Journal articles: 'Direct cardiac reprogramming'

1

Qian, Li, and Deepak Srivastava. "Direct Cardiac Reprogramming." Circulation Research 113, no. 7 (September 13, 2013): 915–21. http://dx.doi.org/10.1161/circresaha.112.300625.

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Sadahiro, Taketaro, Shinya Yamanaka, and Masaki Ieda. "Direct Cardiac Reprogramming." Circulation Research 116, no. 8 (April 10, 2015): 1378–91. http://dx.doi.org/10.1161/circresaha.116.305374.

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Bruneau, Benoit G. "Direct Reprogramming for Cardiac Regeneration." Circulation Research 110, no. 11 (May 25, 2012): 1392–94. http://dx.doi.org/10.1161/circresaha.112.270637.

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Chen, Olivia, and Li Qian. "Direct Cardiac Reprogramming: Advances in Cardiac Regeneration." BioMed Research International 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/580406.

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Heart disease is one of the lead causes of death worldwide. Many forms of heart disease, including myocardial infarction and pressure-loading cardiomyopathies, result in irreversible cardiomyocyte death. Activated fibroblasts respond to cardiac injury by forming scar tissue, but ultimately this response fails to restore cardiac function. Unfortunately, the human heart has little regenerative ability and long-term outcomes following acute coronary events often include chronic and end-stage heart failure. Building upon years of research aimed at restoring functional cardiomyocytes, recent advances have been made in the direct reprogramming of fibroblasts toward a cardiomyocyte cell fate bothin vitroandin vivo. Several experiments show functional improvements in mouse models of myocardial infarction followingin situgeneration of cardiomyocyte-like cells from endogenous fibroblasts. Though many of these studies are in an early stage, this nascent technology holds promise for future applications in regenerative medicine. In this review, we discuss the history, progress, methods, challenges, and future directions of direct cardiac reprogramming.

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Kim, Junyeop, Yujung Chang, Yerim Hwang, Sumin Kim, Yu-Kyoung Oh, and Jongpil Kim. "Graphene Nanosheets Mediate Efficient Direct Reprogramming into Induced Cardiomyocytes." Journal of Biomedical Nanotechnology 18, no. 9 (September 1, 2022): 2171–82. http://dx.doi.org/10.1166/jbn.2022.3416.

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In vivo cardiac reprogramming is a potential therapeutic strategy to replace cardiomyocytes in patients with myocardial infarction. However, low conversion efficiency is a limitation of In vivo cardiac reprogramming for heart failure. In this study, we showed that graphene nanosheets mediated efficient direct reprogramming into induced cardiomyocytes In vivo. We observed that the administration of graphene nanosheets led to the accumulation of H3K4me3, which resulted in direct cardiac reprogramming. Importantly, the administration of graphene nanosheets combined with cardiac reprogramming factors in a mouse model of myocardial infarction enhanced the effectiveness of directly reprogrammed cell-based cardiac repair. Collectively, our findings suggest that graphene nanosheets can be used as an excellent biomaterial to promote cardiac cell fate conversion and provide a robust reprogramming platform for cardiac regeneration in ischemic heart disease.

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Zhang, Zhentao, Jesse Villalpando, Wenhui Zhang, and Young-Jae Nam. "Chamber-Specific Protein Expression during Direct Cardiac Reprogramming." Cells 10, no. 6 (June 16, 2021): 1513. http://dx.doi.org/10.3390/cells10061513.

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Forced expression of core cardiogenic transcription factors can directly reprogram fibroblasts to induced cardiomyocyte-like cells (iCMs) in vitro and in vivo. This cardiac reprogramming approach provides a proof of concept for induced heart regeneration by converting a fibroblast fate to a cardiomyocyte fate. However, it remains elusive whether chamber-specific cardiomyocytes can be generated by cardiac reprogramming. Therefore, we assessed the ability of the cardiac reprogramming approach for chamber specification in vitro and in vivo. We found that in vivo cardiac reprogramming post-myocardial infarction exclusively induces a ventricular-like phenotype, while a major fraction of iCMs generated in vitro failed to determine their chamber identities. Our results suggest that in vivo cardiac reprogramming may have an inherent advantage of generating chamber-matched new cardiomyocytes as a potential heart regenerative approach.

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Sadahiro, Taketaro. "Direct Cardiac Reprogramming ― Converting Cardiac Fibroblasts to Cardiomyocytes ―." Circulation Reports 1, no. 12 (December 10, 2019): 564–67. http://dx.doi.org/10.1253/circrep.cr-19-0104.

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Ieda, Masaki. "Direct cardiac reprogramming by defined factors." Inflammation and Regeneration 33, no. 4 (2013): 190–96. http://dx.doi.org/10.2492/inflammregen.33.190.

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Engel, James L., and Reza Ardehali. "Direct Cardiac Reprogramming: Progress and Promise." Stem Cells International 2018 (2018): 1–10. http://dx.doi.org/10.1155/2018/1435746.

