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Article: Genome-wide profiling of miRNA-gene regulatory networks in mouse postnatal heart development-implications for cardiac regeneration.

Chaudhari, Umesh / Pohjolainen, Lotta / Ruskoaho, Heikki / Talman, Virpi

2023 Volume 10, Page(s) 1148618

Abstract: Background: After birth, mammalian cardiomyocytes substantially lose proliferative capacity with a concomitant switch from glycolytic to oxidative mitochondrial energy metabolism. Micro-RNAs (miRNAs) regulate gene expression and thus control various ... ...

Abstract	Background: After birth, mammalian cardiomyocytes substantially lose proliferative capacity with a concomitant switch from glycolytic to oxidative mitochondrial energy metabolism. Micro-RNAs (miRNAs) regulate gene expression and thus control various cellular processes. Their roles in the postnatal loss of cardiac regeneration are however still largely unclear. Here, we aimed to identify miRNA-gene regulatory networks in the neonatal heart to uncover role of miRNAs in regulation of cell cycle and metabolism. Methods and results: We performed global miRNA expression profiling using total RNA extracted from mouse ventricular tissue samples collected on postnatal day 1 (P01), P04, P09, and P23. We used the miRWalk database to predict the potential target genes of differentially expressed miRNAs and our previously published mRNA transcriptomics data to identify verified target genes that showed a concomitant differential expression in the neonatal heart. We then analyzed the biological functions of the identified miRNA-gene regulatory networks using enriched Gene Ontology (GO) and KEGG pathway analyses. Altogether 46 miRNAs were differentially expressed in the distinct stages of neonatal heart development. For twenty miRNAs, up- or downregulation took place within the first 9 postnatal days thus correlating temporally with the loss of cardiac regeneration. Importantly, for several miRNAs, including miR-150-5p, miR-484, and miR-210-3p there are no previous reports about their role in cardiac development or disease. The miRNA-gene regulatory networks of upregulated miRNAs negatively regulated biological processes and KEGG pathways related to cell proliferation, while downregulated miRNAs positively regulated biological processes and KEGG pathways associated with activation of mitochondrial metabolism and developmental hypertrophic growth. Conclusion: This study reports miRNAs and miRNA-gene regulatory networks with no previously described role in cardiac development or disease. These findings may help in elucidating regulatory mechanism of cardiac regeneration and in the development of regenerative therapies.
Language	English
Publishing date	2023-05-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2781496-8
ISSN	2297-055X
ISSN	2297-055X
DOI	10.3389/fcvm.2023.1148618
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Article ; Online: TAF1 bromodomain inhibition as a candidate epigenetic driver of congenital heart disease.

Leigh, Robert S / Välimäki, Mika J / Kaynak, Bogac L / Ruskoaho, Heikki J

Biochimica et biophysica acta. Molecular basis of disease

2023 Volume 1869, Issue 5, Page(s) 166689

Abstract: Heart formation requires transcriptional regulators that underlie congenital anomalies and the fetal gene program activated during heart failure. Attributing the effects of congenital heart disease (CHD) missense variants to disruption of specific ... ...

