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

Abstract

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.

Surfing the clinical trials of mesenchymal stem cell therapy in ischemic cardiomyopathy

“…Another main challenge is the potential cell-to-cell interactions between injected cells and ischemic cardiomyocytes contributing to attenuate engraftment efficiency [ 74 ]. Indeed, transplantation of pluripotent stem cells may result in increasing the level of intracellular reactive oxygen species in infarcted cardiomyocytes which are harmful to engraftment survival, thereby inducing cell death by their paracrine effects or through a cell-autonomous manner [ 75 ]. Nevertheless, each person reacts in a different way and the outcome of any procedure depends on the body recovery capability.…”

Redox Homeostasis and Regulation in Pluripotent Stem Cells: Uniqueness or Versatility?

“…It is important to note, that both abovementioned studies [109,110] revealed that, after the initial variations, ROS level and GSH/GSSH ratio in differentiating cells returned to their initial values by days 11 and 7 respectively, providing the restoration of the basal redox state. At the same time, evidence exists that if the ROS level remains high at later stages of differentiation process; this, on the contrary, leads to a decrease in the efficiency of differentiation [111].…”

“…In addition to NOX-generated ROS, a contribution of mitochondrial ROS to the early pro-oxidative effects has also been proved [119]. Increased release of mitoROS to the cytoplasm was stimulated by the temporary opening of the mitochondrial pore (mPTP) [111,[120][121][122].…”

“…Interestingly, although the experiments on hESCs [127] revealed redox stimulation of JNK and ERK1/2 signaling, an increase in the intracellular ROS level, on the contrary, led to the inactivation of the p38 MAPK signaling cascade. This may evidence of some specific features of redox-dependent differentiation signaling associated with different types of cells and/or different stages of the differentiation process [111].…”

Long Noncoding RNA ANPODRT Overexpression Protects Nucleus Pulposus Cells from Oxidative Stress and Apoptosis by Activating Keap1‐Nrf2 Signaling

“…Oxidative stress results from an imbalance between the production of reactive oxygen species (ROS) and scavenging capacity of the antioxidant system [ 7 ]. Oxidative stress leads to the damage of nucleic acids, lipids, and proteins through the production of high levels of ROS, which leads to cytotoxicity.…”