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Recent Developments in Molecular and Cellular Cardiology: Mathematical Models, Cell Model, and Organoids

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 31 August 2024 | Viewed by 4164

Special Issue Editors

Dr. Andrea Barbuti

E-Mail Website
Guest Editor
Department of Biosciences, Università degli Studi di Milano, Milan, Italy
Interests: sinoatrial cells; human-induced pluripotent stem cell (iPSC)
Special Issues, Collections and Topics in MDPI journals
Dr. Patrizia Benzoni

E-Mail Website
Guest Editor
Department of Biosciences, Università degli Studi di Milano, Milan, Italy
Interests: pluripotent stem cells; cardiomyocytes; electrophysiology

Special Issue Information

Dear Colleagues,

Many cardiovascular diseases, may be categorized in the same family even though their molecular mechanisms are very different or still poorly known, such as for example atrial fibrillation (AF) sinus node disease (SND), and dilated cardiomyopathies (DCM). Many advances in the treatment of the disease have been achieved once the genetic or molecular causes have been elucidated (such as in LQT syndromes, etc.) or after the understanding that non-ion channels genes/proteins (as in ACM, cardiomyopathies) may play important roles in the onset of cardiac pathological symptoms. This growth of knowledge has been possible thanks to the evolution and use of methods and models applied to cardiac research: from the expression of mutated proteins in heterologous systems to the generation of hiPS-derived cardiomyocytes with the genetic background of the patient, to more complex systems including different types of cells (Organoids, LAB on Chip). Important contributions derived also from mathematical model and artificial intelligence algorithm.

The aim of this special issue is to bring together the latest findings that may shed new light on the mechanism underlying heart diseases, using the various evolving cell/tissue systems and mathematical models.

Dr. Andrea Barbuti
Dr. Patrizia Benzoni
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • arrhythmias
  • cardiovascular diseases
  • ion channels
  • stem-cell derived cardiomyocytes
  • cardiac cellular models
  • cardiomyopathies
  • organoids
  • mathematical models

Published Papers (4 papers)

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Research

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18 pages, 3699 KiB  
Article
Caveolin-3 and Caveolin-1 Interaction Decreases Channel Dysfunction Due to Caveolin-3 Mutations
by Patrizia Benzoni, Elisabetta Gazzerro, Chiara Fiorillo, Serena Baratto, Chiara Bartolucci, Stefano Severi, Raffaella Milanesi, Melania Lippi, Marianna Langione, Carmen Murano, Clarissa Meoni, Vera Popolizio, Alessandro Cospito, Mirko Baruscotti, Annalisa Bucchi and Andrea Barbuti
Int. J. Mol. Sci. 2024, 25(2), 980; https://doi.org/10.3390/ijms25020980 - 12 Jan 2024
Viewed by 812
Abstract
Caveolae constitute membrane microdomains where receptors and ion channels functionally interact. Caveolin-3 (cav-3) is the key structural component of muscular caveolae. Mutations in CAV3 lead to caveolinopathies, which result in both muscular dystrophies and cardiac diseases. In cardiomyocytes, cav-1 participates with cav-3 to [...] Read more.
Caveolae constitute membrane microdomains where receptors and ion channels functionally interact. Caveolin-3 (cav-3) is the key structural component of muscular caveolae. Mutations in CAV3 lead to caveolinopathies, which result in both muscular dystrophies and cardiac diseases. In cardiomyocytes, cav-1 participates with cav-3 to form caveolae; skeletal myotubes and adult skeletal fibers do not express cav-1. In the heart, the absence of cardiac alterations in the majority of cases may depend on a conserved organization of caveolae thanks to the expression of cav-1. We decided to focus on three specific cav-3 mutations (Δ62-64YTT; T78K and W101C) found in heterozygosis in patients suffering from skeletal muscle disorders. We overexpressed both the WT and mutated cav-3 together with ion channels interacting with and modulated by cav-3. Patch-clamp analysis conducted in caveolin-free cells (MEF-KO), revealed that the T78K mutant is dominant negative, causing its intracellular retention together with cav-3 WT, and inducing a significant reduction in current densities of all three ion channels tested. The other cav-3 mutations did not cause significant alterations. Mathematical modelling of the effects of cav-3 T78K would impair repolarization to levels incompatible with life. For this reason, we decided to compare the effects of this mutation in other cell lines that endogenously express cav-1 (MEF-STO and CHO cells) and to modulate cav-1 expression with an shRNA approach. In these systems, the membrane localization of cav-3 T78K was rescued in the presence of cav-1, and the current densities of hHCN4, hKv1.5 and hKir2.1 were also rescued. These results constitute the first evidence of a compensatory role of cav-1 in the heart, justifying the reduced susceptibility of this organ to caveolinopathies. Full article
(This article belongs to the Special Issue Recent Developments in Molecular and Cellular Cardiology: Mathematical Models, Cell Model, and Organoids)
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17 pages, 2512 KiB  
Article
Unravelling Novel SCN5A Mutations Linked to Brugada Syndrome: Functional, Structural, and Genetic Insights
by Anthony Frosio, Emanuele Micaglio, Ivan Polsinelli, Serena Calamaio, Dario Melgari, Rachele Prevostini, Andrea Ghiroldi, Anna Binda, Paola Carrera, Marco Villa, Flavio Mastrocinque, Silvia Presi, Raffaele Salerno, Antonio Boccellino, Luigi Anastasia, Giuseppe Ciconte, Stefano Ricagno, Carlo Pappone and Ilaria Rivolta
Int. J. Mol. Sci. 2023, 24(20), 15089; https://doi.org/10.3390/ijms242015089 - 11 Oct 2023
Viewed by 1126
Abstract
Brugada Syndrome (BrS) is a rare inherited cardiac arrhythmia causing potentially fatal ventricular tachycardia or fibrillation, mainly occurring during rest or sleep in young individuals without heart structural issues. It increases the risk of sudden cardiac death, and its characteristic feature is an [...] Read more.
Brugada Syndrome (BrS) is a rare inherited cardiac arrhythmia causing potentially fatal ventricular tachycardia or fibrillation, mainly occurring during rest or sleep in young individuals without heart structural issues. It increases the risk of sudden cardiac death, and its characteristic feature is an abnormal ST segment elevation on the ECG. While BrS has diverse genetic origins, a subset of cases can be conducted to mutations in the SCN5A gene, which encodes for the Nav1.5 sodium channel. Our study focused on three novel SCN5A mutations (p.A344S, p.N347K, and p.D349N) found in unrelated BrS families. Using patch clamp experiments, we found that these mutations disrupted sodium currents: p.A344S reduced current density, while p.N347K and p.D349N completely abolished it, leading to altered voltage dependence and inactivation kinetics when co-expressed with normal channels. We also explored the effects of mexiletine treatment, which can modulate ion channel function. Interestingly, the p.N347K and p.D349N mutations responded well to the treatment, rescuing the current density, while p.A344S showed a limited response. Structural analysis revealed these mutations were positioned in key regions of the channel, impacting its stability and function. This research deepens our understanding of BrS by uncovering the complex relationship between genetic mutations, ion channel behavior, and potential therapeutic interventions. Full article
(This article belongs to the Special Issue Recent Developments in Molecular and Cellular Cardiology: Mathematical Models, Cell Model, and Organoids)
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Review

