Chemical Enhancement of Direct Cardiac Reprogramming In Vitro and In Vivo
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: GSE81809
PROVIDER: PRJNA322596 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3578680.fastq.gz | Fastqsanger.gz | |||
| SRR3578690.fastq.gz | Fastqsanger.gz | |||
| SRR3578700.fastq.gz | Fastqsanger.gz | |||
| SRR3578710.fastq.gz | Fastqsanger.gz | |||
| SRR3578720.fastq.gz | Fastqsanger.gz |
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Project description:Reprogramming of cardiac fibroblasts into induced cardiomyocyte-like cells (iCMs) in situ represents a promising strategy for cardiac regeneration. A combination of three cardiac transcription factors, Gata4, Mef2c and Tbx5 (GMT), can convert fibroblasts into iCMs, albeit with low efficiency in vitro. Here, we screened 5,500 compounds in primary cardiac fibroblasts and found that a combination of the transforming growth factor (TGF)-β inhibitor SB431542 and the WNT inhibitor XAV939 increased reprogramming efficiency eight-fold when added to GMT-overexpressing cardiac fibroblasts. The small-molecules also enhanced the speed and the quality of cell conversion, as we observed beating cells as early as 1 week after reprogramming compared to 6–8 weeks with GMT alone. In vivo, mice exposed to GMT, SB431542, and XAV939 for 2 weeks after myocardial infarction showed significantly improved reprogramming and cardiac function compared to those exposed to only GMT. Human cardiac reprogramming was similarly enhanced upon TGF-b and WNT inhibition and was achieved most efficiently with GMT plus Myocardin. Thus, TGF-β and WNT inhibitors jointly enhance GMT-induced direct cardiac reprogramming from cardiac fibroblasts in vitro and in vivo and provide a more robust platform for cardiac regeneration.
2016-10-25 | GSE81809 | GEO
Project description:BackgroundReprogramming of cardiac fibroblasts into induced cardiomyocyte-like cells in situ represents a promising strategy for cardiac regeneration. A combination of 3 cardiac transcription factors, Gata4, Mef2c, and Tbx5 (GMT), can convert fibroblasts into induced cardiomyocyte-like cells, albeit with low efficiency in vitro.MethodsWe screened 5500 compounds in primary cardiac fibroblasts to identify the pathways that can be modulated to enhance cardiomyocyte reprogramming.ResultsWe found that a combination of the transforming growth factor-β inhibitor SB431542 and the WNT inhibitor XAV939 increased reprogramming efficiency 8-fold when added to GMT-overexpressing cardiac fibroblasts. The small molecules also enhanced the speed and quality of cell conversion; we observed beating cells as early as 1 week after reprogramming compared with 6 to 8 weeks with GMT alone. In vivo, mice exposed to GMT, SB431542, and XAV939 for 2 weeks after myocardial infarction showed significantly improved reprogramming and cardiac function compared with those exposed to only GMT. Human cardiac reprogramming was similarly enhanced on transforming growth factor-β and WNT inhibition and was achieved most efficiently with GMT plus myocardin.ConclusionsTransforming growth factor-β and WNT inhibitors jointly enhance GMT-induced direct cardiac reprogramming from cardiac fibroblasts in vitro and in vivo and provide a more robust platform for cardiac regeneration.
| S-EPMC5340593 | biostudies-literature
Project description:The direct conversion, or trans-differentiation, of non-cardiac cells into cardiomyocytes by forced expression of transcription factors and microRNAs provide promising ways of cardiac regeneration. However, genetic manipulations are still not desirable in real clinical applications. we report the generation of automatically beating cardiomyocyte-like cells from mouse fibroblasts with only chemical cocktails. These chemical-induced cardiomyocyte-like cells (CiCMs) express cardiomyocyte-specific markers, exhibit sarcomeric organization, and possess typical cardiac calcium flux and electrophysiological features. Microarray-bassed gene expression patterns of Mouse embryonic fibroblasts (MEFs), CiCMs, and cardiomyocytes(CMs) indicated a clear transition from dividing MEFs to differentiated cardiomyocyte-like state in CiCM samples. Mouse embryonic fibroblasts were treated with a small-molecule combination CRFVPT (10 μM CHIR99021 (C); 10 μM RepSox (R); 50 μM Forskolin (F); 0.5 mM VPA (V); 5 μM Parnate, (P); 1 μM TTNPB (T)) to induce transdifferentiation to chemical-induced cardiomyocyte-like cells. CiCMs beating clusters were picked at day 24 for analysis. MEFs were isolated from mouse embryos, and CMs were isolated from mouse hearts. Total RNA of MEFs, CiCMs and CMs were extracted and hybridization on Affymetrix microarrays.
