Commonly used thiol-containing antioxidants reduce cardiac differentiation and alter gene expression ratios of sarcomeric isoforms

Tu, Chunling; Allen, Alicia C.B.; Deng, Wei; Conroy, Olivia; Nambiar, Madhavi; Zoldan, Janet

doi:10.1016/j.yexcr.2018.06.017

Cited by 7 publications

(7 citation statements)

References 39 publications

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“…The role of ROS signaling during cardiomyocyte differentiation and maturation is context-dependent. During early differentiation of mouse ESC-CMs, transient increases in ROS with H 2 O 2 or menadione improves cardiomyocyte differentiation with enhanced expression of sarcomere genes and improved contractility [205,206]. Similarly, elevated glucose levels (25 mM) increases ROS formation in early PSC-CM differentiation compared to physiological levels (5 mM), and high glucose and high ROS promote cardiomyocyte differentiation, while low-glucose or early antioxidant treatment prevents cardiomyocyte differentiation [206,207].…”

Section: Mitophagymentioning

confidence: 99%

Mitochondria and metabolic transitions in cardiomyocytes: lessons from development for stem cell-derived cardiomyocytes

Garbern

Lee

2021

Stem Cell Res Ther

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Current methods to differentiate cardiomyocytes from human pluripotent stem cells (PSCs) inadequately recapitulate complete development and result in PSC-derived cardiomyocytes (PSC-CMs) with an immature or fetal-like phenotype. Embryonic and fetal development are highly dynamic periods during which the developing embryo or fetus is exposed to changing nutrient, oxygen, and hormone levels until birth. It is becoming increasingly apparent that these metabolic changes initiate developmental processes to mature cardiomyocytes. Mitochondria are central to these changes, responding to these metabolic changes and transitioning from small, fragmented mitochondria to large organelles capable of producing enough ATP to support the contractile function of the heart. These changes in mitochondria may not simply be a response to cardiomyocyte maturation; the metabolic signals that occur throughout development may actually be central to the maturation process in cardiomyocytes. Here, we review methods to enhance maturation of PSC-CMs and highlight evidence from development indicating the key roles that mitochondria play during cardiomyocyte maturation. We evaluate metabolic transitions that occur during development and how these affect molecular nutrient sensors, discuss how regulation of nutrient sensing pathways affect mitochondrial dynamics and function, and explore how changes in mitochondrial function can affect metabolite production, the cell cycle, and epigenetics to influence maturation of cardiomyocytes.

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Section: Mitophagymentioning

confidence: 99%

Mitochondria and metabolic transitions in cardiomyocytes: lessons from development for stem cell-derived cardiomyocytes

Garbern

Lee

2021

Stem Cell Res Ther

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“…It has been shown that removal of antioxidants from mouse ESCs (mESCs) differentiation medium elevated ROS levels and reduced cell growth while increasing cardiac differentiation efficiency from 15% to 40%. Furthermore, increased ROS resulted in the significantly increased expression of cardiac progenitor and sarcomeric genes (NKX2.5 by 100%; ISL1 by 100%; MLC2A by 300%; MLC2V by 600%; TNNI3 by 500%; MYH6 by 100%; MYH7 by 150%) and also altered the expression ratios of sarcomeric isoforms [37]. In summary, ROS-mediated cell signaling is vital in regulating basic cellular functions and is a significant determinant in specifying cell fate.…”

Section: Ros In Cell Signaling and Homeostasismentioning

confidence: 99%

The Role of Reactive Oxygen Species in In Vitro Cardiac Maturation

Momtahan

Crosby

Zoldan

2019

Trends in Molecular Medicine

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Recent advances in developmental biology and biomedical engineering have significantly improved the efficiency and purity of cardiomyocytes (CMs) generated from pluripotent stem cells (PSCs). Regardless of the protocol used to derive CMs, these cells exhibit hallmarks of functional immaturity. In this Opinion, we focus on reactive oxygen species (ROS), signaling molecules that can potentially modulate cardiac maturation. We outline how ROS impacts nearly every aspect associated with cardiac maturation, including contractility, calcium handling, metabolism, and hypertrophy. Though the precise role of ROS in cardiac maturation has yet to be elucidated, ROS may provide a valuable perspective for understanding the molecular mechanisms for cardiac maturation under various conditions.

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“…For stem cell culture and maintenance, ROS scavengers or antioxidant supplements are extensively used to prevent cellular oxidative stress [ 41 ]. However, β -mercaptoethanol and other thiol-based antioxidant supplements may cause changes to cellular redox state and then reduce the cardiogenic potential of stem cells [ 42 ]. The molecular mechanisms involved in metabolism and ROS regulation of PSC differentiation are still poorly understood and merit further investigation to optimize stem cell culture methods.…”

Section: Ros Mediate Cardiac Differentiation Of Pscsmentioning

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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Commonly used thiol-containing antioxidants reduce cardiac differentiation and alter gene expression ratios of sarcomeric isoforms

Cited by 7 publications

References 39 publications

Mitochondria and metabolic transitions in cardiomyocytes: lessons from development for stem cell-derived cardiomyocytes

Mitochondria and metabolic transitions in cardiomyocytes: lessons from development for stem cell-derived cardiomyocytes

The Role of Reactive Oxygen Species in In Vitro Cardiac Maturation

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

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