Direct Reprogramming of Cardiac Fibroblasts to Cardiomyocytes Using MicroRNAs

2014 ◽  
pp. 263-272 ◽  
Author(s):  
Tilanthi Jayawardena ◽  
Maria Mirotsou ◽  
Victor J. Dzau
Keyword(s):  
Cardiac Fibroblasts ◽  
Direct Reprogramming

Abstract 126: High Efficiency Reprogramming of Fibroblasts Into Cardiomyocytes Requires Suppression of Pro-fibrotic Signaling

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Kunhua Song ◽  
Yuanbiao Zhao ◽  
Pilar Londono ◽  
Emily Sharpe ◽  
Joshua R Clair ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
High Efficiency ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Rho Kinase ◽  
Transforming Growth Factor Β ◽  
Direct Reprogramming ◽  
Cardiac Gene Expression ◽  
Cardiac Gene ◽  
Kinetics Of

The mammalian heart is composed of ~30% cardiomyocytes which have limited capacity to regenerate and ~70% non-cardiomyocytes including endothelial cells and cardiac fibroblasts. Direct reprogramming of fibroblasts into cardiomyocytes by forced expression of cardiomyogenic transcription factors, GMT (GATA4, Mef2C, Tbx5) or GHMT (GATA4, Hand2, Mef2C, Tbx5), has recently been demonstrated, suggesting a novel therapeutic strategy for cardiac repair. Despite extensive efforts, the efficiency of direct reprogramming of embryonic or adult fibroblasts into cardiomyocytes has yet to exceed 20%, or 0.1% respectively, leading many in the field to question the clinical translatability of this method. Here, we demonstrate that pro-fibrotic signaling events governed by transforming growth factor-β (TGF-β) and Rho kinase (ROCK) are concomitantly activated in GHMT-expressing fibroblasts, leading to potent suppression of cardiac reprogramming ( Figure 1 ). Remarkably, pharmacological inhibition of TGF-β, or ROCK leads to conversion of ≥ 60% of fibroblasts into highly functional cardiomyocytes, displaying global cardiac gene expression, spontaneous contractility, action potentials and calcium transients. Furthermore, inhibition of TGF-β, or ROCK dramatically enhances the kinetics of cardiac reprogramming, with spontaneously contracting cardiomyocytes emerging in less than two weeks, as opposed to 4 weeks with GHMT alone. These findings provide new insights into the molecular mechanisms underlying cardiac conversion of fibroblasts, and should enhance efforts to generate cardiomyocytes for clinical applications.

Abstract P493: Histone Reader PHF7 Cooperates With The SWI/SNF Complex At Cardiac Super Enhancers To Promote Direct Reprogramming

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Glynnis A Garry ◽  
Svetlana Bezprozvannaya ◽  
Huanyu Zhou ◽  
Hisayuki Hashimoto ◽  
Kenian Chen ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cardiac Fibroblasts ◽  
Human Fibroblasts ◽  
Cell Types ◽  
Chromatin Accessibility ◽  
Direct Reprogramming ◽  
Ischemic Disease ◽  
Treat Heart Failure ◽  
Cardiac Transcription Factors ◽  
Adult Fibroblasts

Ischemic heart disease is the leading cause of death worldwide. Direct reprogramming of resident cardiac fibroblasts (CFs) to induced cardiomyocytes (iCLMs) has emerged as a potential therapeutic approach to treat heart failure and ischemic disease. Cardiac reprogramming was first achieved through forced expression of the transcription factors Gata4, Mef2c, and Tbx5 (GMT); our laboratory found that Hand2 (GHMT) and Akt1 (AGHMT) markedly enhanced reprogramming efficiency in embryonic and postnatal cell types. However, adult mouse and human fibroblasts are resistant to reprogramming due to staunch epigenetic barriers. We undertook a screen of mammalian gene regulatory factors to discover novel regulators of cardiac reprogramming in adult fibroblasts and identified the epigenetic reader PHF7 as the most potent activating factor. We validated the findings of this screen and found that PHF7 augmented reprogramming of adult fibroblasts ten-fold. Mechanistically, PHF7 localized to cardiac super enhancers in fibroblasts by reading H3K4me2 marks, and through cooperation with the SWI/SNF complex, increased chromatin accessibility and transcription factor binding at these multivalent enhancers. Further, PHF7 recruited cardiac transcription factors to activate a positive transcriptional autoregulatory circuit in reprogramming. Importantly, PHF7 achieved efficient reprogramming through these mechanisms in the absence of Gata4. Collectively, these studies highlight the underexplored necessity of cardiac epigenetic readers, such as PHF7, in harnessing chromatin remodeling and transcriptional complexes to overcome critical barriers to direct cardiac reprogramming.

scholarly journals MicroRNA-Mediated In Vitro and In Vivo Direct Reprogramming of Cardiac Fibroblasts to Cardiomyocytes

