Adaptation of cardiomyogenesis to the generation and maturation of cardiomyocytes from human pluripotent stem cells

Abstract

The advent of methods for efficient generation and cardiac differentiation of pluripotent stem cells opened new avenues for disease modelling, drug testing, and cell therapies of the heart. However, cardiomyocytes (CM) obtained from such cells demonstrate an immature, foetal‐like phenotype that involves spontaneous contractions, irregular morphology, expression of embryonic isoforms of sarcomere components, and low level of ion channels. These and other features may affect cellular response to putative therapeutic compounds and the efficient integration into the host myocardium after in vivo delivery. Therefore, novel strategies to increase the maturity of pluripotent stem cell‐derived CM are of utmost importance. Several approaches have already been developed relying on molecular changes that occur during foetal and postnatal maturation of the heart, its electromechanical activity, and the cellular composition. As a better understanding of these determinants may facilitate the generation of efficient protocols for in vitro acquisition of an adult‐like phenotype by immature CM, this review summarizes the most important molecular factors that govern CM during embryonic development, postnatal changes that trigger heart maturation, as well as protocols that are currently used to generate mature pluripotent stem cell‐derived cardiomyocytes.

How to fix a broken heart—designing biofunctional cues for effective, environmentally-friendly cardiac tissue engineering

“…Furthermore, when these are short and highly functionalized, high biodegradability can be achieved; 3) In-mass modification of scaffolds with bioactive molecules for their controllable release. The most promising ones include: albuminmodified fatty acids (which could force a switch in the CM metabolic pathway), triiodothyronine (inducing a switch from fetal N2BA to an adult N2B titin isoform) and dexamethasone (both of which affect the CM electrophysiology, and IGF-1 (to induce the hyperplastic growth)) (Martyniak et al, 2023). Preferably, these should be released in a switchable manner, so as to mimic their natural occurrence within the developing and maturing heart; 4) A co-culture with cardiac fibroblasts which could aid in scaffold remodeling and secrete specific signaling molecules that further drive the CM maturation; 5) Introducing exogenous electrical and mechanical stimulation which could "train" the cardiac tissue, thus forcing CM maturation; and 6) Finally, in our opinion, CM culture should be dynamic-the mechanical and electrical properties of the growing tissue should be controllable.…”

“…Important advantages of using iPSCs over other cell sources are their unlimited source and ability to obtain patient-specific cardiomyocytes. The latter becomes favorable when considering tissue engineering strategies with a reduced rejection risk, as well as designing strategies for the in vitro evaluation of various genetic diseases (Martyniak et al, 2023). Pluripotent cells can be subjected to initial differentiation, which already has been proven to yield cardiomyocytes in vitro.…”

“…Some very recent and promising approaches used to enhance the maturation of iPSCs-derived cardiomyocytes (iPSCs-CMs) are gathered in a review by Martyniak et al (Martyniak et al, 2023). This excellent study provides a detailed description of the natural cardio genesis, lists important hallmarks of mature cardiomyocytes, as wells as gives validated protocols enhancing cell maturation efficacy in vitro.…”

“…The heart is composed of multiple cell types, fibroblasts being the second most abundant. Their main role is remodeling of the ECM and secreting signaling molecules that alter CM metabolism-from proliferation through maturation and growth (hypertrophy) (Li et al, 2017a;Karbassi et al, 2020;Martyniak et al, 2023). This clearly indicates that it might be very difficult, if not impossible, to obtain CMs of a mature phenotype in the absence of fibroblasts.…”