What's in a cardiomyocyte – And how do we make one through reprogramming?

Keepers, Benjamin; Liu, Jiandong; Li, Qian

doi:10.1016/j.bbamcr.2019.03.011

Cited by 16 publications

(7 citation statements)

References 70 publications

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“…Therefore, researchers are exhibiting tremendous enthusiasm and interest in the quest to elucidate the mechanisms of iCM generation and further enhance reprogramming efficiency. The current progress in this field has been summarized in other reviews [108,109]. Yet, it remains unknown whether ROS are involved in the process of direct cardiac reprogramming.…”

Section: Unexploited Role Of Ros In Direct Cardiac Reprogrammingmentioning

confidence: 99%

Roles of Reactive Oxygen Species in Cardiac Differentiation, Reprogramming, and Regenerative Therapies

Liang

Chen

et al. 2020

Oxidative Medicine and Cellular Longevity

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Reactive oxygen species (ROS) have been implicated in mechanisms of heart development and regenerative therapies such as the use of pluripotent stem cells. The roles of ROS mediating cell fate are dependent on the intensity of stimuli, cellular context, and metabolic status. ROS mainly act through several targets (such as kinases and transcription factors) and have diverse roles in different stages of cardiac differentiation, proliferation, and maturation. Therefore, further detailed investigation and characterization of redox signaling will help the understanding of the molecular mechanisms of ROS during different cellular processes and enable the design of targeted strategies to foster cardiac regeneration and functional recovery. In this review, we focus on the roles of ROS in cardiac differentiation as well as transdifferentiation (direct reprogramming). The potential mechanisms are discussed in regard to ROS generation pathways and regulation of downstream targets. Further methodological optimization is required for translational research in order to robustly enhance the generation efficiency of cardiac myocytes through metabolic modulations. Additionally, we highlight the deleterious effect of the host’s ROS on graft (donor) cells in a paracrine manner during stem cell-based implantation. This knowledge is important for the development of antioxidant strategies to enhance cell survival and engraftment of tissue engineering-based technologies. Thus, proper timing and level of ROS generation after a myocardial injury need to be tailored to ensure the maximal efficacy of regenerative therapies and avoid undesired damage.

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Section: Unexploited Role Of Ros In Direct Cardiac Reprogrammingmentioning

confidence: 99%

Roles of Reactive Oxygen Species in Cardiac Differentiation, Reprogramming, and Regenerative Therapies

Liang

Chen

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…The combination of miR-1and miR-133 with GMTH cocktail generated significantly more matured iCMs [ 93 , 100 ]. Supplementing the viral GMT, GMTH, or GMTHMyMe cocktail with a TGF-β inhibitor or synthetic mimics of miR-1, miR-133, or miR-590 increased the CM reprogramming efficiency and speed of mouse, pig, or human cells, which provided new insight into the molecular mechanism of cardiac reprogramming [ 80 , 101 , 102 ].…”

Section: Direct Cardiac Reprogramming For Heart Regenerationmentioning

confidence: 99%

Strategies and Challenges to Improve Cellular Programming-Based Approaches for Heart Regeneration Therapy

Jiang

Liang

Huang

et al. 2020

IJMS

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Limited adult cardiac cell proliferation after cardiovascular disease, such as heart failure, hampers regeneration, resulting in a major loss of cardiomyocytes (CMs) at the site of injury. Recent studies in cellular reprogramming approaches have provided the opportunity to improve upon previous techniques used to regenerate damaged heart. Using these approaches, new CMs can be regenerated from differentiation of iPSCs (similar to embryonic stem cells), the direct reprogramming of fibroblasts [induced cardiomyocytes (iCMs)], or induced cardiac progenitors. Although these CMs have been shown to functionally repair infarcted heart, advancements in technology are still in the early stages of development in research laboratories. In this review, reprogramming-based approaches for generating CMs are briefly introduced and reviewed, and the challenges (including low efficiency, functional maturity, and safety issues) that hinder further translation of these approaches into a clinical setting are discussed. The creative and combined optimal methods to address these challenges are also summarized, with optimism that further investigation into tissue engineering, cardiac development signaling, and epigenetic mechanisms will help to establish methods that improve cell-reprogramming approaches for heart regeneration.

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“…The prevalence of CVDs nearly doubled from 1993 to 2019 and is predicted to increase at the same rate in the coming years globally 1 . Since cardiomyocytes are responsible for the contractile function of the heart, which is achieved by controlling the intracellular calcium ion ([Ca 2+ ]) concentrations, 2,3 cardiomyocyte damage is the primary pathophysiologic cause of cardiac dysfunctions including heart failure and myocardial infarction 4,5 . Aging and stress cause DNA damage, endoplasmic reticulum stress, and mitochondrial dysfunction, leading to cardiomyocyte damage, 6 wherein these insults result in apoptotic and necrotic responses 3 …”

Section: Introductionmentioning

confidence: 99%

Fludioxonil induces cardiotoxicity via mitochondrial dysfunction and oxidative stress in two cardiomyocyte models

Seong,

Go,

Lee

et al. 2024

Environmental Toxicology

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Fludioxonil (Flu) is a phenylpyrrole fungicide and is currently used in over 900 agricultural products globally. Flu possesses endocrine‐disrupting chemical‐like properties and has been shown to mediate various physiological and pathological changes, such as apoptosis and differentiation, in diverse cell lines. However, the effects of Flu on cardiomyocytes have not been studied so far. The present study investigated the effects of Flu on mitochondria in AC16 human cardiomyocytes and H9c2 rat cardiomyoblasts. Flu decreased cell viability in a water‐soluble tetrazolium assay and mediated morphological changes suggestive of apoptosis in AC16 and H9c2 cells. We confirmed that annexin V positive cells were increased by Flu through annexin V/propidium iodide staining. This suggests that the decrease in cell viability due to Flu may be associated with increased apoptotic changes. Flu consistently increased the expression of pro‐apoptotic markers such as Bcl‐2‐associated X protein (Bax) and cleaved‐caspase 3. Further, Flu reduced the oxygen consumption rate (OCR) in AC16 and H9c2 cells, which is associated with decreased mitochondrial membrane potential (MMP) as observed through JC‐1 staining. In addition, Flu augmented the production of mitochondrial reactive oxygen species, which can trigger oxidative stress in cardiomyocytes. Taken together, these results indicate that Flu induces mitochondrial dysregulation in cardiomyocytes via the downregulation of the OCR and MMP and upregulation of the oxidative stress, consequently resulting in the apoptosis of cardiomyocytes. This study provides evidence of the risk of Flu toxicity on cardiomyocytes leading to the development of cardiovascular diseases and suggests that the use of Flu in agriculture should be done with caution and awareness of the probable health consequences of exposure to Flu.

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What's in a cardiomyocyte – And how do we make one through reprogramming?

Cited by 16 publications

References 70 publications

Roles of Reactive Oxygen Species in Cardiac Differentiation, Reprogramming, and Regenerative Therapies

Roles of Reactive Oxygen Species in Cardiac Differentiation, Reprogramming, and Regenerative Therapies

Strategies and Challenges to Improve Cellular Programming-Based Approaches for Heart Regeneration Therapy

Fludioxonil induces cardiotoxicity via mitochondrial dysfunction and oxidative stress in two cardiomyocyte models

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