Högskolan i Skövde

his.sePublications
Change search
Link to record
Permanent link

Direct link
Sartipy, Peter
Publications (10 of 41) Show all publications
Johansson, M., Tangruksa, B., Heydarkhan-Hagvall, S., Jeppsson, A., Sartipy, P. & Synnergren, J. (2022). Data Mining Identifies CCN2 and THBS1 as Biomarker Candidates for Cardiac Hypertrophy. Life, 12(5), Article ID 726.
Open this publication in new window or tab >>Data Mining Identifies CCN2 and THBS1 as Biomarker Candidates for Cardiac Hypertrophy
Show others...
2022 (English)In: Life, E-ISSN 2075-1729, Vol. 12, no 5, article id 726Article in journal (Refereed) Published
Abstract [en]

Cardiac hypertrophy is a condition that may contribute to the development of heart failure. In this study, we compare the gene-expression patterns of our in vitro stem-cell-based cardiac hypertrophy model with the gene expression of biopsies collected from hypertrophic human hearts. Twenty-five differentially expressed genes (DEGs) from both groups were identified and the expression of selected corresponding secreted proteins were validated using ELISA and Western blot. Several biomarkers, including CCN2, THBS1, NPPA, and NPPB, were identified, which showed significant overexpressions in the hypertrophic samples in both the cardiac biopsies and in the endothelin-1-treated cells, both at gene and protein levels. The protein-interaction network analysis revealed CCN2 as a central node among the 25 overlapping DEGs, suggesting that this gene might play an important role in the development of cardiac hypertrophy. GO-enrichment analysis of the 25 DEGs revealed many biological processes associated with cardiac function and the development of cardiac hypertrophy. In conclusion, we identified important similarities between ET-1-stimulated human-stem-cell-derived cardiomyocytes and human hypertrophic cardiac tissue. Novel putative cardiac hypertrophy biomarkers were identified and validated on the protein level, lending support for further investigations to assess their potential for future clinical applications. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Place, publisher, year, edition, pages
MDPI, 2022
Keywords
biomarker, cardiac hypertrophy, disease model, endothelin-1, stem cells, transcriptomics
National Category
Cell and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Bioinformatics and Systems Biology
Research subject
Bioinformatics
Identifiers
urn:nbn:se:his:diva-21200 (URN)10.3390/life12050726 (DOI)000802500000001 ()35629393 (PubMedID)2-s2.0-85130327246 (Scopus ID)
Funder
Knowledge Foundation, 20160294Knowledge Foundation, 20160330Knowledge Foundation, 20200014AstraZeneca
Note

CC BY 4.0

© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

This research was funded by the Systems Biology Research Centre at the University of Skövde under grants from the Knowledge Foundation (20160294, 20160330, 20200014), Takara Bio Europe, Gothenburg, Sweden, and AstraZeneca R&D, Gothenburg.

Data Availability Statement: This study is based on two trancriptomics datasets, which are available for download at ArrayExpress (https://www.ebi.ac.uk/arrayexpress/, accessed on 4 April 2022) accession numbers: E-MTAB-11030 and E-MEXP-2296.

Acknowledgments :The graphical abstract was created with BioRender software. The networks and functional analyses were generated through the use of IPA (Qiagen Inc., https://www.qiagenbioinformatics.com/products/ingenuity-pathway-analysis, accessed on 1 March 2022)

Available from: 2022-06-02 Created: 2022-06-02 Last updated: 2022-07-12Bibliographically approved
Johansson, M., Ulfenborg, B., Andersson, C. X., Heydarkhan-Hagvall, S., Jeppsson, A., Sartipy, P. & Synnergren, J. (2022). Multi-Omics Characterization of a Human Stem Cell-Based Model of Cardiac Hypertrophy. Life, 12(2), Article ID 293.
Open this publication in new window or tab >>Multi-Omics Characterization of a Human Stem Cell-Based Model of Cardiac Hypertrophy
Show others...
2022 (English)In: Life, E-ISSN 2075-1729, Vol. 12, no 2, article id 293Article in journal (Refereed) Published
Abstract [en]