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The human adult heart lacks a robust endogenous repair mechanism to fully restore cardiac function after insult; thus, the ability to regenerate and repair the injured myocardium remains a top priority in treating heart failure. The ability to efficiently generate a large number of functioning cardiomyocytes capable of functional integration within the injured heart has been difficult. However, the ability to directly convert fibroblasts into cardiomyocyte-like cells both in vitro and in vivo offers great promise in overcoming this problem. In this review, we describe the insights and progress that have been gained from the investigation of direct cardiac reprogramming. We focus on the use of key transcription factors and cardiogenic genes as well as on the use of other biological molecules such as small molecules, cytokines, noncoding RNAs, and epigenetic modifiers to improve the efficiency of cardiac reprogramming. Finally, we discuss the development of safer reprogramming approaches for future clinical application.

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Kurotsu, Shota, Takeshi Suzuki, and Masaki Ieda. "Mechanical stress regulates cardiac direct reprogramming." Proceedings for Annual Meeting of The Japanese Pharmacological Society WCP2018 (2018): OR15–1. http://dx.doi.org/10.1254/jpssuppl.wcp2018.0_or15-1.

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Osakabe, Rina, Takeshi Suzuki, and Masaki Ieda. "Heart repair using direct cardiac reprogramming." Folia Pharmacologica Japonica 150, no. 6 (2017): 276–81. http://dx.doi.org/10.1254/fpj.150.276.

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Srivastava, Deepak, and Penghzi Yu. "Recent advances in direct cardiac reprogramming." Current Opinion in Genetics & Development 34 (October 2015): 77–81. http://dx.doi.org/10.1016/j.gde.2015.09.004.

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Ieda, Masaki. "Direct Cardiac Reprogramming for Regenerative Medicine." Journal of Cardiac Failure 21, no. 10 (October 2015): S160. http://dx.doi.org/10.1016/j.cardfail.2015.08.093.

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Kurotsu, Shota, Takeshi Suzuki, and Masaki Ieda. "Direct Reprogramming, Epigenetics, and Cardiac Regeneration." Journal of Cardiac Failure 23, no. 7 (July 2017): 552–57. http://dx.doi.org/10.1016/j.cardfail.2017.05.009.

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Vaseghi, Haley, Jiandong Liu, and Li Qian. "Molecular barriers to direct cardiac reprogramming." Protein & Cell 8, no. 10 (April 7, 2017): 724–34. http://dx.doi.org/10.1007/s13238-017-0402-x.

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Tani, Hidenori, Taketaro Sadahiro, and Masaki Ieda. "Direct Cardiac Reprogramming: A Novel Approach for Heart Regeneration." International Journal of Molecular Sciences 19, no. 9 (September 5, 2018): 2629. http://dx.doi.org/10.3390/ijms19092629.

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Cardiac diseases are among the most common causes of death globally. Cardiac muscle has limited proliferative capacity, and regenerative therapies are highly in demand as a new treatment strategy. Although pluripotent reprogramming has been developed, it has obstacles, such as a potential risk of tumor formation, poor survival of the transplanted cells, and high cost. We previously reported that fibroblasts can be directly reprogrammed to cardiomyocytes by overexpressing a combination of three cardiac-specific transcription factors (Gata4, Mef2c, Tbx5 (together, GMT)). We and other groups have promoted cardiac reprogramming by the addition of certain miRNAs, cytokines, and epigenetic factors, and unraveled new molecular mechanisms of cardiac reprogramming. More recently, we discovered that Sendai virus (SeV) vector expressing GMT could efficiently and rapidly reprogram fibroblasts into integration-free cardiomyocytes in vitro via robust transgene expression. Gene delivery of SeV-GMT also improves cardiac function and reduces fibrosis after myocardial infarction in mice. Through direct cardiac reprogramming, new cardiomyocytes can be generated and scar tissue reduced to restore cardiac function, and, thus, direct cardiac reprogramming may serve as a powerful strategy for cardiac regeneration. Here, we provide an overview of the previous reports and current challenges in this field.

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Tang, Yawen, Sajesan Aryal, Xiaoxiao Geng, Xinyue Zhou, Vladimir G. Fast, Jianyi Zhang, Rui Lu, and Yang Zhou. "TBX20 Improves Contractility and Mitochondrial Function During Direct Human Cardiac Reprogramming." Circulation 146, no. 20 (November 15, 2022): 1518–36. http://dx.doi.org/10.1161/circulationaha.122.059713.