2012 ◽  
Vol 110 (11) ◽  
pp. 1465-1473 ◽  
Author(s):  
Tilanthi M. Jayawardena ◽  
Bakytbek Egemnazarov ◽  
Elizabeth A. Finch ◽  
Lunan Zhang ◽  
J. Alan Payne ◽  
...  
Keyword(s):  
Cardiac Fibroblasts ◽  
Direct Reprogramming

scholarly journals Peptide-enhanced mRNA transfection in cultured mouse cardiac fibroblasts and direct reprogramming towards cardiomyocyte-like cells

2015 ◽  
pp. 1841 ◽  
Author(s):  
Niren Murthy ◽  
Kunwoo Lee ◽  
Pengzhi Yu ◽  
Nithya Lingampalli ◽  
Hyun Jin Kim ◽  
...  
Keyword(s):  
Cardiac Fibroblasts ◽  
Direct Reprogramming ◽  
Mrna Transfection

scholarly journals Cardiac regeneration by direct reprogramming in this decade and beyond

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
Hiroyuki Yamakawa ◽  
Masaki Ieda
Keyword(s):  
Growth Factor ◽  
Molecular Mechanisms ◽  
Cardiac Fibroblasts ◽  
Therapeutic Option ◽  
Cardiac Regeneration ◽  
Notch Signaling Pathway ◽  
Culture Conditions ◽  
Potential Candidate ◽  
Direct Reprogramming ◽  
Reprogramming Efficiency

AbstractJapan faces an increasing incidence of heart disease, owing to a shift towards a westernized lifestyle and an aging demographic. In cases where conventional interventions are not appropriate, regenerative medicine offers a promising therapeutic option. However, the use of stem cells has limitations, and therefore, “direct cardiac reprogramming” is emerging as an alternative treatment. Myocardial regeneration transdifferentiates cardiac fibroblasts into cardiomyocytes in situ.Three cardiogenic transcription factors: Gata4, Mef2c, and Tbx5 (GMT) can induce direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs), in mice. However, in humans, additional factors, such as Mesp1 and Myocd, are required. Inflammation and immune responses hinder the reprogramming process in mice, and epigenetic modifiers such as TET1 are involved in direct cardiac reprogramming in humans. The three main approaches to improving reprogramming efficiency are (1) improving direct cardiac reprogramming factors, (2) improving cell culture conditions, and (3) regulating epigenetic factors. miR-133 is a potential candidate for the first approach. For the second approach, inhibitors of TGF-β and Wnt signals, Akt1 overexpression, Notch signaling pathway inhibitors, such as DAPT ((S)-tert-butyl 2-((S)-2-(2-(3,5-difluorophenyl) acetamido) propanamido)-2-phenylacetate), fibroblast growth factor (FGF)-2, FGF-10, and vascular endothelial growth factor (VEGF: FFV) can influence reprogramming. Reducing the expression of Bmi1, which regulates the mono-ubiquitination of histone H2A, alters histone modification, and subsequently the reprogramming efficiency, in the third approach. In addition, diclofenac, a non-steroidal anti-inflammatory drug, and high level of Mef2c overexpression could improve direct cardiac reprogramming.Direct cardiac reprogramming needs improvement if it is to be used in humans, and the molecular mechanisms involved remain largely elusive. Further advances in cardiac reprogramming research are needed to bring us closer to cardiac regenerative therapy.

scholarly journals Direct Reprogramming of Cardiac Fibroblasts to Repair the Injured Heart

2021 ◽  
Vol 8 (7) ◽  
pp. 72
Author(s):  
Emma Adams ◽  
Rachel McCloy ◽  
Ashley Jordan ◽  
Kaitlin Falconer ◽  
Iain M. Dykes
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Cardiac Fibroblasts ◽  
Significant Risk ◽  
Scar Tissue ◽  
Micro Rna ◽  
Cardiovascular Development ◽  
Direct Reprogramming ◽  
Cardiac Progenitors ◽  
Mortality And Morbidity

Coronary heart disease is a leading cause of mortality and morbidity. Those that survive acute myocardial infarction are at significant risk of subsequent heart failure due to fibrotic remodelling of the infarcted myocardium. By applying knowledge from the study of embryonic cardiovascular development, modern medicine offers hope for treatment of this condition through regeneration of the myocardium by direct reprogramming of fibrotic scar tissue. Here, we will review mechanisms of cell fate specification leading to the generation of cardiovascular cell types in the embryo and use this as a framework in which to understand direct reprogramming. Driving expression of a network of transcription factors, micro RNA or small molecule epigenetic modifiers can reverse epigenetic silencing, reverting differentiated cells to a state of induced pluripotency. The pluripotent state can be bypassed by direct reprogramming in which one differentiated cell type can be transdifferentiated into another. Transdifferentiating cardiac fibroblasts to cardiomyocytes requires a network of transcription factors similar to that observed in embryonic multipotent cardiac progenitors. There is some flexibility in the composition of this network. These studies raise the possibility that the failing heart could one day be regenerated by directly reprogramming cardiac fibroblasts within post-infarct scar tissue.