Cardiac hypertrophy is an important and independent risk factor for the development of cardiac myopathy that may lead to heart failure. The mechanisms underlying the development of cardiac hypertrophy are yet not well understood. To increase the knowledge about mechanisms and regulatory pathways involved in the progression of cardiac hypertrophy, we have developed a human induced pluripotent stem cell (hiPSC)-based in vitro model of cardiac hypertrophy and performed extensive characterization using a multi-omics approach. In a series of experiments, hiPSC-derived cardiomyocytes were stimulated with Endothelin-1 for 8, 24, 48, and 72 h, and their transcriptome and secreted proteome were analyzed. The transcriptomic data show many enriched canonical pathways related to cardiac hypertrophy already at the earliest time point, e.g., cardiac hypertrophy signaling. An integrated transcriptome–secretome analysis enabled the identification of multimodal biomarkers that may prove highly relevant for monitoring early cardiac hypertrophy progression. Taken together, the results from this study demonstrate that our in vitro model displays a hypertrophic response on both transcriptomic- and secreted-proteomic levels. The results also shed novel insights into the underlying mechanisms of cardiac hypertrophy, and novel putative early cardiac hypertrophy biomarkers have been identified that warrant further investigation to assess their potential clinical relevance.

Place, publisher, year, edition, pages
MDPI, 2022
Keywords
cardiac hypertrophy, cardiomyocytes, disease model, endothelin-1, stem cells, transcriptomics, proteomics
National Category
Cell Biology
Research subject
Bioinformatics
Identifiers
urn:nbn:se:his:diva-20931 (URN)10.3390/life12020293 (DOI)000763058200001 ()35207580 (PubMedID)2-s2.0-85125071986 (Scopus ID)
Funder
Knowledge Foundation, 20160294Knowledge Foundation, 20160330AstraZeneca
Note

CC BY 4.0

Correspondence: markus.johansson@his.se

This article belongs to the Special Issue The Molecular Mechanism of Cardiovascular Disease

This research was funded by the Systems Biology Research Centre at the University of Skövde under grants from the Knowledge Foundation (20160294, 20160330), Takara Bio Europe, Gothenburg, Sweden, and AstraZeneca R&D, Gothenburg.

Available from: 2022-02-22 Created: 2022-02-22 Last updated: 2023-02-21Bibliographically approved
Stefánsson, B. V., Heerspink, H. J. L., Wheeler, D. C., Sjöström, C. D., Greasley, P. J., Sartipy, P., . . . Correa-Rotter, R. (2021). Data from a pooled post hoc analysis of 14 placebo-controlled, dapagliflozin treatment studies in patients with type 2 diabetes with and without anemia at baseline. Data in Brief, 37, 1-11, Article ID 107237.
Open this publication in new window or tab >>Data from a pooled post hoc analysis of 14 placebo-controlled, dapagliflozin treatment studies in patients with type 2 diabetes with and without anemia at baseline
Show others...
2021 (English)In: Data in Brief, E-ISSN 2352-3409, Vol. 37, p. 1-11, article id 107237Article in journal (Refereed) Published
Abstract [en]

Dapagliflozin is a highly selective sodium-glucose cotransporter 2 inhibitor associated with stabilization of estimated glomerular filtration rate (eGFR); reductions in glycated hemoglobin (HbA1c), systolic blood pressure, body weight, and albuminuria; and a small and consistent increase in hematocrit [1–4]. This data set is based on the associated article [5] analyzing data from 5325 patients with type 2 diabetes from 14 placebo-controlled, phase 3 (one phase 2/3), double-blind dapagliflozin treatment studies of 24–104 weeks’ duration. Data on dapagliflozin's effects (vs. placebo) on hemoglobin (Hb), hematocrit, serum albumin, serum total protein concentrations, urine albumin/creatinine ratio, eGFR, heart rate, blood pressure, body weight, and safety in patients with type 2 diabetes with and without anemia were pooled and analyzed. Patients were divided into two groups according to baseline Hb levels: anemia (Hb <13 g/dL in men and <12 g/dL in women) and no anemia. Some biomarkers associated with erythropoiesis and the presence of anemia, such as iron, transferrin, ferritin, reticulocytes, and hepcidin, were not included in the original studies and therefore data for these biomarkers were not available. Descriptive statistics were used for baseline characteristics and safety data and a longitudinal repeated-measures mixed model for efficacy data. Changes in Hb concentrations were evaluated, and the proportion of patients with baseline anemia who were no longer anemic at week 24 was determined, as was the occurrence of polycythemia (Hb >16.5 g/dL in men and >16.0 g/dL in women). Because anemia commonly occurs in patients with diabetes and chronic kidney disease [6], the data can be of value to further analyze trends in relevant physiological and pathophysiological parameters.