Abstract	Heart formation requires transcriptional regulators that underlie congenital anomalies and the fetal gene program activated during heart failure. Attributing the effects of congenital heart disease (CHD) missense variants to disruption of specific protein domains allows for a mechanistic understanding of CHDs and improved diagnostics. A combined chemical and genetic approach was employed to identify novel CHD drivers, consisting of chemical screening during pluripotent stem cell (PSC) differentiation, gene expression analyses of native tissues and primary cell culture models, and the in vitro study of damaging missense variants from CHD patients. An epigenetic inhibitor of the TATA-Box Binding Protein Associated Factor 1 (TAF1) bromodomain was uncovered in an unbiased chemical screen for activators of atrial and ventricular fetal myosins in differentiating PSCs, leading to the development of a high affinity inhibitor (5.1 nM) of the TAF1 bromodomain, a component of the TFIID complex. TAF1 bromodomain inhibitors were tested for their effects on stem cell viability and cardiomyocyte differentiation, implicating a role for TAF1 in cardiogenesis. Damaging TAF1 missense variants from CHD patients were studied by mutational analysis of the TAF1 bromodomain, demonstrating a repressive role of TAF1 that can be abrogated by the introduction of damaging bromodomain variants or chemical TAF1 bromodomain inhibition. These results indicate that targeting the TAF1/TFIID complex with chemical compounds modulates cardiac transcription and identify an epigenetically-driven CHD mechanism due to damaging variants within the TAF1 bromodomain.
MeSH term(s)	Humans ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Protein Domains ; Nuclear Proteins/metabolism ; Transcription Factor TFIID/genetics ; Transcription Factor TFIID/metabolism ; Heart Defects, Congenital/genetics ; Epigenesis, Genetic
Chemical Substances	Transcription Factors ; Nuclear Proteins ; Transcription Factor TFIID
Language	English
Publishing date	2023-03-21
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-260X ; 1879-2596 ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-260X ; 1879-2596 ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbadis.2023.166689
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Article ; Online: Affinity chromatography reveals direct binding of the GATA4-NKX2-5 interaction inhibitor (3i-1000) with GATA4.

Jumppanen, Mikael / Kinnunen, Sini M / Zore, Matej / Välimäki, Mika J / Talman, Virpi / Gennäs, Gustav Boije Af / Ruskoaho, Heikki J / Yli-Kauhaluoma, Jari

Scientific reports

2024 Volume 14, Issue 1, Page(s) 8938

Abstract: Heart failure is a serious medical condition with a poor prognosis. Current treatments can only help manage the symptoms and slow the progression of heart failure. However, there is currently no cure to prevent and reverse cardiac remodeling. ... ...

Abstract	Heart failure is a serious medical condition with a poor prognosis. Current treatments can only help manage the symptoms and slow the progression of heart failure. However, there is currently no cure to prevent and reverse cardiac remodeling. Transcription factors are in a central role in various cellular processes, and in the heart, GATA4 and NKX2-5 transcription factors mediate hypertrophic responses and remodeling. We have identified compounds that modulate the synergistic interaction of GATA4 and NKX2-5 and shown that the most promising compound (1, 3i-1000) is cardioprotective in vitro and in vivo. However, direct evidence of its binding site and mechanism of action has not been available. Due to the disordered nature of transcription factors, classical target engagement approaches cannot be utilized. Here, we synthesized a small-molecule ligand-binding pulldown probe of compound 1 to utilize affinity chromatography alongside CETSA, AlphaScreen, and molecular modeling to study ligand binding. These results provide the first evidence of direct physical binding of compound 1 selectively to GATA4. While developing drugs that target transcription factors presents challenges, advances in technologies and knowledge of intrinsically disordered proteins enable the identification of small molecules that can selectively target transcription factors.
MeSH term(s)	Humans ; Homeobox Protein Nkx-2.5/metabolism ; Ligands ; Transcription Factors/metabolism ; Heart Failure ; Chromatography, Affinity ; GATA4 Transcription Factor/metabolism ; Homeodomain Proteins/metabolism
Chemical Substances	Homeobox Protein Nkx-2.5 ; Ligands ; Transcription Factors ; GATA4 Transcription Factor ; Homeodomain Proteins ; NKX2-5 protein, human ; GATA4 protein, human
Language	English
Publishing date	2024-04-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-024-59418-4
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Article ; Online: Targeting GATA4 for cardiac repair.

Välimäki, Mika J / Ruskoaho, Heikki J

IUBMB life

2019 Volume 72, Issue 1, Page(s) 68–79

Abstract: Various strategies have been applied to replace the loss of cardiomyocytes in order to restore reduced cardiac function and prevent the progression of heart disease. Intensive research efforts in the field of cellular reprogramming and cell ... ...