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Background: Direct cardiac reprogramming of fibroblasts into cardiomyocytes has emerged as a promising strategy to remuscularize injured myocardium. However, it is insufficient to generate functional induced cardiomyocytes from human fibroblasts using conventional reprogramming cocktails, and the underlying molecular mechanisms are not well studied. Methods: To discover potential missing factors for human direct reprogramming, we performed transcriptomic comparison between human induced cardiomyocytes and functional cardiomyocytes. Results: We identified TBX20 (T-box transcription factor 20) as the top cardiac gene that is unable to be activated by the MGT133 reprogramming cocktail ( MEF2C , GATA4 , TBX5 , and miR-133 ). TBX20 is required for normal heart development and cardiac function in adult cardiomyocytes, yet its role in cardiac reprogramming remains undefined. We show that the addition of TBX20 to the MGT133 cocktail (MGT+TBX20) promotes cardiac reprogramming and activates genes associated with cardiac contractility, maturation, and ventricular heart. Human induced cardiomyocytes produced with MGT+TBX20 demonstrated more frequent beating, calcium oscillation, and higher energy metabolism as evidenced by increased mitochondria numbers and mitochondrial respiration. Mechanistically, comprehensive transcriptomic, chromatin occupancy, and epigenomic studies revealed that TBX20 colocalizes with MGT reprogramming factors at cardiac gene enhancers associated with heart contraction, promotes chromatin binding and co-occupancy of MGT factors at these loci, and synergizes with MGT for more robust activation of target gene transcription. Conclusions: TBX20 consolidates MGT cardiac reprogramming factors to activate cardiac enhancers to promote cardiac cell fate conversion. Human induced cardiomyocytes generated with TBX20 showed enhanced cardiac function in contractility and mitochondrial respiration.

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Perveen, Sadia, Roberto Vanni, Marco Lo Iacono, Raffaella Rastaldo, and Claudia Giachino. "Direct Reprogramming of Resident Non-Myocyte Cells and Its Potential for In Vivo Cardiac Regeneration." Cells 12, no. 8 (April 15, 2023): 1166. http://dx.doi.org/10.3390/cells12081166.

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Cardiac diseases are the foremost cause of morbidity and mortality worldwide. The heart has limited regenerative potential; therefore, lost cardiac tissue cannot be replenished after cardiac injury. Conventional therapies are unable to restore functional cardiac tissue. In recent decades, much attention has been paid to regenerative medicine to overcome this issue. Direct reprogramming is a promising therapeutic approach in regenerative cardiac medicine that has the potential to provide in situ cardiac regeneration. It consists of direct cell fate conversion of one cell type into another, avoiding transition through an intermediary pluripotent state. In injured cardiac tissue, this strategy directs transdifferentiation of resident non-myocyte cells (NMCs) into mature functional cardiac cells that help to restore the native tissue. Over the years, developments in reprogramming methods have suggested that regulation of several intrinsic factors in NMCs can help to achieve in situ direct cardiac reprogramming. Among NMCs, endogenous cardiac fibroblasts have been studied for their potential to be directly reprogrammed into both induced cardiomyocytes and induced cardiac progenitor cells, while pericytes can transdifferentiate towards endothelial cells and smooth muscle cells. This strategy has been indicated to improve heart function and reduce fibrosis after cardiac injury in preclinical models. This review summarizes the recent updates and progress in direct cardiac reprogramming of resident NMCs for in situ cardiac regeneration.

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Muniyandi, Priyadharshni, Toru Maekawa, Tatsuro Hanajiri, and Vivekanandan Palaninathan. "Direct Cardiac Reprogramming with Engineered miRNA Scaffolds." Current Pharmaceutical Design 26, no. 34 (October 13, 2020): 4285–303. http://dx.doi.org/10.2174/1381612826666200327161112.

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Ischemic heart disease is a predominant cause of death worldwide. The loss or death of cardiomyocytes due to restricted blood flow often results in a cardiac injury. Myofibroblasts replace these injured cardiomyocytes to preserve structural integrity. However, the depleted cardiomyocytes lead to cardiac dysfunction such as pathological cardiac dilation, reduced cardiac contraction, and fibrosis. Repair and regeneration of myocardium are the best possible therapy for end-stage heart failure patients because the current cardiomyocytes restoration therapies are limited to heart transplantation only. The emergence of interests to directly reprogram a mammalian heart with minimal regenerative capacity holds a promising future in the field of cardiovascular regenerative medicine. Repair and regeneration become the two crucial factors in the field of cardiovascular regenerative medicine since heart muscles have no substitutes, like heart valves or blood vessels. Cardiac regeneration includes strategies to reprogram with diverse factors like small molecules, genetic and epigenetic regulators. However, there are some constraints like low efficacy, immunogenic problems, and unsafe delivery systems that pose a daunting challenge in human trial translations. Hence, there is a need for a holistic nanoscale approach in regulating cell fate effectively and efficiently with a safer delivery and a suitable microenvironment that mimics the extracellular matrix. In this review, we have discussed the current state-of-the-art techniques, challenges in direct reprogramming of fibroblasts to cardiac muscle, and prospects of biomaterials in miRNA delivery and cardiac regeneration predominantly during the past decade (2008-2019).

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Wang, Li, Hong Ma, Peisen Huang, Yifang Xie, David Near, Haofei Wang, Jun Xu, et al. "Down-regulation of Beclin1 promotes direct cardiac reprogramming." Science Translational Medicine 12, no. 566 (October 21, 2020): eaay7856. http://dx.doi.org/10.1126/scitranslmed.aay7856.