Place, publisher, year, edition, pages
Elsevier, 2021
Keywords
Anemia, Chronic kidney disease, Dapagliflozin, eGFR, Hematocrit, Hemoglobin, SGLT2 inhibitor, Type 2 diabetes
National Category
Bioinformatics and Systems Biology
Research subject
Bioinformatics
Identifiers
urn:nbn:se:his:diva-20212 (URN)10.1016/j.dib.2021.107237 (DOI)000689359300003 ()34258337 (PubMedID)2-s2.0-85108879138 (Scopus ID)
Funder
AstraZeneca
Note

CC BY 4.0

Corresponding author: E-mail address: correarotter@gmail.com (R. Correa-Rotter).

Available from: 2021-07-08 Created: 2021-07-08 Last updated: 2021-10-26Bibliographically approved
Savarese, G., Bodegard, J., Norhammar, A., Sartipy, P., Thuresson, M., Cowie, M. R., . . . Coats, A. J. S. (2021). Heart failure drug titration, discontinuation, mortality and heart failure hospitalization risk: a multinational observational study (US, UK and Sweden). European Journal of Heart Failure, 23(9), 1499-1511
Open this publication in new window or tab >>Heart failure drug titration, discontinuation, mortality and heart failure hospitalization risk: a multinational observational study (US, UK and Sweden)
Show others...
2021 (English)In: European Journal of Heart Failure, ISSN 1388-9842, E-ISSN 1879-0844, Vol. 23, no 9, p. 1499-1511Article in journal (Refereed) Published
Abstract [en]

Aims: Use and dosing of guideline-directed medical therapy (GDMT) in patients with heart failure (HF) have been shown to be suboptimal. Among new users of GDMT in HF, we followed the real-life patterns of dose titration and discontinuation of angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), beta-blockers, mineralocorticoid receptor antagonists (MRA) and angiotensin receptor-neprilysin inhibitors (ARNI).

Methods and results: New users were identified in health care databases in Sweden, UK and US between 2016–2019. Inclusion criterion was a recent HF hospitalization (HHF) triggering the initiation of GDMT. Patients were grouped by GDMT, i.e. ACEi, ARB, beta-blocker, MRA and ARNI, and stratified by initial dose. Follow-up was 12 months, until death or study end. Outcomes were dose titration within each drug class, discontinuation and first HHF or death. Dose/discontinuation follow-up was assessed daily based on the coverage length of a filled prescription and reported on day 365. New users of ACEi (n = 8426), ARB (n = 2303), beta-blockers (n = 10 476), MRA (n = 17 421), and ARNI (n = 29 546) were identified. Over 12 months, target dose achievement was 15%, 10%, 12%, 30%, and discontinuation was 55%, 33%, 24% and 27% for ACEi, ARB, beta-blockers and ARNI, respectively. MRA was rarely titrated and discontinuation rates were high (40%). Event rates for HHF or death ranged from 40.0–86.9 per 100 patient-years across the treatment groups.

Conclusion: Despite high risk of clinical events following HHF, new initiation of GDMT was followed by consistent patterns of low up-titration and early GDMT discontinuation in three countries with different health care and economies. Our data highlight the urgent need for moving away from long sequential approach when initiating HF treatment and for improving just-in-time decision support for patients and health care providers.