Abstract	Various strategies have been applied to replace the loss of cardiomyocytes in order to restore reduced cardiac function and prevent the progression of heart disease. Intensive research efforts in the field of cellular reprogramming and cell transplantation may eventually lead to efficient in vivo applications for the treatment of cardiac injuries, representing a novel treatment strategy for regenerative medicine. Modulation of cardiac transcription factor (TF) networks by chemical entities represents another viable option for therapeutic interventions. Comprehensive screening projects have revealed a number of molecular entities acting on molecular pathways highly critical for cellular lineage commitment and differentiation, including compounds targeting Wnt- and transforming growth factor beta (TGFβ)-signaling. Furthermore, previous studies have demonstrated that GATA4 and NKX2-5 are essential TFs in gene regulation of cardiac development and hypertrophy. For example, both of these TFs are required to fully activate mechanical stretch-responsive genes such as atrial natriuretic peptide and brain natriuretic peptide (BNP). We have previously reported that the compound 3i-1000 efficiently inhibited the synergy of the GATA4-NKX2-5 interaction. Cellular effects of 3i-1000 have been further characterized in a number of confirmatory in vitro bioassays, including rat cardiac myocytes and animal models of ischemic injury and angiotensin II-induced pressure overload, suggesting the potential for small molecule-induced cardioprotection.
MeSH term(s)	Animals ; Embryonic Development ; GATA4 Transcription Factor/genetics ; GATA4 Transcription Factor/metabolism ; Gene Expression Regulation, Developmental ; Heart/embryology ; Humans ; Organogenesis ; Signal Transduction
Chemical Substances	GATA4 Transcription Factor
Language	English
Publishing date	2019-08-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1492141-8
ISSN	1521-6551 ; 1521-6543
ISSN (online)	1521-6551
ISSN	1521-6543
DOI	10.1002/iub.2150
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Article ; Online: Distinct Regulation of Cardiac Fibroblast Proliferation and Transdifferentiation by Classical and Novel Protein Kinase C Isoforms: Possible Implications for New Antifibrotic Therapies.

Karhu, S Tuuli / Ruskoaho, Heikki / Talman, Virpi

Molecular pharmacology

2020 Volume 99, Issue 2, Page(s) 104–113

Abstract: Cardiac fibrosis is characterized by accumulation and activation of fibroblasts and excessive production of extracellular matrix, which results in myocardial stiffening and eventually leads to heart failure. Although previous work suggests that protein ... ...

Abstract	Cardiac fibrosis is characterized by accumulation and activation of fibroblasts and excessive production of extracellular matrix, which results in myocardial stiffening and eventually leads to heart failure. Although previous work suggests that protein kinase C (PKC) isoforms play a role in cardiac fibrosis and remodeling, the results are conflicting. Moreover, the potential of targeting PKC with pharmacological tools to inhibit pathologic fibrosis has not been fully evaluated. Here we investigated the effects of selected PKC agonists and inhibitors on cardiac fibroblast (CF) phenotype, proliferation, and gene expression using primary adult mouse CFs, which spontaneously transdifferentiate into myofibroblasts in culture. A 48-hour exposure to the potent PKC activator phorbol 12-myristate 13-acetate (PMA) at 10 nM concentration reduced the intensity of
MeSH term(s)	Actins/metabolism ; Animals ; Carbazoles/pharmacology ; Cell Adhesion Molecules/genetics ; Cell Proliferation/drug effects ; Cell Transdifferentiation/drug effects ; Cells, Cultured ; Female ; Fibroblasts/cytology ; Fibroblasts/metabolism ; Fibroblasts/pathology ; Fibrosis ; Humans ; Indoles/pharmacology ; Maleimides/pharmacology ; Mice ; Myocardium/cytology ; Myocardium/metabolism ; Myocardium/pathology ; Myofibroblasts/cytology ; Myofibroblasts/drug effects ; Myofibroblasts/metabolism ; Primary Cell Culture ; Protein Kinase C/antagonists & inhibitors ; Protein Kinase C/metabolism ; Tetradecanoylphorbol Acetate/pharmacology
Chemical Substances	2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide ; Acta2 protein, mouse ; Actins ; Carbazoles ; Cell Adhesion Molecules ; Indoles ; Maleimides ; Postn protein, mouse ; Go 6976 (136194-77-9) ; Protein Kinase C (EC 2.7.11.13) ; Tetradecanoylphorbol Acetate (NI40JAQ945)
Language	English
Publishing date	2020-11-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	124034-1
ISSN	1521-0111 ; 0026-895X
ISSN (online)	1521-0111
ISSN	0026-895X
DOI	10.1124/molpharm.120.000094
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Article ; Online: Cholecystokinin peptide signaling is regulated by a TBX5-MEF2 axis in the heart.