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Direct reprogramming of fibroblasts to alternative cell fates by forced expression of transcription factors offers a platform to explore fundamental molecular events governing cell fate identity. The discovery and study of induced cardiomyocytes (iCMs) not only provides alternative therapeutic strategies for heart disease but also sheds lights on basic biology underlying CM fate determination. The iCM field has primarily focused on early transcriptome and epigenome repatterning, whereas little is known about how reprogramming iCMs remodel, erase, and exit the initial fibroblast lineage to acquire final cell identity. Here, we show that autophagy-related 5 (Atg5)–dependent autophagy, an evolutionarily conserved self-digestion process, was induced and required for iCM reprogramming. Unexpectedly, the autophagic factor Beclin1 (Becn1) was found to suppress iCM induction in an autophagy-independent manner. Depletion of Becn1 resulted in improved iCM induction from both murine and human fibroblasts. In a mouse genetic model, Becn1 haploinsufficiency further enhanced reprogramming factor–mediated heart function recovery and scar size reduction after myocardial infarction. Mechanistically, loss of Becn1 up-regulated Lef1 and down-regulated Wnt inhibitors, leading to activation of the canonical Wnt/β-catenin signaling pathway. In addition, Becn1 physically interacts with other classical class III phosphatidylinositol 3-kinase (PI3K III) complex components, the knockdown of which phenocopied Becn1 depletion in cardiac reprogramming. Collectively, our study revealed an inductive role of Atg5-dependent autophagy as well as a previously unrecognized autophagy-independent inhibitory function of Becn1 in iCM reprogramming.

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Song, Seuk Young, Jin Yoo, Seokhyeong Go, Jihye Hong, Hee Su Sohn, Ju-Ro Lee, Mikyung Kang, et al. "Cardiac-mimetic cell-culture system for direct cardiac reprogramming." Theranostics 9, no. 23 (2019): 6734–44. http://dx.doi.org/10.7150/thno.35574.

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Bektik, Emre, and Ji-dong Fu. "Ameliorating the Fibrotic Remodeling of the Heart through Direct Cardiac Reprogramming." Cells 8, no. 7 (July 4, 2019): 679. http://dx.doi.org/10.3390/cells8070679.

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Coronary artery disease is the most common form of cardiovascular diseases, resulting in the loss of cardiomyocytes (CM) at the site of ischemic injury. To compensate for the loss of CMs, cardiac fibroblasts quickly respond to injury and initiate cardiac remodeling in an injured heart. In the remodeling process, cardiac fibroblasts proliferate and differentiate into myofibroblasts, which secrete extracellular matrix to support the intact structure of the heart, and eventually differentiate into matrifibrocytes to form chronic scar tissue. Discovery of direct cardiac reprogramming offers a promising therapeutic strategy to prevent/attenuate this pathologic remodeling and replace the cardiac fibrotic scar with myocardium in situ. Since the first discovery in 2010, many progresses have been made to improve the efficiency and efficacy of reprogramming by understanding the mechanisms and signaling pathways that are activated during direct cardiac reprogramming. Here, we overview the development and recent progresses of direct cardiac reprogramming and discuss future directions in order to translate this promising technology into an effective therapeutic paradigm to reverse cardiac pathological remodeling in an injured heart.

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Doppler, Stefanie, Marcus-André Deutsch, Rüdiger Lange, and Markus Krane. "Direct Reprogramming—The Future of Cardiac Regeneration?" International Journal of Molecular Sciences 16, no. 8 (July 29, 2015): 17368–93. http://dx.doi.org/10.3390/ijms160817368.

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Kojima, Hidenori, and Masaki Ieda. "Discovery and progress of direct cardiac reprogramming." Cellular and Molecular Life Sciences 74, no. 12 (February 14, 2017): 2203–15. http://dx.doi.org/10.1007/s00018-017-2466-4.

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Talkhabi, Mahmood, Elmira Rezaei Zonooz, and Hossein Baharvand. "Boosters and barriers for direct cardiac reprogramming." Life Sciences 178 (June 2017): 70–86. http://dx.doi.org/10.1016/j.lfs.2017.04.013.

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Wang, Li, Peisen Huang, David Near, Karan Ravi, Yangxi Xu, Jiandong Liu, and Li Qian. "Isoform Specific Effects of Mef2C during Direct Cardiac Reprogramming." Cells 9, no. 2 (January 22, 2020): 268. http://dx.doi.org/10.3390/cells9020268.

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Direct conversion of cardiac fibroblasts into induced cardiomyocytes (iCMs) by forced expression of defined factors holds great potential for regenerative medicine by offering an alternative strategy for treatment of heart disease. Successful iCM conversion can be achieved by minimally using three transcription factors, Mef2c (M), Gata4(G), and Tbx5 (T). Despite increasing interest in iCM mechanistic studies using MGT(polycistronic construct with optimal expression of M,G and T), the reprogramming efficiency varies among different laboratories. Two main Mef2c isoforms (isoform2, Mi2 and isoform4, Mi4) are present in heart and are used separately by different labs, for iCM reprogramming. It is currently unknown if differently spliced isoform of Mef2c contributes to varied reprogramming efficiency. Here, we used Mi2 and Mi4 together with Gata4 and Tbx5 in separate vectors or polycistronic vector, to convert fibroblasts to iCMs. We found that Mi2 can induce higher reprogramming efficiency than Mi4 in MEFs. Addition of Hand2 to MGT retroviral cocktail or polycistronic Mi2-GT retroviruses further enhanced the iCM conversion. Overall, this study demonstrated the isoform specific effects of Mef2c, during iCM reprogramming, clarified some discrepancy about varied efficiency among labs and might lead to future research into the role of alternative splicing and the consequent variants in cell fate determination.