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17 pages, 2356 KiB  
Review
State-of-the-Art Differentiation Protocols for Patient-Derived Cardiac Pacemaker Cells
by Eleonora Torre, Matteo E. Mangoni, Alain Lacampagne, Albano C. Meli and Pietro Mesirca
Int. J. Mol. Sci. 2024, 25(6), 3387; https://doi.org/10.3390/ijms25063387 - 16 Mar 2024
Viewed by 537
Abstract
Human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes raise the possibility of generating pluripotent stem cells from a wide range of human diseases. In the cardiology field, hiPSCs have been used to address the mechanistic bases of primary arrhythmias and in investigations of drug safety. [...] Read more.
Human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes raise the possibility of generating pluripotent stem cells from a wide range of human diseases. In the cardiology field, hiPSCs have been used to address the mechanistic bases of primary arrhythmias and in investigations of drug safety. These studies have been focused primarily on atrial and ventricular pathologies. Consequently, many hiPSC-based cardiac differentiation protocols have been developed to differentiate between atrial- or ventricular-like cardiomyocytes. Few protocols have successfully proposed ways to obtain hiPSC-derived cardiac pacemaker cells, despite the very limited availability of human tissues from the sinoatrial node. Providing an in vitro source of pacemaker-like cells would be of paramount importance in terms of furthering our understanding of the mechanisms underlying sinoatrial node pathophysiology and testing innovative clinical strategies against sinoatrial node dysfunction (i.e., biological pacemakers and genetic- and pharmacological- based therapy). Here, we summarize and detail the currently available protocols used to obtain patient-derived pacemaker-like cells. Full article
(This article belongs to the Special Issue Recent Developments in Molecular and Cellular Cardiology: Mathematical Models, Cell Model, and Organoids)
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19 pages, 1484 KiB  
Review
MicroRNAs: Midfielders of Cardiac Health, Disease and Treatment
by Emman Asjad and Halina Dobrzynski
Int. J. Mol. Sci. 2023, 24(22), 16207; https://doi.org/10.3390/ijms242216207 - 11 Nov 2023
Cited by 3 | Viewed by 1240
Abstract
MicroRNAs (miRNAs) are a class of small non-coding RNA molecules that play a role in post-transcriptional gene regulation. It is generally accepted that their main mechanism of action is the negative regulation of gene expression, through binding to specific regions in messenger RNA [...] Read more.
MicroRNAs (miRNAs) are a class of small non-coding RNA molecules that play a role in post-transcriptional gene regulation. It is generally accepted that their main mechanism of action is the negative regulation of gene expression, through binding to specific regions in messenger RNA (mRNA) and repressing protein translation. By interrupting protein synthesis, miRNAs can effectively turn genes off and influence many basic processes in the body, such as developmental and apoptotic behaviours of cells and cardiac organogenesis. Their importance is highlighted by inhibiting or overexpressing certain miRNAs, which will be discussed in the context of coronary artery disease, atrial fibrillation, bradycardia, and heart failure. Dysregulated levels of miRNAs in the body can exacerbate or alleviate existing disease, and their omnipresence in the body makes them reliable as quantifiable markers of disease. This review aims to provide a summary of miRNAs as biomarkers and their interactions with targets that affect cardiac health, and intersperse it with current therapeutic knowledge. It intends to succinctly inform on these topics and guide readers toward more comprehensive works if they wish to explore further through a wide-ranging citation list. Full article
(This article belongs to the Special Issue Recent Developments in Molecular and Cellular Cardiology: Mathematical Models, Cell Model, and Organoids)
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