Leigh, Robert S / Ruskoaho, Heikki J / Kaynak, Bogac L

Peptides

2020 Volume 136, Page(s) 170459

Abstract: The procholecystokinin (proCCK) gene encodes a secreted peptide known to regulate the digestive, endocrine, and nervous systems. Though recently proposed as a biomarker for heart dysfunction, its physiological role in both the embryonic and adult heart ... ...

Abstract	The procholecystokinin (proCCK) gene encodes a secreted peptide known to regulate the digestive, endocrine, and nervous systems. Though recently proposed as a biomarker for heart dysfunction, its physiological role in both the embryonic and adult heart is poorly understood, and there are no reports of tissue-specific regulators of cholecystokinin signaling in the heart or other tissues. In the present study, mRNA of proCCK was observed in cardiac tissues during mouse embryonic development, establishing proCCK as an early marker of differentiated cardiomyocytes which is later restricted to anatomical subdomains of the neonatal heart. Three-dimensional analysis of the expression of proCCK and CCKAR/CCKBR receptors was performed using in situ hybridization and optical projection tomography, illustrating chamber-specific expression patterns in the postnatal heart. Transcription factor motif analyses indicated developmental cardiac transcription factors TBX5 and MEF2C as upstream regulators of proCCK, and this regulatory activity was confirmed in reporter gene assays. proCCK mRNA levels were also measured in the infarcted heart and in response to cyclic mechanical stretch and endothelin-1, indicating dynamic transcriptional regulation which might be leveraged for improved biomarker development. Functional analyses of exogenous cholecystokinin octapeptide (CCK-8) administration were performed in differentiating mouse embryonic stem cells (mESCs), and the results suggest that CCK-8 does not act as a differentiation modulator of cardiomyocyte subtypes. Collectively, these findings indicate that proCCK is regulated at the transcriptional level by TBX5-MEF2 and neurohormonal signaling, informing use of proCCK as a biomarker and future strategies for upstream manipulation of cholecystokinin signaling in the heart and other tissues.
MeSH term(s)	Animals ; Cell Differentiation/genetics ; Cholecystokinin/genetics ; Embryonic Development/genetics ; Female ; Gene Expression Regulation, Developmental ; Heart/growth & development ; MEF2 Transcription Factors/genetics ; Mice ; Mouse Embryonic Stem Cells ; Peptides/genetics ; Pregnancy ; Signal Transduction/genetics ; T-Box Domain Proteins/genetics
Chemical Substances	MEF2 Transcription Factors ; Peptides ; T-Box Domain Proteins ; T-box transcription factor 5 ; Cholecystokinin (9011-97-6)
Language	English
Publishing date	2020-11-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	769028-9
ISSN	1873-5169 ; 0196-9781
ISSN (online)	1873-5169
ISSN	0196-9781
DOI	10.1016/j.peptides.2020.170459
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Article: Pharmacological Protein Kinase C Modulators Reveal a Pro-hypertrophic Role for Novel Protein Kinase C Isoforms in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Pohjolainen, Lotta / Easton, Julia / Solanki, Reesha / Ruskoaho, Heikki / Talman, Virpi

Frontiers in pharmacology

2021 Volume 11, Page(s) 553852

Abstract: Background: ...

Abstract	Background:
Language	English
Publishing date	2021-01-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2020.553852
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Article: Cholecystokinin peptide signaling is regulated by a TBX5-MEF2 axis in the heart

