**1. Introduction**

Stem cells have been reported to recover damaged hearts from myocardial infarction and have been investigated for use in myocardial regeneration [1–3]. Cardiac progenitor cells (CPCs) were first identified by Anversa et al. [4]. CPCs are classified as a prevailing stem cell population in the heart and have crucial roles in cardiac homeostasis [5,6]. CPCs can differentiate into multiple cell lineages of the heart, and thus, are a promising cell resource for regenerating ischemic hearts [7]. Recent preclinical studies suggest that transplantation of CPCs into the ischemic myocardium can significantly improve cardiac regeneration via the formation of vasculature and new myocytes [8–10]. Furthermore, CPCs have the potential to produce and remodel extracellular matrix (ECM) proteins [11], trigger CPC proliferation, and stimulate growth factor secretion [12]. According to these positive results, CPC might be a promising stem cell source in cardiovascular regeneration. However, current evidence suggests that poor viability of engrafted CPCs in the infarcted myocardium primarily restricts the therapeutic efficacy of CPCs [13,14]. Thus, increasing the survival of CPCs can be a beneficial strategy to enhance the therapeutic effect in ischemic heart disease.

Reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), superoxide radicals, and hydroxyl radicals, are produced during infarction or reperfusion of ischemic hearts [15]. ROS involvement has been reported in various important development processes, cell signaling, and regulation of homeostasis [16]. Low levels of ROS are involved in the regulation of stem cell fate decision, stem cell proliferation, differentiation, and survival [17]. However, excessive ROS production leads to impaired cell metabolism and decreased cell viability [18], thereby inhibiting transplanted CPCs to regenerate the damaged heart [19]. Consequently, protecting CPCs from undergoing apoptosis and enhancing their ability to survive under oxidative stress is crucial in optimizing CPC-based therapy.

Echinochrome A is a common sea urchin pigment [20] that has a chemical structure of 6-ethyl-2,3,5,7,8-pentahydroxy-1,4-naphthoquinone (Figure 1A) and exhibits antioxidant, anti-viral [21], anti-inflammatory [22], and anti-diabetic activities [23]. Echinochrome A prevents mitochondrial dysfunction and activation of mitogen-activated protein kinase (MAPK) cell death signaling pathways caused by cardiotoxic drug treatment [24]. Echinochrome A regulates mitochondrial biogenesis in cardiomyocytes by upregulating the transcription of mitochondrial regulatory genes, such as mitochondrial transcriptional factor A (TFAM), nuclear respiratory factor (NRF-1), and proliferator-activated receptor gamma co-activator (PGC-1α) [25]. Echinochrome A inhibits the phosphorylation of serine-16 and threonine-17, located in the active center of phospholamban (membrane phosphoprotein and main regulator of the SERCA2A receptor responsible for the transfer of calcium ions from the cytosol to the sarcoplasmic reticulum), preventing ischemic myocardial damage by reducing the infarction zone [26].

Echinochrome A is insoluble in water, however, its water-soluble sodium salt is used for medical applications, which is manufactured under inert conditions in ampoules and is known as the Histochrome® drug. Histochrome has been used in Russia in ophtalmological and cardiological clinical practice. In ophthalmology, histochrome is used for the treatment of degenerative diseases of the retina and cornea, macular degeneration, primary open-angle glaucoma, diabetic retinopathy, hemorrhage in the vitreous body, retina, and anterior chamber, and dyscirculatory disorder in the central artery and vein of the retina [27]. An overview of clinical applications of histochrome in cardiology is presented in monography [28]. In the first place, histochrome has been used for the treatment of myocardial ischemia/reperfusion injury. Even a single injection of histochrome immediately after reperfusion recovered the ECG signs of myocardial necrosis and significantly (up to 30%) reduces the necrosis zone after a 10-day course. The use of histochrome prevented lipid peroxidation, reduced the frequency of left ventricular failure, did not affect the level of blood pressure and heart rate, and decreased the frequency of post-infarction angina pectoris. Practical experience of histochrome treatment confirmed the absence of any adverse effects and the safety of its application [28].

The cardioprotective effect of histochrome on patient-derived CPCs has never been reported. Thus, we investigated whether pretreatment of CPCs with histochrome promotes cell survival against oxidative stress during cardiac regeneration.