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Paoletti, Camilla, Elena Marcello, Maria Luna Melis, Carla Divieto, Daria Nurzynska, and Valeria Chiono. "Cardiac Tissue-like 3D Microenvironment Enhances Route towards Human Fibroblast Direct Reprogramming into Induced Cardiomyocytes by microRNAs." Cells 11, no. 5 (February 25, 2022): 800. http://dx.doi.org/10.3390/cells11050800.

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The restoration of cardiac functionality after myocardial infarction represents a major clinical challenge. Recently, we found that transient transfection with microRNA combination (miRcombo: miR-1, miR-133, miR-208 and 499) is able to trigger direct reprogramming of adult human cardiac fibroblasts (AHCFs) into induced cardiomyocytes (iCMs) in vitro. However, achieving efficient direct reprogramming still remains a challenge. The aim of this study was to investigate the influence of cardiac tissue-like biochemical and biophysical stimuli on direct reprogramming efficiency. Biomatrix (BM), a cardiac-like extracellular matrix (ECM), was produced by in vitro culture of AHCFs for 21 days, followed by decellularization. In a set of experiments, AHCFs were transfected with miRcombo and then cultured for 2 weeks on the surface of uncoated and BM-coated polystyrene (PS) dishes and fibrin hydrogels (2D hydrogel) or embedded into 3D fibrin hydrogels (3D hydrogel). Cell culturing on BM-coated PS dishes and in 3D hydrogels significantly improved direct reprogramming outcomes. Biochemical and biophysical cues were then combined in 3D fibrin hydrogels containing BM (3D BM hydrogel), resulting in a synergistic effect, triggering increased CM gene and cardiac troponin T expression in miRcombo-transfected AHCFs. Hence, biomimetic 3D culture environments may improve direct reprogramming of miRcombo-transfected AHCFs into iCMs, deserving further study.

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Passaro, Fabiana, Gianluca Testa, Luigi Ambrosone, Ciro Costagliola, Carlo Gabriele Tocchetti, Francesca di Nezza, Michele Russo, et al. "Nanotechnology-Based Cardiac Targeting and Direct Cardiac Reprogramming: The Betrothed." Stem Cells International 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/4940397.

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Cardiovascular diseases represent the first cause of morbidity in Western countries, and chronic heart failure features a significant health care burden in developed countries. Efforts in the attempt of finding new possible strategies for the treatment of CHF yielded several approaches based on the use of stem cells. The discovery of direct cardiac reprogramming has unveiled a new approach to heart regeneration, allowing, at least in principle, the conversion of one differentiated cell type into another without proceeding through a pluripotent intermediate. First developed for cancer treatment, nanotechnology-based approaches have opened new perspectives in many fields of medical research, including cardiovascular research. Nanotechnology could allow the delivery of molecules with specific biological activity at a sustained and controlled rate in heart tissue, in a cell-specific manner. Potentially, all the mediators and structural molecules involved in the fibrotic process could be selectively targeted by nanocarriers, but to date, only few experiences have been made in cardiac research. This review highlights the most prominent concepts that characterize both the field of cardiac reprogramming and a nanomedicine-based approach to cardiovascular diseases, hypothesizing a possible synergy between these two very promising fields of research in the treatment of heart failure.

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Ghazizadeh, Z., H. Rassouli, H. Fonoudi, M. Alikhani, G. H. Salekdeh, N. Aghdami, and H. Baharvand. "Direct reprogramming of human fibroblasts to a cardiac fate using reprogramming proteins." Cytotherapy 16, no. 4 (April 2014): S39. http://dx.doi.org/10.1016/j.jcyt.2014.01.134.

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Adams, Emma, Rachel McCloy, Ashley Jordan, Kaitlin Falconer, and Iain M. Dykes. "Direct Reprogramming of Cardiac Fibroblasts to Repair the Injured Heart." Journal of Cardiovascular Development and Disease 8, no. 7 (June 22, 2021): 72. http://dx.doi.org/10.3390/jcdd8070072.

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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.

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Baksh, Syeda Samara, and Conrad P. Hodgkinson. "Conservation of miR combo based direct cardiac reprogramming." Biochemistry and Biophysics Reports 31 (September 2022): 101310. http://dx.doi.org/10.1016/j.bbrep.2022.101310.

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Guo, Chuner, Kishan Patel, and Li Qian. "Direct Somatic Cell Reprogramming: Treatment of Cardiac Diseases." Current Gene Therapy 13, no. 2 (March 1, 2013): 133–38. http://dx.doi.org/10.2174/1566523211313020007.