Mini Review: Recent Advances in the Cell-Based Therapies for Cardiac Regeneration

2020 ◽  
Vol 15 (8) ◽  
pp. 649-660 ◽  
Author(s):  
Lan Luo ◽  
Tao-Sheng Li
Keyword(s):  
Cardiac Fibroblasts ◽  
Cardiac Regeneration ◽  
Cell Types ◽  
Cardiac Stem Cells ◽  
Direct Reprogramming ◽  
Promising Candidate ◽  
Surgical Interventions ◽  
Skeletal Myoblasts ◽  
Novel Approach ◽  
Induced Pluripotent

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality globally, and traditional pharmaceutical and surgical interventions delay the progression of CVDs. Recently, stem cell therapy has emerged as a promising candidate for treating and preventing heart failure. Increasing efforts have been devoted towards the exploration and identification of potential cell types to repair the injured heart, such as skeletal myoblasts, embryonic, induced pluripotent, bone marrowderived, mesenchymal, and resident cardiac stem cells. In addition, direct reprogramming of cardiac fibroblasts into cardiomyocytes represents a novel approach to cardiac regeneration. Herein, we summarize the recent progress in the use of various cell types for cardiac regeneration and discuss major challenges and future perspectives of cell-based therapies for CVDs.

Abstract 350: The Developmental Origin Of Cardiac Fibroblasts Influences the Efficiency of Direct Reprogramming to Cardiomyocytes

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Sara Ranjbarvaziri ◽  
Reza Ardehali
Keyword(s):  
Neural Crest ◽  
Cardiac Fibroblasts ◽  
Cardiac Regeneration ◽  
Light Sheet ◽  
Direct Conversion ◽  
Direct Reprogramming ◽  
Epigenetic Memory ◽  
A Minor ◽  
Cardiac Transcription Factors ◽  
Regenerative Therapies

Direct conversion of fibroblasts to cardiomyocytes (CM) is advancing the field of cardiac regeneration. Despite advantages of direct reprogramming, the presence of residual epigenetic memory of the original cells may hinder clinical transition. Thus, choosing a starting cell with similar ontogeny to the desired reprogrammed cell may overcome some of the limitations. Expression of key cardiogenic genes shared between cardiac fibroblasts (CFb) and CM in addition to the abundance of these cells, suggest that CFb may be the optimal autologous cell source for therapeutic manipulation in treating heart disease. We hypothesized that progenitors, transiently expressing Mesp1 generate a sub-population of CFb which are more prone to direct reprogramming and adopt a cardiomyocyte gene profile due to their maintained epigenetic memory. We generated a Mesp1CremTmG mouse to label all cells expressing Mesp1 and their progeny and we observed that the majority of the cells in the heart including CFb are derived from Mesp1 cells. We showed that ~80% of resident CFb are derived from Mesp1 while a minor non-Mesp1 subset also exists. We compared the reprogramming efficiency of CFb of Mesp1 origin to CFb of other origin to induced CM (iCM) by overexpression of specific cardiac transcription factors. Results from immunostaining and gene analysis showed higher expression of cardiac muscle markers in CM induced from Mesp1 CFb. To further delineate potential differences between two subsets, we performed RNAseq and our results showed that the non Mesp1 CFb were enriched in neural crest related genes. We generated Pax3CremTmG mice to lineage trace neural crest-derived cells. Our results confirmed a minor contribution of Pax3 cells to CFb. We developed a modified CLARITY technique to transform the heart into an optically-transparent organ for light-sheet fluorescence imaging. We observed that Pax3 CFb were mainly located in the wall of aorta while Mesp1 CFb were distributed throughout the heart. Additionally, we are studying whether each CFb subset has the tendency to generate a specific subtype of iCM (ventricular, atrial, and nodal CM). These results can identify distinct sub-populations of CFb, which can generate functional cardiomyocytes for cardiac-regenerative therapies.

Protective role of peroxiredoxin-4 in heart failure

2020 ◽  
Vol 134 (1) ◽  
pp. 71-72
Author(s):  
Naseer Ahmed ◽  
Masooma Naseem ◽  
Javeria Farooq
Keyword(s):  
Heart Failure ◽  
Cardiac Fibroblasts ◽  
Protective Role ◽  
Oxidative Stress Markers ◽  
Stress Markers ◽  
Total Antioxidant ◽  
Galectin 3 ◽  
Consequent Increase ◽  
And Oxidative Stress

Abstract Recently, we have read with great interest the article published by Ibarrola et al. (Clin. Sci. (Lond.) (2018) 132, 1471–1485), which used proteomics and immunodetection methods to show that Galectin-3 (Gal-3) down-regulated the antioxidant peroxiredoxin-4 (Prx-4) in cardiac fibroblasts. Authors concluded that ‘antioxidant activity of Prx-4 had been identified as a protein down-regulated by Gal-3. Moreover, Gal-3 induced a decrease in total antioxidant capacity which resulted in a consequent increase in peroxide levels and oxidative stress markers in cardiac fibroblasts.’ We would like to point out some results stated in the article that need further investigation and more detailed discussion to clarify certain factors involved in the protective role of Prx-4 in heart failure.

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