Place, publisher, year, edition, pages
John Wiley & Sons, 2021
Keywords
Angiotensin receptor blocker, Angiotensin receptor–neprilysin inhibitor, Angiotensin-converting enzyme inhibitor, Beta-blocker, Guideline-directed medical therapy, Heart failure with reduced ejection fraction, Mineralocorticoid receptor antagonist
National Category
Bioinformatics and Systems Biology
Research subject
Bioinformatics
Identifiers
urn:nbn:se:his:diva-20214 (URN)10.1002/ejhf.2271 (DOI)000667516100001 ()34132001 (PubMedID)2-s2.0-85108824115 (Scopus ID)
Note

CC BY-NC 4.0

Corresponding author: Division of Cardiology, Department of Medicine, Karolinska Institutet, Norrbacka, S1:02, Karolinska University Hospital, Stockholm 171 76, Sweden. Tel: +46764165215, Email: gianluigi.savarese@ki.se

Available from: 2021-07-08 Created: 2021-07-08 Last updated: 2021-10-26Bibliographically approved
Ulfenborg, B., Karlsson, A., Riveiro, M., Andersson, C. X., Sartipy, P. & Synnergren, J. (2021). Multi-Assignment Clustering: Machine learning from a biological perspective. Journal of Biotechnology, 326, 1-10
Open this publication in new window or tab >>Multi-Assignment Clustering: Machine learning from a biological perspective
Show others...
2021 (English)In: Journal of Biotechnology, ISSN 0168-1656, E-ISSN 1873-4863, Vol. 326, p. 1-10Article in journal (Refereed) Published
Abstract [en]

A common approach for analyzing large-scale molecular data is to cluster objects sharing similar characteristics. This assumes that genes with highly similar expression profiles are likely participating in a common molecular process. Biological systems are extremely complex and challenging to understand, with proteins having multiple functions that sometimes need to be activated or expressed in a time-dependent manner. Thus, the strategies applied for clustering of these molecules into groups are of key importance for translation of data to biologically interpretable findings. Here we implemented a multi-assignment clustering (MAsC) approach that allows molecules to be assigned to multiple clusters, rather than single ones as in commonly used clustering techniques. When applied to high-throughput transcriptomics data, MAsC increased power of the downstream pathway analysis and allowed identification of pathways with high biological relevance to the experimental setting and the biological systems studied. Multi-assignment clustering also reduced noise in the clustering partition by excluding genes with a low correlation to all of the resulting clusters. Together, these findings suggest that our methodology facilitates translation of large-scale molecular data into biological knowledge. The method is made available as an R package on GitLab (https://gitlab.com/wolftower/masc).

Place, publisher, year, edition, pages
Elsevier, 2021
Keywords
Clustering, K-means, annotation enrichment, multiple cluster assignment, pathways, transcriptomics
National Category
Bioinformatics and Systems Biology
Research subject
Bioinformatics; Skövde Artificial Intelligence Lab (SAIL)
Identifiers
urn:nbn:se:his:diva-19329 (URN)10.1016/j.jbiotec.2020.12.002 (DOI)000616124700001 ()33285150 (PubMedID)2-s2.0-85097644109 (Scopus ID)
Note

CC BY 4.0

Available from: 2020-12-16 Created: 2020-12-16 Last updated: 2021-03-11Bibliographically approved
Correia, C., Wang, Q.-D., Linhardt, G., Carlsson, L. G., Ulfenborg, B., Walentinsson, A., . . . Synnergren, J. (2021). Unraveling the Metabolic Derangements Occurring in Non-infarcted Areas of Pig Hearts With Chronic Heart Failure. Frontiers in Cardiovascular Medicine, 8, Article ID 753470.
Open this publication in new window or tab >>Unraveling the Metabolic Derangements Occurring in Non-infarcted Areas of Pig Hearts With Chronic Heart Failure
Show others...
2021 (English)In: Frontiers in Cardiovascular Medicine, E-ISSN 2297-055X, Vol. 8, article id 753470Article in journal (Refereed) Published
Abstract [en]