2015-08-23 | E-GEOD-69924 | biostudies-arrayexpress
Project description:Pseudouridine-chemical probes-Nanopore direct RNA sequencing
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Project description:The direct conversion, or trans-differentiation, of non-cardiac cells into cardiomyocytes by forced expression of transcription factors and microRNAs provide promising ways of cardiac regeneration. However, genetic manipulations are still not desirable in real clinical applications. we report the generation of automatically beating cardiomyocyte-like cells from mouse fibroblasts with only chemical cocktails. These chemical-induced cardiomyocyte-like cells (CiCMs) express cardiomyocyte-specific markers, exhibit sarcomeric organization, and possess typical cardiac calcium flux and electrophysiological features. Microarray-bassed gene expression patterns of Mouse embryonic fibroblasts (MEFs), CiCMs, and cardiomyocytes(CMs) indicated a clear transition from dividing MEFs to differentiated cardiomyocyte-like state in CiCM samples.
2015-08-23 | GSE69924 | GEO
Project description:Chemical Pretreatment Activated a Plastic State Amenable to Direct Lineage Reprogramming
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Project description:Repopulation of the injured heart with new, functional cardiomyocytes remains a daunting challenge for cardiac regenerative medicine. An ideal therapeutic approach would involve an effective method at achieving direct conversion of injured areas to functional tissue in situ.The aim of this study was to develop a strategy that identified and evaluated the potential of specific micro (mi)RNAs capable of inducing reprogramming of cardiac fibroblasts directly to cardiomyocytes in vitro and in vivo.Using a combinatorial strategy, we identified a combination of miRNAs 1, 133, 208, and 499 capable of inducing direct cellular reprogramming of fibroblasts to cardiomyocyte-like cells in vitro. Detailed studies of the reprogrammed cells demonstrated that a single transient transfection of the miRNAs can direct a switch in cell fate as documented by expression of mature cardiomyocyte markers, sarcomeric organization, and exhibition of spontaneous calcium flux characteristic of a cardiomyocyte-like phenotype. Interestingly, we also found that miRNA-mediated reprogramming was enhanced 10-fold on JAK inhibitor I treatment. Importantly, administration of miRNAs into ischemic mouse myocardium resulted in evidence of direct conversion of cardiac fibroblasts to cardiomyocytes in situ. Genetic tracing analysis using Fsp1Cre-traced fibroblasts from both cardiac and noncardiac cell sources strongly suggests that induced cells are most likely of fibroblastic origin.The findings from this study provide proof-of-concept that miRNAs have the capability of directly converting fibroblasts to a cardiomyocyte-like phenotype in vitro. Also of significance is that this is the first report of direct cardiac reprogramming in vivo. Our approach may have broad and important implications for therapeutic tissue regeneration in general.
| S-EPMC3380624 | biostudies-literature
Project description:We established a chemical cocktail that converts astrocytes into neuronal-like cells in vitro.
2021-01-08 | GSE164421 | GEO
Project description:Enhancement of direct reprogramming from fibroblasts to epithelial lineages by OVOL2-induced mesenchymal-to-epithelial transition
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Project description:Ischemic stroke causes extensive neuronal cell death. Antithrombotic agents and rehabilitation are the primary treatment options but have limited efficacy. Therefore, to achieve radical neurological improvement, practical neuroregenerative technologies must be developed. Recently, direct chemical reprogramming using small molecules to transdifferentiate somatic cells into neurons has garnered much attention. We investigated the possibility of applying this technology for the treatment of ischemic stroke. During the acute phase of ischemic stroke, circulating monocytes increase chemotaxis and accumulate in the infarct area through the disrupted blood-brain barrier, where they differentiate into macrophages involved in inflammation and remodeling. Direct reprogramming of these monocyte-derived macrophages into neuronal cells in vivo is theoretically possible with the administration of small-molecule drugs. However, the efficacy of this neuroregenerative therapy cannot be verified because the optimal chemical compounds that convert macrophages into neurons have not yet been identified.
2022-10-05 | GSE214644 | GEO