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Major characteristics of cardiomyocyte maturation. Dynamic changes of structure and function of cardiomyocytes occur during maturation. Major characteristics of human pluripotent stem cell-derived cardiomyocytes (representing immature cardiomyocyte) and adult-like cardiomyocytes (representing mature cardiomyocyte) as discussed in the text.
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With the in-depth study of heart development, many human cardiomyocytes (CMs) have been generated in a laboratory environment. CMs derived from pluripotent stem cells (PSCs) have been widely used for a series of applications such as laboratory studies, drug toxicology screening, cardiac disease models, and as an unlimited resource for cell-based ca...
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... more excellent ATP production (48,49). During maturation, striking changes of shape, morphology, and the biochemical content of cardiac mitochondria enable an amble and steady ATP production rate for contraction. PSC-CMs have immature mitochondria localized in the perinuclear region, exhibiting disorganized and fewer quantities and smaller sizes (Fig. 2). By contrast, mitochondria in adult CMs are well organized in a highly mature network that is about 40% of the cell volume (50) and are arranged in a straight line in the orientation of the sarcomeres and attached to SR, leading to efficient ATP transport (51, 52). Cristae, the inner membrane invaginations that offer a sufficient ...
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... in the adult Nav1.5 over the fetal Nav1.5 after extended culture (79). Some studies report that after＞60 days in culture, L-type calcium channel in hPSC-CM is remarkably comparable to L-type calcium channel densities measured in adult human ventricular (80). The action potential of immature hPSC-CMs does not display an exact plateau phase (Fig. ...
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... polyploidization. In rodents, ＞75% of CMs become polyploid and largely binucleated resulting from DNA synthesis and nuclear division without cytokinesis (92). By contrast, a similarly high percentage of human and other primate CMs are polyploid containing high DNA contents ranging from 4c to 16c due to DNA synthesis without karyokinesis (93) (Fig. 2). Moreover, the number of polyploid cells improves after myocardial infarction and other injuries. Cardiomyocyte polyploidization is likely negatively correlated with regenerative capacity. Inactivation of tnni3k causes mononuclear diploid CMs to enhance cardiomyocyte proliferation. In turn, overexpression of tnni3k in zebrafish ...
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Cardiac regeneration is one of the grand challenges in repairing injured human hearts. Numerous studies of signaling pathways and metabolism on cardiac development and disease pave the way for endogenous cardiomyocyte regeneration. New drug delivery approaches, high-throughput screening, as well as novel therapeutic compounds combined with gene edi...
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... In human and rodent hearts, proteins, involved in the structure and function of cardiac tissue, can exist in different isoforms, and their expression levels differ between fetal and adult CMs. For example, the heavy chain of myosin with two isoforms, MYH6 and MYH7, builds thick filaments (myosin) of sarcomeres [41,60]. MYH7 expression was upregulated in mature human ventricular CMs, whereas MYH6 gene expression was upregulated in mature rodent cardiac cells [41,42]. ...
... During the development of the heart from the fetal to the adult stage, the electrophysiology of CMs is changed, which is based on the transport of sodium, potassium, and calcium ions [53][54][55]60]. Calcium ions play an essential role in the contraction of CMs. ...
Currently, numerous studies are conducted using nanofibers as a scaffold for culture cardiac cells; however, there still needs to be more research evaluating the impact of the physicochemical properties of polymer nanofibers on the structure and function of cardiac cells. We have studied how poly(ε-caprolactone) (PCL) and polyurethane (PU) nanofibrous mats with different physicochemical properties influence the viability, morphology, orientation, and maturation of cardiac cells. For this purpose, the cells taken from different species were used. They were rat ventricular cardiomyoblasts (H9c2), mouse atrial cardiomyocytes (HL-1), and human ventricular cardiomyocytes (HCM). Based on the results, it can be concluded that cardiac cells cultured on nanofibers exhibit greater maturity in terms of orientation, morphology, and gene expression levels compared to cells cultured on polystyrene plates (PS). Additionally, the physicochemical properties of nanofibers affecting the functionality of cardiac cells from different species and different parts of the heart were evaluated. These studies can support research on understanding and explaining mechanisms leading to cellular maturity present in the heart and the selection of nanofibers that will effectively help the maturation of cardiomyocytes.
... (Qian et al., 2012). Cardiomyogenesis from iPSCs has been attempted previously (Yang et al., 2017;Wu et al., 2023); however, iPSC-derived CMs (iPSC-CMs) largely expressed fetal phenotypes and failed to efficiently function as adult CMs (Liao et al., 2021), limiting their clinical applicability. Recently, progress has been made to enhance the maturity of iPSC-CMs Hsueh et al., 2023). ...
Stem/progenitor cells have been widely evaluated as a promising therapeutic option for heart failure (HF). Numerous clinical trials with stem/progenitor cell-based therapy (SCT) for HF have demonstrated encouraging results, but not without limitations or discrepancies. Recent technological advancements in multiomics, bioinformatics, precision medicine, artificial intelligence (AI), and machine learning (ML) provide new approaches and insights for stem cell research and therapeutic development. Integration of these new technologies into stem/progenitor cell therapy for HF may help address: 1) the technical challenges to obtain reliable and high-quality therapeutic precursor cells, 2) the discrepancies between preclinical and clinical studies, and 3) the personalized selection of optimal therapeutic cell types/populations for individual patients in the context of precision medicine. This review summarizes the current status of SCT for HF in clinics and provides new perspectives on the development of computation-aided SCT in the era of precision medicine and AI/ML.
Current methods to generate cardiomyocytes from induced pluripotent stem cells (iPSc) utilize broad-spectrum pharmacological inhibitors. These methods give rise to cardiomyocytes which are typically immature. Since we have recently demonstrated that cardiomyogenesis in vitro and in vivo requires Sfrp2, we asked if Sfrp2 would drive differentiation of human iPSc into cardiomyocytes. Indeed, we found that Sfrp2 induced robust cardiac differentiation. Importantly, replacement of broad spectrum pharmacological inhibitors with Sfrp2 gave rise to mature cardiomyocytes as evidenced by their sarcomere structure, electrophysiological profiles, and ability to form gap junctions.