Objective: After myocardial infarction (MI), the non-infarcted left ventricle (LV) ensures appropriate contractile function of the heart. Metabolic disturbance in this region greatly exacerbates post-MI heart failure (HF) pathology. This study aimed to provide a comprehensive understanding of the metabolic derangements occurring in the non-infarcted LV that could trigger cardiovascular deterioration. Methods and Results: We used a pig model that progressed into chronic HF over 3 months following MI induction. Integrated gene and metabolite signatures revealed region-specific perturbations in amino acid- and lipid metabolism, insulin signaling and, oxidative stress response. Remote LV, in particular, showed impaired glutamine and arginine metabolism, altered synthesis of lipids, glucose metabolism disorder, and increased insulin resistance. LPIN1, PPP1R3C, PTPN1, CREM, and NR0B2 were identified as the main effectors in metabolism dysregulation in the remote zone and were found differentially expressed also in the myocardium of patients with ischemic and/or dilated cardiomyopathy. In addition, a simultaneous significant decrease in arginine levels and altered PRCP, PTPN1, and ARF6 expression suggest alterations in vascular function in remote area. Conclusions: This study unravels an array of dysregulated genes and metabolites putatively involved in maladaptive metabolic and vascular remodeling in the non-infarcted myocardium and may contribute to the development of more precise therapies to mitigate progression of chronic HF post-MI.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2021
Keywords
chronic heart failure, decompensated heart failure, metabolome, myocardial infarction (MI), transcriptome (RNA-seq)
National Category
Cardiac and Cardiovascular Systems
Research subject
Bioinformatics
Identifiers
urn:nbn:se:his:diva-20688 (URN)10.3389/fcvm.2021.753470 (DOI)000713488600001 ()34722683 (PubMedID)
Funder
AstraZenecaKnowledge Foundation, 2014/301Knowledge Foundation, 2016/294Knowledge Foundation, 2016/330
Note

CC BY 4.0

Received: 04 August 2021. Accepted: 16 September 2021. Published: 13 October 2021 

Correspondence:

Cláudia Correia claudia.correia@astrazeneca.com

Jane Synnergren jane.synnergren@his.se

Funding: This work was supported by AstraZeneca and the University of Skövde, Sweden under grants from the Knowledge Foundation [2014/301, 2016/294, and 2016/330]. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.

Available from: 2021-11-04 Created: 2021-11-04 Last updated: 2023-01-23Bibliographically approved
Johansson, M., Ulfenborg, B., Andersson, C. X., Heydarkhan-Hagvall, S., Jeppsson, A., Sartipy, P. & Synnergren, J. (2020). Cardiac hypertrophy in a dish: a human stem cell based model. Biology open, 9(9), Article ID bio052381.
Open this publication in new window or tab >>Cardiac hypertrophy in a dish: a human stem cell based model
Show others...
2020 (English)In: Biology open, ISSN 2046-6390, Vol. 9, no 9, article id bio052381Article in journal (Refereed) Published
Abstract [en]

Cardiac hypertrophy is an important and independent risk factor for the development of heart failure. To better understand the mechanisms and regulatory pathways involved in cardiac hypertrophy, there is a need for improved in vitro models. In this study, we investigated how hypertrophic stimulation affected human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs). The cells were stimulated with endothelin-1 (ET-1) for 8, 24, 48, 72, or 96 h. Parameters including cell size, ANP-, proBNP-, and lactate concentration were analyzed. Moreover, transcriptional profiling using RNA-sequencing was performed to identify differentially expressed genes following ET-1 stimulation. The results show that the CMs increase in size by approximately 13% when exposed to ET-1 in parallel to increases in ANP and proBNP protein and mRNA levels. Furthermore, the lactate concentration in the media was increased indicating that the CMs consume more glucose, a hallmark of cardiac hypertrophy. Using RNA-seq, a hypertrophic gene expression pattern was also observed in the stimulated CMs. Taken together, these results show that hiPSC-derived CMs stimulated with ET-1 display a hypertrophic response. The results from this study also provide new molecular insights about the underlying mechanisms of cardiac hypertrophy and may help accelerate the development of new drugs against this condition.

Place, publisher, year, edition, pages
The Company of Biologists, 2020
Keywords
Cardiac hypertrophy, Cardiomyocytes, Disease model, Endothelin-1, Stem cells
National Category
Cell and Molecular Biology Cardiac and Cardiovascular Systems Physiology
Research subject
Bioinformatics
Identifiers
urn:nbn:se:his:diva-19131 (URN)10.1242/bio.052381 (DOI)000581926400005 ()32878883 (PubMedID)2-s2.0-85091406466 (Scopus ID)
Note