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Guo, Chuner, Kishan Patel, and Li Qian. "Direct Somatic Cell Reprogramming: Treatment of Cardiac Diseases." Current Gene Therapy 999, no. 999 (February 1, 2013): 1–7. http://dx.doi.org/10.2174/15665232113139990023.

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Sadahiro, Taketaro, and Masaki Ieda. "Direct Cardiac Reprogramming for Cardiovascular Regeneration and Differentiation." Keio Journal of Medicine 69, no. 3 (2020): 49–58. http://dx.doi.org/10.2302/kjm.2019-0008-oa.

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Garbutt, Tiffany A., Yang Zhou, Benjamin Keepers, Jiandong Liu, and Li Qian. "An Optimized Protocol for Human Direct Cardiac Reprogramming." STAR Protocols 1, no. 1 (June 2020): 100010. http://dx.doi.org/10.1016/j.xpro.2019.100010.

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Inagawa, Kohei, and Masaki Ieda. "Direct Reprogramming of Mouse Fibroblasts into Cardiac Myocytes." Journal of Cardiovascular Translational Research 6, no. 1 (October 3, 2012): 37–45. http://dx.doi.org/10.1007/s12265-012-9412-5.

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Batty, Jonathan A., Jose A. C. Lima, and Vijay Kunadian. "Direct cellular reprogramming for cardiac repair and regeneration." European Journal of Heart Failure 18, no. 2 (December 3, 2015): 145–56. http://dx.doi.org/10.1002/ejhf.446.

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Yamada, Yu, Taketaro Sadahiro, and Masaki Ieda. "Development of direct cardiac reprogramming for clinical applications." Journal of Molecular and Cellular Cardiology 178 (May 2023): 1–8. http://dx.doi.org/10.1016/j.yjmcc.2023.03.002.

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Bektik, Emre, Yu Sun, Adrienne T. Dennis, Phraew Sakon, Dandan Yang, Isabelle Deschênes, and Ji-Dong Fu. "Inhibition of CREB-CBP Signaling Improves Fibroblast Plasticity for Direct Cardiac Reprogramming." Cells 10, no. 7 (June 22, 2021): 1572. http://dx.doi.org/10.3390/cells10071572.

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Direct cardiac reprogramming of fibroblasts into induced cardiomyocytes (iCMs) is a promising approach but remains a challenge in heart regeneration. Efforts have focused on improving the efficiency by understanding fundamental mechanisms. One major challenge is that the plasticity of cultured fibroblast varies batch to batch with unknown mechanisms. Here, we noticed a portion of in vitro cultured fibroblasts have been activated to differentiate into myofibroblasts, marked by the expression of αSMA, even in primary cell cultures. Both forskolin, which increases cAMP levels, and TGFβ inhibitor SB431542 can efficiently suppress myofibroblast differentiation of cultured fibroblasts. However, SB431542 improved but forskolin blocked iCM reprogramming of fibroblasts that were infected with retroviruses of Gata4, Mef2c, and Tbx5 (GMT). Moreover, inhibitors of cAMP downstream signaling pathways, PKA or CREB-CBP, significantly improved the efficiency of reprogramming. Consistently, inhibition of p38/MAPK, another upstream regulator of CREB-CBP, also improved reprogramming efficiency. We then investigated if inhibition of these signaling pathways in primary cultured fibroblasts could improve their plasticity for reprogramming and found that preconditioning of cultured fibroblasts with CREB-CBP inhibitor significantly improved the cellular plasticity of fibroblasts to be reprogrammed, yielding ~2-fold more iCMs than untreated control cells. In conclusion, suppression of CREB-CBP signaling improves fibroblast plasticity for direct cardiac reprogramming.

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López-Muneta, Leyre, Josu Miranda-Arrubla, and Xonia Carvajal-Vergara. "The Future of Direct Cardiac Reprogramming: Any GMT Cocktail Variety?" International Journal of Molecular Sciences 21, no. 21 (October 26, 2020): 7950. http://dx.doi.org/10.3390/ijms21217950.

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Abstract:

Direct cardiac reprogramming has emerged as a novel therapeutic approach to treat and regenerate injured hearts through the direct conversion of fibroblasts into cardiac cells. Most studies have focused on the reprogramming of fibroblasts into induced cardiomyocytes (iCMs). The first study in which this technology was described, showed that at least a combination of three transcription factors, GATA4, MEF2C and TBX5 (GMT cocktail), was required for the reprogramming into iCMs in vitro using mouse cells. However, this was later demonstrated to be insufficient for the reprogramming of human cells and additional factors were required. Thereafter, most studies have focused on implementing reprogramming efficiency and obtaining fully reprogrammed and functional iCMs, by the incorporation of other transcription factors, microRNAs or small molecules to the original GMT cocktail. In this respect, great advances have been made in recent years. However, there is still no consensus on which of these GMT-based varieties is best, and robust and highly reproducible protocols are still urgently required, especially in the case of human cells. On the other hand, apart from CMs, other cells such as endothelial and smooth muscle cells to form new blood vessels will be fundamental for the correct reconstruction of damaged cardiac tissue. With this aim, several studies have centered on the direct reprogramming of fibroblasts into induced cardiac progenitor cells (iCPCs) able to give rise to all myocardial cell lineages. Especially interesting are reports in which multipotent and highly expandable mouse iCPCs have been obtained, suggesting that clinically relevant amounts of these cells could be created. However, as of yet, this has not been achieved with human iCPCs, and exactly what stage of maturity is appropriate for a cell therapy product remains an open question. Nonetheless, the major concern in regenerative medicine is the poor retention, survival, and engraftment of transplanted cells in the cardiac tissue. To circumvent this issue, several cell pre-conditioning approaches are currently being explored. As an alternative to cell injection, in vivo reprogramming may face fewer barriers for its translation to the clinic. This approach has achieved better results in terms of efficiency and iCMs maturity in mouse models, indicating that the heart environment can favor this process. In this context, in recent years some studies have focused on the development of safer delivery systems such as Sendai virus, Adenovirus, chemical cocktails or nanoparticles. This article provides an in-depth review of the in vitro and in vivo cardiac reprograming technology used in mouse and human cells to obtain iCMs and iCPCs, and discusses what challenges still lie ahead and what hurdles are to be overcome before results from this field can be transferred to the clinical settings.

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Liu, Liu, Yijing Guo, Zhaokai Li, and Zhong Wang. "Improving Cardiac Reprogramming for Heart Regeneration in Translational Medicine." Cells 10, no. 12 (November 25, 2021): 3297. http://dx.doi.org/10.3390/cells10123297.

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Abstract:

Direct reprogramming of fibroblasts into CM-like cells has emerged as an attractive strategy to generate induced CMs (iCMs) in heart regeneration. However, low conversion rate, poor purity, and the lack of precise conversion of iCMs are still present as significant challenges. In this review, we summarize the recent development in understanding the molecular mechanisms of cardiac reprogramming with various strategies to achieve more efficient iCMs. reprogramming. Specifically, we focus on the identified critical roles of transcriptional regulation, epigenetic modification, signaling pathways from the cellular microenvironment, and cell cycling regulation in cardiac reprogramming. We also discuss the progress in delivery system optimization and cardiac reprogramming in human cells related to preclinical applications. We anticipate that this will translate cardiac reprogramming-based heart therapy into clinical applications. In addition to optimizing the cardiogenesis related transcriptional regulation and signaling pathways, an important strategy is to modulate the pathological microenvironment associated with heart injury, including inflammation, pro-fibrotic signaling pathways, and the mechanical properties of the damaged myocardium. We are optimistic that cardiac reprogramming will provide a powerful therapy in heart regenerative medicine.

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Zhou, Yang, Sahar Alimohamadi, Li Wang, Ziqing Liu, Joseph B. Wall, Chaoying Yin, Jiandong Liu, and Li Qian. "A Loss of Function Screen of Epigenetic Modifiers and Splicing Factors during Early Stage of Cardiac Reprogramming." Stem Cells International 2018 (2018): 1–14. http://dx.doi.org/10.1155/2018/3814747.

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Abstract:

Direct reprogramming of cardiac fibroblasts (CFs) to induced cardiomyocytes (iCMs) is a newly emerged promising approach for cardiac regeneration, disease modeling, and drug discovery. However, its potential has been drastically limited due to the low reprogramming efficiency and largely unknown underlying molecular mechanisms. We have previously screened and identified epigenetic factors related to histone modification during iCM reprogramming. Here, we used shRNAs targeting an additional battery of epigenetic factors involved in chromatin remodeling and RNA splicing factors to further identify inhibitors and facilitators of direct cardiac reprogramming. Knockdown of RNA splicing factors Sf3a1 or Sf3b1 significantly reduced the percentage and total number of cardiac marker positive iCMs accompanied with generally repressed gene expression. Removal of another RNA splicing factor Zrsr2 promoted the acquisition of CM molecular features in CFs and mouse embryonic fibroblasts (MEFs) at both protein and mRNA levels. Moreover, a consistent increase of reprogramming efficiency was observed in CFs and MEFs treated with shRNAs targeting Bcor (component of BCOR complex superfamily) or Stag2 (component of cohesin complex). Our work thus reveals several additional epigenetic and splicing factors that are either inhibitory to or required for iCM reprogramming and highlights the importance of epigenetic regulation and RNA splicing process during cell fate conversion.

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Engel, James L., and Reza Ardehali. "Sendai virus based direct cardiac reprogramming: what lies ahead?" Stem Cell Investigation 5 (October 2018): 37. http://dx.doi.org/10.21037/sci.2018.10.02.

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Xie, Yifang, Ben Van Handel, Li Qian, and Reza Ardehali. "Recent advances and future prospects in direct cardiac reprogramming." Nature Cardiovascular Research 2, no. 12 (December 11, 2023): 1148–58. http://dx.doi.org/10.1038/s44161-023-00377-w.

