In vivo cardiac reprogramming by delivery of PHF7
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PROVIDER: PRJNA1126099 | ENA |
REPOSITORIES: ENA
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Project description:Cellular reprogramming of cardiac fibroblasts to cardiomyocytes following myocardial infarction (MI) is an attractive strategy to redirect the fibrotic response of the non-regenerative adult heart to a more functional myocardium. Current reprogramming strategies are inefficient or require an excess of factors in adult and human cells due to staunch epigenetic barriers. Recently, we identified the epigenetic factor PHF7 as a potent activating factor of in vitro adult fibroblast reprogramming through modification of chromatin accessibility at cardiac super-enhancers. Here, we report the ability of PHF7 to activate adult fibroblast reprogramming alongside minimal co-factors in vitro, and the efficacy of these cocktails in vivo following MI in mice. Further, delivery of PHF7 as a single factor to the mouse heart following MI induced reprogramming and improved cardiac function. Deployment of single nuclear multi-omics revealed that PHF7 induced fundamental changes in chromatin structure by enhancing accessibility at CTCF binding sites and inhibiting Jun/Fos transcription factor activity to permit reprogramming in the injured heart. Together, these data support the potential for epigenetic factors like PHF7 to achieve in vivo reprogramming in isolation when utilized in the appropriate niche.
2025-08-13 | GSE270266 | GEO
Project description:Cellular reprogramming of cardiac fibroblasts to cardiomyocytes following myocardial infarction (MI) is an attractive strategy to redirect the fibrotic response of the non-regenerative adult heart to a more functional myocardium. Current reprogramming strategies are inefficient or require an excess of factors in adult and human cells due to staunch epigenetic barriers. Recently, we identified the epigenetic factor PHF7 as a potent activating factor of in vitro adult fibroblast reprogramming through modification of chromatin accessibility at cardiac super-enhancers. Here, we report the ability of PHF7 to activate adult fibroblast reprogramming alongside minimal co-factors in vitro, and the efficacy of these cocktails in vivo following MI in mice. Further, delivery of PHF7 as a single factor to the mouse heart following MI induced reprogramming and improved cardiac function. Deployment of single nuclear multi-omics revealed that PHF7 induced fundamental changes in chromatin structure by enhancing accessibility at CTCF binding sites and inhibiting Jun/Fos transcription factor activity to permit reprogramming in the injured heart. Together, these data support the potential for epigenetic factors like PHF7 to achieve in vivo reprogramming in isolation when utilized in the appropriate niche.
2025-08-13 | GSE270268 | GEO
Project description:Cellular reprogramming of cardiac fibroblasts to cardiomyocytes following myocardial infarction (MI) is an attractive strategy to redirect the fibrotic response of the non-regenerative adult heart to a more functional myocardium. Current reprogramming strategies are inefficient or require an excess of factors in adult and human cells due to staunch epigenetic barriers. Recently, we identified the epigenetic factor PHF7 as a potent activating factor of in vitro adult fibroblast reprogramming through modification of chromatin accessibility at cardiac super-enhancers. Here, we report the ability of PHF7 to activate adult fibroblast reprogramming alongside minimal co-factors in vitro, and the efficacy of these cocktails in vivo following MI in mice. Further, delivery of PHF7 as a single factor to the mouse heart following MI induced reprogramming and improved cardiac function. Deployment of single nuclear multi-omics revealed that PHF7 induced fundamental changes in chromatin structure by enhancing accessibility at CTCF binding sites and inhibiting Jun/Fos transcription factor activity to permit reprogramming in the injured heart. Together, these data support the potential for epigenetic factors like PHF7 to achieve in vivo reprogramming in isolation when utilized in the appropriate niche.
2025-08-13 | GSE270267 | GEO
Project description:In vivo cardiac reprogramming by delivery of PHF7 [snATAC-seq multiome]
| PRJNA1126098 | ENA
Project description:In vivo cardiac reprogramming by delivery of PHF7 [snRNA-seq multiome]
| PRJNA1126097 | ENA
Project description:Direct cardiac reprogramming of fibroblasts to cardiomyocytes presents an attractive therapeutic strategy to restore cardiac function following injury. Cardiac reprogramming was initially achieved through the overexpression of the transcription factors Gata4, Mef2c, and Tbx5 (GMT), and later, Hand2 (GHMT) and Akt1 (AGHMT) were found to further enhance this process. Yet, staunch epigenetic barriers severely limit the ability of these cocktails to reprogram adult fibroblasts. We undertook a screen of mammalian gene regulatory factors to discover novel regulators of cardiac reprogramming in adult fibroblasts and identified the histone reader PHF7 as the most potent activating factor. Mechanistically, PHF7 localizes to cardiac super-enhancers in fibroblasts, and through cooperation with the SWI/SNF complex, increases chromatin accessibility and transcription factor binding at these sites. Importantly, PHF7 is the first epigenetic factor found to achieve efficient reprogramming in the absence of Gata4. Here, we highlight the underexplored necessity of cardiac epigenetic modifiers, such as PHF7, in harnessing chromatin remodeling complexes to overcome critical barriers to direct cardiac reprogramming.
2021-02-26 | GSE151328 | GEO
Project description:Direct cardiac reprogramming to induce cardiomyocyte-like cells, e.g. by GMT (Gata4, Mef2c and Tbx5), is a promising route for regenerating damaged heart in vivo and disease modeling in vitro. Supplementation with additional factors and chemical agents can enhance efficiency but raises concerns regarding selectivity to cardiac fibroblasts and complicates delivery for in situ cardiac reprogramming. Here, we screened 2000 chemicals with known biological activities and found that a combination of 2C (SB431542 and Baricitinib) significantly enhances cardiac reprogramming by GMT. Without Gata4, MT (Mef2c and Tbx5) plus 2C could selectively reprogram cardiac fibroblasts with enhanced efficiency, kinetics and cardiomyocyte function. More importantly, 2C+MYOCD selectively reprograms human cardiac fibroblasts into cardiomyocyte-like cells. 2C enhances cardiac reprogramming by inhibiting Alk5, Tyk2 and downregulating Oas2, Oas3, Serpina3n and Tgfbi. 2C thus enables selective and robust cardiac reprogramming that can greatly facilitate disease modeling in vitro and advance clinical therapeutic heart regeneration in vivo.
2023-12-13 | GSE213021 | GEO
Project description:Heart failure (HF) is a leading cause of morbidity and mortality. As adult cardiomyocytes (CMs) have little regenerative capacity, after myocardial infarction (MI), resident cardiac fibroblasts (CFs) synthesize extracellular matrix to form scar tissues, resulting in myocardial remodeling and HF. Thus, both cardiac regeneration and fibrosis are therapeutic targets for chronic MI. We previously reported that fibroblasts were directly reprogrammed into induced CMs (iCMs) by overexpression of cardiogenic transcription factors in acute and chronic MI. Here we show that in vivo cardiac reprogramming improved cardiac function, and reversed cardiac remodeling in chronic MI using a novel transgenic mouse system. Transcriptome analysis revealed that in vivo cardiac reprogramming suppressed signs of fibrosis and inflammation. Thus, in vivo cardiac reprogramming may be a promising approach for chronic HF.
2024-07-01 | GSE240310 | GEO
Project description:The histone reader PHF7 cooperates with the SWI/SNF complex at cardiac super-enhancers to promote direct cardiac reprogramming
| PRJNA635457 | ENA
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