Leigh, Robert S / Ruskoaho, Heikki J / Kaynak, Bogac L

Peptides. 2021 Feb., v. 136

2021

Abstract	The procholecystokinin (proCCK) gene encodes a secreted peptide known to regulate the digestive, endocrine, and nervous systems. Though recently proposed as a biomarker for heart dysfunction, its physiological role in both the embryonic and adult heart is poorly understood, and there are no reports of tissue-specific regulators of cholecystokinin signaling in the heart or other tissues. In the present study, mRNA of proCCK was observed in cardiac tissues during mouse embryonic development, establishing proCCK as an early marker of differentiated cardiomyocytes which is later restricted to anatomical subdomains of the neonatal heart. Three-dimensional analysis of the expression of proCCK and CCKAR/CCKBR receptors was performed using in situ hybridization and optical projection tomography, illustrating chamber-specific expression patterns in the postnatal heart. Transcription factor motif analyses indicated developmental cardiac transcription factors TBX5 and MEF2C as upstream regulators of proCCK, and this regulatory activity was confirmed in reporter gene assays. proCCK mRNA levels were also measured in the infarcted heart and in response to cyclic mechanical stretch and endothelin-1, indicating dynamic transcriptional regulation which might be leveraged for improved biomarker development. Functional analyses of exogenous cholecystokinin octapeptide (CCK-8) administration were performed in differentiating mouse embryonic stem cells (mESCs), and the results suggest that CCK-8 does not act as a differentiation modulator of cardiomyocyte subtypes. Collectively, these findings indicate that proCCK is regulated at the transcriptional level by TBX5-MEF2 and neurohormonal signaling, informing use of proCCK as a biomarker and future strategies for upstream manipulation of cholecystokinin signaling in the heart and other tissues.
Keywords	adults ; biomarkers ; cardiomyocytes ; cholecystokinin ; embryogenesis ; endothelins ; hybridization ; mice ; reporter genes ; tomography ; transcription (genetics) ; transcription factors
Language	English
Dates of publication	2021-02
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	769028-9
ISSN	1873-5169 ; 0196-9781
ISSN (online)	1873-5169
ISSN	0196-9781
DOI	10.1016/j.peptides.2020.170459
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Article ; Online: Switching of hypertrophic signalling towards enhanced cardiomyocyte identity and maturity by a GATA4-targeted compound.

Pohjolainen, Lotta / Kinnunen, Sini M / Auno, Samuli / Kiriazis, Alexandros / Pohjavaara, Saana / Kari-Koskinen, Julia / Zore, Matej / Jumppanen, Mikael / Yli-Kauhaluoma, Jari / Talman, Virpi / Ruskoaho, Heikki / Välimäki, Mika J

Stem cell research & therapy

2024 Volume 15, Issue 1, Page(s) 5

Abstract: Background: The prevalence of heart failure is constantly increasing, and the prognosis of patients remains poor. New treatment strategies to preserve cardiac function and limit cardiac hypertrophy are therefore urgently needed. Human induced ... ...

Abstract	Background: The prevalence of heart failure is constantly increasing, and the prognosis of patients remains poor. New treatment strategies to preserve cardiac function and limit cardiac hypertrophy are therefore urgently needed. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are increasingly used as an experimental platform for cardiac in vitro studies. However, in contrast to adult cardiomyocytes, hiPSC-CMs display immature morphology, contractility, gene expression and metabolism and hence express a naive phenotype that resembles more of a foetal cardiomyocyte. Methods: A library of 14 novel compounds was synthesized in-house and screened for GATA4-NKX2-5 reporter activity and cellular toxicity. The most potent compound, 3i-1262, along with previously reported GATA4-acting compounds, were selected to investigate their effects on hypertrophy induced by endothelin-1 or mechanical stretch. Morphological changes and protein expression were characterized using immunofluorescence staining and high-content analysis. Changes in gene expression were studied using qPCR and RNA sequencing. Results: The prototype compound 3i-1262 inhibited GATA4-NKX2-5 synergy in a luciferase reporter assay. Additionally, the isoxazole compound 3i-1262 inhibited the hypertrophy biomarker B-type natriuretic peptide (BNP) by reducing BNP promoter activity and proBNP expression in neonatal rat ventricular myocytes and hiPSC-CMs, respectively. Treatment with 3i-1262 increased metabolic activity and cardiac troponin T expression in hiPSC-CMs without affecting GATA4 protein levels. RNA sequencing analysis revealed that 3i-1262 induces gene expression related to metabolic activity and cell cycle exit, indicating a change in the identity and maturity status of hiPSC-CMs. The biological processes that were enriched in upregulated genes in response to 3i-1262 were downregulated in response to mechanical stretch, and conversely, the downregulated processes in response to 3i-1262 were upregulated in response to mechanical stretch. Conclusions: There is currently a lack of systematic understanding of the molecular modulation and control of hiPSC-CM maturation. In this study, we demonstrated that the GATA4-interfering compound 3i-1262 reorganizes the cardiac transcription factor network and converts hypertrophic signalling towards enhanced cardiomyocyte identity and maturity. This conceptually unique approach provides a novel structural scaffold for further development as a modality to promote cardiomyocyte specification and maturity.
MeSH term(s)	Humans ; Rats ; Animals ; Myocytes, Cardiac/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Hypertrophy/metabolism ; Transcription Factors/metabolism ; Signal Transduction ; GATA4 Transcription Factor/genetics ; GATA4 Transcription Factor/metabolism
Chemical Substances	Transcription Factors ; GATA4 protein, human ; GATA4 Transcription Factor
Language	English
Publishing date	2024-01-02
Publishing country	England
Document type	Journal Article
ZDB-ID	2548671-8
ISSN	1757-6512 ; 1757-6512
ISSN (online)	1757-6512
ISSN	1757-6512
DOI	10.1186/s13287-023-03623-x
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Article ; Online: A novel dual reporter embryonic stem cell line for toxicological assessment of teratogen-induced perturbation of anterior-posterior patterning of the heart.