CC BY 4.0

Available from: 2020-10-01 Created: 2020-10-01 Last updated: 2022-12-28Bibliographically approved
Stefánsson, B. V., Heerspink, H. J. L., Wheeler, D. C., Sjöström, C. D., Greasley, P. J., Sartipy, P., . . . Correa-Rotter, R. (2020). Correction of anemia by dapagliflozin in patients with type 2 diabetes. Journal of diabetes and its complications, 34(12), Article ID 107729.
Open this publication in new window or tab >>Correction of anemia by dapagliflozin in patients with type 2 diabetes
Show others...
2020 (English)In: Journal of diabetes and its complications, ISSN 1056-8727, E-ISSN 1873-460X, Vol. 34, no 12, article id 107729Article in journal (Refereed) Published
Abstract [en]

Aims: Anemia is common in type 2 diabetes (T2D), particularly in patients with kidney impairment, and often goes unrecognized. Dapagliflozin treatment increases hemoglobin and serum erythropoietin levels. We investigated the effect of dapagliflozin 10-mg/day on hemoglobin in T2D patients with and without anemia. Methods: Data from 5325 patients from 14 placebo-controlled, dapagliflozin-treatment studies of at least 24-weeks duration were pooled. Dapagliflozin's effects (vs. placebo) on hemoglobin, serum albumin, estimated glomerular filtration rate (eGFR), systolic blood pressure, body weight, and safety in patients with and without anemia were evaluated. Results: At baseline, 13% of all T2D patients and 28% of those with chronic kidney disease (eGFR &lt;60 mL/min/1.73 m2) had anemia. Hemoglobin increased continuously to at least week 8 and was sustained throughout 24-weeks follow-up in dapagliflozin-treated patients. Serum albumin increased in dapagliflozin-treated patients at week 4 and remained stable thereafter. Dapagliflozin was well tolerated and corrected anemia in 52% of patients with anemia at baseline (placebo: 26%). Incidences of new-onset anemia were lower in dapagliflozin-treated (2.3%) versus placebo-treated (6.5%) patients. Conclusions: Treatment with dapagliflozin can correct and prevent anemia in T2D patients. A gradual increase in hemoglobin beyond week 4 may indicate an erythropoiesis-stimulating effect of sodium-glucose cotransporter 2 inhibition. 

Place, publisher, year, edition, pages
Elsevier, 2020
Keywords
Anemia, Chronic kidney disease, Dapagliflozin, Hemoglobin, Type 2 diabetes
National Category
Endocrinology and Diabetes
Research subject
Bioinformatics
Identifiers
urn:nbn:se:his:diva-19100 (URN)10.1016/j.jdiacomp.2020.107729 (DOI)000613521800008 ()32948397 (PubMedID)2-s2.0-85090988664 (Scopus ID)
Available from: 2020-09-24 Created: 2020-09-24 Last updated: 2021-02-22Bibliographically approved
Ghosheh, N., Küppers-Munther, B., Asplund, A., Andersson, C. X., Björquist, P., Andersson, T. B., . . . Synnergren, J. (2020). Human Pluripotent Stem Cell-Derived Hepatocytes Show Higher Transcriptional Correlation with Adult Liver Tissue than with Fetal Liver Tissue. ACS Omega, 5(10), 4816-4827
Open this publication in new window or tab >>Human Pluripotent Stem Cell-Derived Hepatocytes Show Higher Transcriptional Correlation with Adult Liver Tissue than with Fetal Liver Tissue
Show others...
2020 (English)In: ACS Omega, E-ISSN 2470-1343, Vol. 5, no 10, p. 4816-4827Article in journal (Refereed) Published
Abstract [en]

Human pluripotent stem cell-derived hepatocytes (hPSC-HEP) display many properties of mature hepatocytes, including expression of important genes of the drug metabolizing machinery, glycogen storage, and production of multiple serum proteins. To this date, hPSC-HEP do not, however, fully recapitulate the complete functionality of in vivo mature hepatocytes. In this study, we applied versatile bioinformatic algorithms, including functional annotation and pathway enrichment analyses, transcription factor binding-site enrichment, and similarity and correlation analyses, to datasets collected from different stages during hPSC-HEP differentiation and compared these to developmental stages and tissues from fetal and adult human liver. Our results demonstrate a high level of similarity between the in vitro differentiation of hPSC-HEP and in vivo hepatogenesis. Importantly, the transcriptional correlation of hPSC-HEP with adult liver (AL) tissues was higher than with fetal liver (FL) tissues (0.83 and 0.70, respectively). Functional data revealed mature features of hPSC-HEP including cytochrome P450 enzymes activities and albumin secretion. Moreover, hPSC-HEP showed expression of many genes involved in drug absorption, distribution, metabolism, and excretion. Despite the high similarities observed, we identified differences of specific pathways and regulatory players by analyzing the gene expression between hPSC-HEP and AL. These findings will aid future intervention and improvement of in vitro hepatocyte differentiation protocol in order to generate hepatocytes displaying the complete functionality of mature hepatocytes. Finally, on the transcriptional level, our results show stronger correlation and higher similarity of hPSC-HEP to AL than to FL. In addition, potential targets for further functional improvement of hPSC-HEP were also identified. 

