 .- 1066-5099. ; 26:7, s. 1831-40
  • Tidskriftsartikel (refereegranskat)abstract
    • Human embryonic stem cells (hESCs) can differentiate in vitro into spontaneously contracting cardiomyocytes (CMs). These cells may prove extremely useful for various applications in basic research, drug discovery, and regenerative medicine. To fully use the potential of the cells, they need to be extensively characterized, and the regulatory mechanisms that control hESC differentiation toward the cardiac lineage need to be better defined. In this study, we used microarrays to analyze, for the first time, the global gene expression profile of isolated hESC-derived CM clusters. By comparing the clusters with undifferentiated hESCs and using stringent selection criteria, we identified 530 upregulated and 40 downregulated genes in the contracting clusters. To further characterize the family of upregulated genes in the hESC-derived CM clusters, the genes were classified according to their Gene Ontology annotation. The results indicate that the hESC-derived CM clusters display high similarities, on a molecular level, to human heart tissue. Moreover, using the family of upregulated genes, we created protein interaction maps that revealed topological characteristics. We also searched for cellular pathways among the upregulated genes in the hESC-derived CM clusters and identified eight significantly upregulated pathways. Real-time quantitative polymerase chain reaction and immunohistochemical analysis confirmed the expression of a subset of the genes identified by the microarrays. Taken together, the results presented here provide a molecular signature of hESC-derived CM clusters and further our understanding of the biological processes that are active in these cells.
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9.
  • Synnergren, Jane, 1967, et al. (författare)
  • Transcriptional profiling of human embryonic stem cells differentiating to definitive and primitive endoderm and further toward the hepatic lineage.
  • 2010
  • Ingår i: Stem cells and development. - : Mary Ann Liebert Inc. - 1557-8534 .- 1547-3287. ; 19:7, s. 961-78
  • Tidskriftsartikel (refereegranskat)abstract
    • Human embryonic stem cells (hESC) can differentiate into a variety of specialized cell types, and they constitute a useful model system to study embryonic development in vitro. In order to fully utilize the potential of these cells, the mechanisms that regulate the developmental processes of specific lineage differentiation need to be better defined. The aim of this study was to explore the molecular program involved in the differentiation of hESC toward definitive endoderm (DE) and further into the hepatic lineage, and to compare that with primitive endoderm (PrE) differentiation. To that end, we applied two protocols: a specific DE differentiation protocol and an intrinsic differentiation protocol that mainly mediates PrE formation. We collected hESC, hESC-derived DE, DE-derived hepatocyte-progenitors (DE-Prog), DE-derived hepatocyte-like cells (DE-Hep), and the corresponding PrE derivatives. The samples were analyzed using microarrays, and we identified sets of genes that were exclusively up-regulated in DE derivatives (compared to PrE derivatives) at discrete developmental stages. We also investigated known protein interactions among the set of up-regulated genes in DE-Hep. The results demonstrate important differences between DE and PrE differentiation on the transcriptional level. In particular, our results identify a unique molecular program, exclusively activated during development of DE and the subsequent differentiation of DE toward the hepatic lineage. We identified key genes and pathways of potential importance for future efforts to improve hepatic differentiation from hESC. These results reveal new opportunities for rational design of specific interventions with the purpose of generating enriched populations of DE derivatives, including functional hepatocytes.
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10.
  • Synnergren, Jane, et al. (författare)
  • Transcriptional sex and regional differences in paired human atrial and ventricular cardiac biopsies collected in vivo
  • 2020
  • Ingår i: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 52:2, s. 110-120
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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