“Triplet” polycistronic vectors encoding Gata4, Mef2c, and Tbx5 enhances postinfarct ventricular functional improvement compared with singlet vectors

Mathison, Megumi; Singh, Vivek P.; Gersch, Robert P.; Ramirez, Maricela; Cooney, Austin J.; Kaminsky, Stephen M.; Chiuchiolo, Marı́a J.; Nasser, Ahmed; Yang, Jianchang; Crystal, Ronald G.; Rosengart, Todd K.

doi:10.1016/j.jtcvs.2014.03.033

Cited by 48 publications

(56 citation statements)

References 24 publications

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“…Similar reports have used small molecules in combination with the pluripotency factor OCT4 to produce CMC-like cells from fibroblasts [185, 186]. Importantly, cellular reprogramming strategies have proven efficacious in blunting cardiac dysfunction and remodeling in rodent models of MI [182, 187, 188]. It is interesting to speculate that forced expression of reprogramming factors may lead to improved cardiac performance by diverting CFs away from the pro-fibrotic phenotype in addition to stimulating CMC production [189].…”

Section: Fibroblast Resolution and Reprogrammingmentioning

confidence: 95%

Transcriptional control of cardiac fibroblast plasticity

Lighthouse

Small

2016

Journal of Molecular and Cellular Cardiology

108

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Cardiac fibroblasts help maintain the normal architecture of the healthy heart and are responsible for scar formation and the healing response to pathological insults. Various genetic, biomechanical, or humoral factors stimulate fibroblasts to become contractile smooth muscle-like cells called myofibroblasts that secrete large amounts of extracellular matrix. Unfortunately, unchecked myofibroblast activation in heart disease leads to pathological fibrosis, which is a major risk factor for the development of cardiac arrhythmias and heart failure. A better understanding of the molecular mechanisms that control fibroblast plasticity and myofibroblast activation is essential to develop novel strategies to specifically target pathological cardiac fibrosis without disrupting the adaptive healing response. This review highlights the major transcriptional mediators of fibroblast origin and function in development and disease. The contribution of the fetal epicardial gene program will be discussed in the context of fibroblast origin in development and following injury, primarily focusing on Tcf21 and C/EBP. We will also highlight the major transcriptional regulatory axes that control fibroblast plasticity in the adult heart, including transforming growth factor β (TGFβ)/Smad signaling, the Rho/myocardin-related transcription factor (MRTF)/serum response factor (SRF) axis, and Calcineurin/transient receptor potential channel (TRP)/nuclear factor of activated T-Cell (NFAT) signaling. Finally, we will discuss recent strategies to divert the fibroblast transcriptional program in an effort to promote cardiomyocyte regeneration. This article is a part of a Special Issue entitled “Fibrosis and Myocardial Remodeling”.

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Section: Fibroblast Resolution and Reprogrammingmentioning

confidence: 95%

Transcriptional control of cardiac fibroblast plasticity

Lighthouse

Small

2016

Journal of Molecular and Cellular Cardiology

108

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“…Additionally, we have shown the stoichiometry of these three lineage-specific transcription factors within this construct, with high expression of Mef2C and low expression of Gata4 and Tbx5 (MGT), leads to increased efficiency and quality of reprogramming (Ma et al, 2015; Mathison et al, 2014; Wang et al, 2015a, 2015b). The underlying mechanisms by which this construct (MGT) governs the direct reprogramming of mouse fibroblasts into iCMs are relatively unknown.…”

Section: Introductionmentioning

confidence: 99%

Initiating Events in Direct Cardiomyocyte Reprogramming

et al. 2018

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SUMMARY Direct reprogramming of fibroblasts into cardiomyocyte-like cells (iCM) holds great potential for heart regeneration and disease modeling and may lead to future therapeutic applications. Currently, application of this technology is limited by our lack of understanding of the molecular mechanisms that drive direct iCM reprogramming. Using a quantitative mass spectrometry-based proteomic approach, we identified the temporal global changes in protein abundance that occur during initial phases of iCM reprogramming. Collectively, our results show systematic and temporally distinct alterations in levels of specific functional classes of proteins during the initiating steps of reprogramming including extracellular matrix proteins, translation factors, and chromatin-binding proteins. We have constructed protein relational networks associated with the initial transition of a fibroblast into an iCM. These findings demonstrate the presence of an orchestrated series of temporal steps associated with dynamic changes in protein abundance in a defined group of protein pathways during the initiating events of direct reprogramming.