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Sadahiro, Taketaro. "Cardiac regeneration with pluripotent stem cell-derived cardiomyocytes and direct cardiac reprogramming." Regenerative Therapy 11 (December 2019): 95–100. http://dx.doi.org/10.1016/j.reth.2019.06.004.

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Muniyandi, Priyadharshni, Vivekanandan Palaninathan, Tatsuro Hanajiri, and Toru Maekawa. "Direct Cardiac Epigenetic Reprogramming through Codelivery of 5′Azacytidine and miR-133a Nanoformulation." International Journal of Molecular Sciences 23, no. 23 (December 2, 2022): 15179. http://dx.doi.org/10.3390/ijms232315179.

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Abstract:

Direct reprogramming of cardiac fibroblasts to induced cardiomyocytes (iCMs) is a promising approach to cardiac regeneration. However, the low yield of reprogrammed cells and the underlying epigenetic barriers limit its potential. Epigenetic control of gene regulation is a primary factor in maintaining cellular identities. For instance, DNA methylation controls cell differentiation in adults, establishing that epigenetic factors are crucial for sustaining altered gene expression patterns with subsequent rounds of cell division. This study attempts to demonstrate that 5′AZA and miR-133a encapsulated in PLGA-PEI nanocarriers induce direct epigenetic reprogramming of cardiac fibroblasts to cardiomyocyte-like cells. The results present a cardiomyocyte-like phenotype following seven days of the co-delivery of 5′AZA and miR-133a nanoformulation into human cardiac fibroblasts. Further evaluation of the global DNA methylation showed a decreased global 5-methylcytosine (5-medCyd) levels in the 5′AZA and 5′AZA/miR-133a treatment group compared to the untreated group and cells with void nanocarriers. These results suggest that the co-delivery of 5′AZA and miR-133a nanoformulation can induce the direct reprogramming of cardiac fibroblasts to cardiomyocyte-like cells in-vitro, in addition to demonstrating the influence of miR-133a and 5′AZA as epigenetic regulators in dictating cell fate.

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Tendean, Marshel, Yudi Her Oktaviono, and Ferry Sandra. "Cardiomyocyte Reprogramming: A Potential Strategy for Cardiac Regeneration." Molecular and Cellular Biomedical Sciences 1, no. 1 (March 1, 2017): 1. http://dx.doi.org/10.21705/mcbs.v1i1.5.

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Heart disease is the leading cause of death worldwide. Within decades a limited process of cardiac cell regeneration was under observation. Embryonic stem cell (ESC) shows great potential for cell and tissue regeneration. Studies indicate that ESC has the potential to enhance myocardial perfusion and/or contractile performance in ischemic myocardium. However there is still challenge to evaluate the issues of teratoma. Then induced pluripotent stem cell was invented by introducing four transcriptional factors (Oct4, Sox2, Klf4, c-Myc). iPSC was created from murine fibroblast and then differentiated into cardiomyocyte. Reprogramming the adult cell could be performed in full, partial or direct reprogramming. Several studies add the significance by reprogramming the cells through more efficient techniques. However several limitations are still remained.Keywords: cardiomyocyte, reprogramming, iPSC, fibroblast

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Testa, Gianluca, Giorgia Di Benedetto, and Fabiana Passaro. "Advanced Technologies to Target Cardiac Cell Fate Plasticity for Heart Regeneration." International Journal of Molecular Sciences 22, no. 17 (September 1, 2021): 9517. http://dx.doi.org/10.3390/ijms22179517.

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The adult human heart can only adapt to heart diseases by starting a myocardial remodeling process to compensate for the loss of functional cardiomyocytes, which ultimately develop into heart failure. In recent decades, the evolution of new strategies to regenerate the injured myocardium based on cellular reprogramming represents a revolutionary new paradigm for cardiac repair by targeting some key signaling molecules governing cardiac cell fate plasticity. While the indirect reprogramming routes require an in vitro engineered 3D tissue to be transplanted in vivo, the direct cardiac reprogramming would allow the administration of reprogramming factors directly in situ, thus holding great potential as in vivo treatment for clinical applications. In this framework, cellular reprogramming in partnership with nanotechnologies and bioengineering will offer new perspectives in the field of cardiovascular research for disease modeling, drug screening, and tissue engineering applications. In this review, we will summarize the recent progress in developing innovative therapeutic strategies based on manipulating cardiac cell fate plasticity in combination with bioengineering and nanotechnology-based approaches for targeting the failing heart.

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Miki, Kenji, Yoshinori Yoshida, and Shinya Yamanaka. "Making Steady Progress on Direct Cardiac Reprogramming Toward Clinical Application." Circulation Research 113, no. 1 (June 21, 2013): 13–15. http://dx.doi.org/10.1161/circresaha.113.301788.

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Fu, Ji-Dong, and Deepak Srivastava. "Direct Reprogramming of Fibroblasts into Cardiomyocytes for Cardiac Regenerative Medicine." Circulation Journal 79, no. 2 (2015): 245–54. http://dx.doi.org/10.1253/circj.cj-14-1372.

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Journal articles on the topic 'Direct cardiac reprogramming'

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