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2020
National Category
Cell and Molecular Biology Gastroenterology and Hepatology Bioinformatics and Systems Biology
Research subject
Bioinformatics
Identifiers
urn:nbn:se:his:diva-18337 (URN)10.1021/acsomega.9b03514 (DOI)000520853400013 ()32201767 (PubMedID)2-s2.0-85081208923 (Scopus ID)
Note

CC BY-NC-ND 4.0

Available from: 2020-03-20 Created: 2020-03-20 Last updated: 2023-09-21Bibliographically approved
Scholtes, R. A., van Raalte, D. H., Correa-Rotter, R., Toto, R. D., Heerspink, H. J. L., Cain, V., . . . Stefánsson, B. V. (2020). The effects of dapagliflozin on cardio-renal risk factors in patients with type 2 diabetes with or without renin-angiotensin system inhibitor treatment: a post hoc analysis. Diabetes, obesity and metabolism, 22(4), 549-556
Open this publication in new window or tab >>The effects of dapagliflozin on cardio-renal risk factors in patients with type 2 diabetes with or without renin-angiotensin system inhibitor treatment: a post hoc analysis
Show others...
2020 (English)In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 22, no 4, p. 549-556Article in journal (Refereed) Published
Abstract [en]

Aims: Renin-angiotensin system inhibitors (RASi) are the most effective treatments for diabetic kidney disease but significant residual renal risk remains, possibly because of other mechanisms of kidney disease progression unrelated to RAS that may be present. Sodium-glucose co-transporter-2 inhibitors reduce albuminuria and may complement RASi by offering additional renal protection. This post hoc analysis investigated the effects of dapagliflozin on cardio-renal risk factors in patients with type 2 diabetes (T2D) with increased albuminuria treated with or without RASi at baseline. Materials and methods: We evaluated the effects of dapagliflozin 10 mg/day over 12–24 weeks across 13 placebo-controlled studies in patients with T2D with a urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g at baseline. Patients were divided into two subgroups based on treatment with or without RASi at baseline. Results: Compared with patients with RASi at baseline (n = 957), patients without RASi (n = 302) were younger, had a shorter duration of diabetes (7 vs. 12 years), higher estimated glomerular filtration rate (eGFR) and lower UACR, serum uric acid (sUA), body weight and systolic blood pressure. Placebo-adjusted treatment effects of dapagliflozin on UACR, eGFR, glycated haemoglobin and haematocrit over 24 weeks were similar across groups. Mean reductions in body weight and sUA were more distinct in patients without RASi treatment at baseline. Conclusions: Treatment with dapagliflozin over 24 weeks provides similar clinically relevant improvements in metabolic and haemodynamic parameters, and similar reductions in UACR, in patients with T2D with elevated albuminuria treated with or without RASi at baseline. © 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Place, publisher, year, edition, pages
John Wiley & Sons, 2020
Keywords
cardiac and renal risk factors, dapagliflozin, RASi, SGLT-2 inhibitors, type 2 diabetes
National Category
Endocrinology and Diabetes Cardiac and Cardiovascular Systems
Research subject
Bioinformatics
Identifiers
urn:nbn:se:his:diva-18057 (URN)10.1111/dom.13923 (DOI)000518560300009 ()31742881 (PubMedID)2-s2.0-85076732648 (Scopus ID)
Note

CC BY-NC-ND 4.0

Available from: 2020-01-02 Created: 2020-01-02 Last updated: 2023-09-21Bibliographically approved
Organisations

Search in DiVA

Show all publications