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“…1,2 Immediately after coronary ligation, animals received direct administration (total of 100μL, 5 uniformly distributed 20 μL injections) into the myocardial infarct zone of lentivirus (1×10 5 TU) encoding Gata4, GFP, or a combination of Gata4, Mef2c, and Tbx5 (3×10 5 total dose; GMT). 1,2 Four animals that did not survive to study completion were excluded from final analysis (one animal received Gata4, 3 animals received GMT). All 6 animals with ejection fractions at baseline (3 days after coronary ligation) that were outside the 75% boundary (i.e., median ± quartile boundary, 49 ± 14; Supplemental Figure 2) were also excluded from final analysis, based on Tukey’s outlier detection method (1 received Gata4, 5 received GFP).…”

Section: Methodsmentioning

confidence: 99%

Cardiac reprogramming factor Gata4 reduces postinfarct cardiac fibrosis through direct repression of the profibrotic mediator snail

Mathison

Singh

Sanagasetti

et al. 2017

The Journal of Thoracic and Cardiovascular Surgery

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Objective The administration of a variety of reprogramming factor cocktails has now been shown to reprogram cardiac fibroblasts into induced cardiomyocyte-like cells (iCMs). Reductions in ventricular fibrosis observed after reprogramming factor administration, however, seem to far exceed the extent of iCM generation in vivo. We therefore investigated whether reprogramming factor administration might primarily play a role in activating anti-fibrotic molecular pathways. Methods Adult rat cardiac fibroblasts (RCFs) were infected with lentivirus encoding the transcription factors Gata4, Mef2c or Tbx5, all three vectors (GMT) or a GFP control vector. Gene and protein expression assays were performed to identify relevant anti-fibrotic targets of these factors. The anti-fibrotic effects of these factors were then investigated in a rat coronary ligation model. Results GMT administration to RCFs in vitro significantly downregulated expression of Snail, and the pro-fibrotic factors, CTGF, Collagen1a1, and Fibronectin. Of these factors, Gata4 was shown to be the one responsible for the downregulation of the pro-fibrotic factors, and Snail (mRNA expression fold change relative to GFP for Snail, Gata4: 0.5 ± 0.3, Mef2c: 1.3 ± 1.0, Tbx5: 0.9 ± 0.5, GMT: 0.6 ± 0.2, p<0.05). ChIP qPCR identified Gata4 binding sites in the Snail promoter. In a rat coronary ligation model, only Gata4 administration alone also improved post– infarct ventricular function and also reduced the extent of post-infarct fibrosis. Conclusions Gata4 administration reduces post–infarct ventricular fibrosis and improves ventricular function in a rat coronary ligation model, potentially as a result of Gata4 mediated downregulation of the pro-fibrotic mediator Snail.

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“Triplet” polycistronic vectors encoding Gata4, Mef2c, and Tbx5 enhances postinfarct ventricular functional improvement compared with singlet vectors

Abstract: These data have confirmed that the in situ administration of G, M, and T induces postinfarct ventricular functional improvement and that GMT polycistronic vectors enhance the efficacy of this strategy.

Cited by 48 publications

References 24 publications

Transcriptional control of cardiac fibroblast plasticity

Transcriptional control of cardiac fibroblast plasticity

Initiating Events in Direct Cardiomyocyte Reprogramming

Cardiac reprogramming factor Gata4 reduces postinfarct cardiac fibrosis through direct repression of the profibrotic mediator snail

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