Environmental Alterations during Embryonic Development: Studying the Impact of Stressors on Pluripotent Stem Cell-Derived Cardiomyocytes

Abstract

Non-communicable diseases (NCDs) sauch as diabetes, obesity and cardiovascular diseases are rising rapidly in all countries world-wide. Environmental maternal factors (e.g., diet, oxidative stress, drugs and many others), maternal illnesses and other stressors can predispose the newborn to develop diseases during different stages of life. The connection between environmental factors and NCDs was formulated by David Barker and colleagues as the Developmental Origins of Health and Disease (DOHaD) hypothesis. In this review, we describe the DOHaD concept and the effects of several environmental stressors on the health of the progeny, providing both animal and human evidence. We focus on cardiovascular diseases which represent the leading cause of death worldwide. The purpose of this review is to discuss how in vitro studies with pluripotent stem cells (PSCs), such as embryonic and induced pluripotent stem cells (ESC, iPSC), can underpin the research on non-genetic heart conditions. The PSCs could provide a tool to recapitulate aspects of embryonic development “in a dish”, studying the effects of environmental exposure during cardiomyocyte (CM) differentiation and maturation, establishing a link to molecular mechanism and epigenetics.

Indicators of Bioelectrical Activity of the Rat Heart After Prenatal Hypoxia and Pharmacological Correction

“…Tiazotic acid in experimental myocardial infarction normalized heart rate, reduced the total deviation of the ST segment. Tiazotic acid in acute non-ST segment elevation coronary syndrome, increased left ventricular ejection fraction, reduced end-systolic and enddiastolic heart volumes, reduced the total duration of myocardial ischemia episodes and the number of ventricular and supraventricular arrhythmias [2]. Meldonium is an inhibitor of the biosynthesis, transport and reabsorption of L-carnitine, prevents the accumulation of toxic acylcarnitines in ischemic tissue and shifts cell metabolism towards increased glucose consumption, which is beneficial in ischemic conditions.…”

“…In the structure of morbidity in newborns, both full-term and premature, the leading place is occupied by hypoxia. The complex of changes that occur in this case has an adverse effect on the central nervous system (CNS), disrupting the regulatory influence of the subcortical structures of the brain on the functional state of internal organs, in particular on the cardiovascular system (CVS) [1,2]. The functional changes in the cardiovascular system in the syndrome of posthypoxic circulatory maladaptation are based on a violation of neurohumoral regulation of vascular tone, transient neonatal pulmonary hypertension (PH) and long-term persistence of fetal communications (PFC), as well as a delay in the formation of a mature type of cardiomyocyte metabolism [3].…”

Chronic Cardiotoxicity Assays Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hiPSC-CMs)

“…Another example of hiPSC-CMs assay being used to study cardiotoxicity induced by a non-drug compound is the sub-chronic (12–24 h) exposure of dichlorodiphenyltrichloroethane (DDT), an insecticide that was used in agriculture until its ban in 1972 but is still ubiquitously found in the environment and associated with cardiovascular disease, which was studied in hiPSC-CMs (iCell CM 2 ) [ 38 ]. Exposure to environmental chemicals and compounds such as Perfluorooctane sulfonate and bisphenol A (BPA) demonstrated mitochondrial damage and altered hESC-CMs morphology and cardiac gene expression [ 39 , 40 , 41 ] post long-term exposure. Our laboratory is currently developing a chronic hiPSC-CMs-based assay to be applied to the safety evaluation of the implantable medical devices that are designed to improve cardiac contractility in heart failure patients.…”

Altered Blood Molecular Markers of Cardiovascular Function in Rats After Intrauterine Hypoxia and Drug Therapy

“…Post-hypoxic disorders of the cardiovascular system occupy one of the leading places in the structure of morbidity in newborns, occurring, according to various sources, in 40-70% infants who have experienced prenatal hypoxia. These disorders contribute significantly to a multitude of often severe ailments in both children and adults [1,2]. The mechanisms underlying the emergence of posthypoxic cardiac disorders have received limited investigation, rendering them a pressing concern within pediatric cardiology.…”

“…The clinical symptoms of this pathology in the acute period are polymorphic, often disguised as other diseases, it is often necessary to carry out differential diagnostics with congenital heart defects, congenital carditis, cardiomyopathies [3,4]. 2 Experimental and clinical research has unveiled a connection between prenatal hypoxia and an increased risk of coronary disease in later adulthood. Moreover, this delayed effect of perinatal hypoxia lies in the expression of a number of factors leading to a change in the tolerance of the heart to acute oxygen deficiency at a later age.…”