Cross-lineage potential of Ascl1 uncovered by comparing diverse reprogramming regulatomes

Wang, Haofei; Keepers, Benjamin; Qian, Yunzhe; Xie, Yifang; Colon, Marazzano; Liu, Jiandong; Li, Qian

doi:10.1016/j.stem.2022.09.006

Cited by 23 publications

(11 citation statements)

References 47 publications

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“…13 ASCL1 has been characterized as a “pioneer factor” that opens chromatin for accessibility by other transcriptional regulators. 14 A recent report also showed that the combination of ASCL1 and MEF2C is sufficient to reprogram hCFs to iCMs, 15 corroborating our findings that ASCL1 can contribute to cardiac reprogramming. Nevertheless, the coding sequence for MEF2C alone exceeds the packaging capacity of AAV, limiting its potential use in an AAV-based gene therapy.…”

Section: Resultssupporting

confidence: 90%

Improved Cardiac Function in Postischemic Rats Using an Optimized Cardiac Reprogramming Cocktail Delivered in a Single Novel Adeno-Associated Virus

Zhou,

Yang,

Srinath

et al. 2023

Circulation

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BACKGROUND: Cardiac reprogramming is a technique to directly convert nonmyocytes into myocardial cells using genes or small molecules. This intervention provides functional benefit to the rodent heart when delivered at the time of myocardial infarction or activated transgenically up to 4 weeks after myocardial infarction. Yet, several hurdles have prevented the advancement of cardiac reprogramming for clinical use. METHODS: Through a combination of screening and rational design, we identified a cardiac reprogramming cocktail that can be encoded in a single adeno-associated virus. We also created a novel adeno-associated virus capsid that can transduce cardiac fibroblasts more efficiently than available parental serotypes by mutating posttranslationally modified capsid residues. Because a constitutive promoter was needed to drive high expression of these cell fate–altering reprogramming factors, we included binding sites to a cardiomyocyte-restricted microRNA within the 3’ untranslated region of the expression cassette that limits expression to nonmyocytes. After optimizing this expression cassette to reprogram human cardiac fibroblasts into induced cardiomyocyte-like cells in vitro, we also tested the ability of this capsid/cassette combination to confer functional benefit in acute mouse myocardial infarction and chronic rat myocardial infarction models. RESULTS: We demonstrated sustained, dose-dependent improvement in cardiac function when treating a rat model 2 weeks after myocardial infarction, showing that cardiac reprogramming, when delivered in a single, clinically relevant adeno-associated virus vector, can support functional improvement in the postremodeled heart. This benefit was not observed with GFP (green fluorescent protein) or a hepatocyte reprogramming cocktail and was achieved even in the presence of immunosuppression, supporting myocyte formation as the underlying mechanism. CONCLUSIONS: Collectively, these results advance the application of cardiac reprogramming gene therapy as a viable therapeutic approach to treat chronic heart failure resulting from ischemic injury.

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Section: Resultssupporting

confidence: 90%

Improved Cardiac Function in Postischemic Rats Using an Optimized Cardiac Reprogramming Cocktail Delivered in a Single Novel Adeno-Associated Virus

Zhou,

Yang,

Srinath

et al. 2023

Circulation

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“…Recent work suggests that Epas1 may not be alone in influencing fibroblast cell fate. ChIP-seq and RNA-seq studies indicated that Mef2C, one of the constituents of the transcription factor cocktail for fibroblast to cardiomyocyte reprogramming, shifted ASCL1 binding from neuronal genes to cardiomyocyte genes ( 30 ). Another question is the signal which induces Epas1 expression.…”

Section: Discussionmentioning

confidence: 99%

Neonatal and adult cardiac fibroblasts exhibit inherent differences in cardiac regenerative capacity

Sun¹,

Pratt²,

Dzau³

et al. 2023

Journal of Biological Chemistry

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“…In addition to 2C, Bmi1 knock-down 16 or PHF7 over-expression 18 can both complement the loss of Gata4 in reprogramming mouse cardiac fibroblasts, although further investigation is required to determine whether those factor combinations are also selective to cardiac fibroblasts. More recently, Ascl1+Mef2c was also reported to induce iCMs from cardiac fibroblasts, highlighting the cross-lineage potential of Ascl1, but shows poor selectivity towards cardiac fibroblasts, since MEF can also be reprogrammed 54 .…”

Section: Discussionmentioning

confidence: 99%

Robust Small Molecule-Aided Cardiac Reprogramming Systems Selective to Cardiac Fibroblasts

Tao,

Yang,

Yang

et al. 2023

Preprint

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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 modelling 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. Moreover, 2C significantly enhanced cardiac reprogramming in human cardiac fibroblasts. 2C synergistically enhances cardiac reprogramming by inhibiting Alk5, Tyk2 and downregulating Oas2, Oas3, Serpina3n and Tgfbi. 2C enables selective and robust cardiac reprogramming that can greatly facilitate disease modelling in vitro and advance clinical therapeutic heart regeneration in vivo.

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Cross-lineage potential of Ascl1 uncovered by comparing diverse reprogramming regulatomes

Cited by 23 publications

References 47 publications

Improved Cardiac Function in Postischemic Rats Using an Optimized Cardiac Reprogramming Cocktail Delivered in a Single Novel Adeno-Associated Virus

Improved Cardiac Function in Postischemic Rats Using an Optimized Cardiac Reprogramming Cocktail Delivered in a Single Novel Adeno-Associated Virus

Neonatal and adult cardiac fibroblasts exhibit inherent differences in cardiac regenerative capacity

Robust Small Molecule-Aided Cardiac Reprogramming Systems Selective to Cardiac Fibroblasts

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