Leigh, Robert S / Ruskoaho, Heikki J / Kaynak, Bogac L

Archives of toxicology

2019 Volume 94, Issue 2, Page(s) 631–645

Abstract: Reliable in vitro models to assess developmental toxicity of drugs and chemicals would lead to improvement in fetal safety and a reduced cost of drug development. The validated embryonic stem cell test (EST) uses cardiac differentiation of mouse ... ...

Abstract	Reliable in vitro models to assess developmental toxicity of drugs and chemicals would lead to improvement in fetal safety and a reduced cost of drug development. The validated embryonic stem cell test (EST) uses cardiac differentiation of mouse embryonic stem cells (mESCs) to predict in vivo developmental toxicity, but does not take into account the stage-specific patterning of progenitor populations into anterior (ventricular) and posterior (atrial) compartments. In this study, we generated a novel dual reporter mESC line with fluorescent reporters under the control of anterior and posterior cardiac promoters. Reporter expression was observed in nascent compartments in transgenic mouse embryos, and mESCs were used to develop differentiation assays in which chemical modulators of Wnt (XAV939: 3, 10 µM), retinoic acid (all-trans retinoic acid: 0.1, 1, 10 µM; 9-cis retinoic acid: 0.1, 1, 10 µM; bexarotene 0.1, 1, 10 µM), and Tgf-β (SB431542: 3, 10 µM) pathways were tested for stage- and dose-dependent effects on in vitro anterior-posterior patterning. Our results suggest that with further development, the inclusion of anterior-posterior reporter expression could be part of a battery of high-throughput tests used to identify and characterize teratogens.
MeSH term(s)	Animals ; Body Patterning/drug effects ; Cell Differentiation/drug effects ; Cell Differentiation/genetics ; Cell Line ; Female ; Gene Editing ; Gene Expression Regulation, Developmental ; Genes, Reporter ; Green Fluorescent Proteins/genetics ; Heart/drug effects ; Heart/embryology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mouse Embryonic Stem Cells/cytology ; Myocytes, Cardiac/cytology ; Myosin Light Chains/genetics ; Pregnancy ; Retinoids/pharmacology ; Teratogens/toxicity ; Toxicity Tests/methods
Chemical Substances	Myosin Light Chains ; Retinoids ; Teratogens ; Green Fluorescent Proteins (147336-22-9)
Language	English
Publishing date	2019-12-06
Publishing country	Germany
Document type	Journal Article
ZDB-ID	124992-7
ISSN	1432-0738 ; 0340-5761
ISSN (online)	1432-0738
ISSN	0340-5761
DOI	10.1007/s00204-019-02632-1
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