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Cell Programming for Cardiovascular Disease Modeling and Therapy 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 7673

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Special Issue Editor

Prof. Dr. Robert David

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Guest Editor

1. Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany
2. Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
Interests: cardiovascular diseases; pluripotent stem cells; ESCs; iPSCs; adult stem cells; cell replacement; direct reprogramming; cardiac regeneration; stem cell optimisation; cell targeting; sinus node; biological pacemaker; cell therapy; gene therapy; forward programming; organoid; disease-in-the-dish
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Special Issue Information

Dear Colleagues,

Cardiovascular diseases still represent a leading cause of mortality in the developed countries with highly limited therapy options. A main reason is the very limited regeneration potential of collapsed cardiomyocytes – therefore novel approaches toward personalized regenerative therapy and drug development are of major importance. In recent years, forward programming of iPSCs as well as Direct Reprogramming of somatic cells and adult stem cells have introduced entirely novel options to circumvent obstacles commonly encountered in regenerative medicine by utilizing autologous cells as the source of treatment. This has greatly benefitted from efforts to identify and optimize master regulator combinations to redefine cellular fates. Multiple research groups have shown direct somatic cell conversion towards cardiovascular cells, thereby avoiding a pluripotent intermediate state. Moreover, in vitro test systems based on organoid cultures derived from patient specific programmed cardiovascular cells are being developed which will enable personalized drug testing in precision medicine. In this Special Issue, we are aiming to broadly adress topics from understanding the basic science of somatic and stem cell reprogramming to their applications in cardiovascular regeneration and disease treatment as well as in vitro disease modeling approaches.

The current Special Issue will accept original studies, reviews and technical reports in the field of cardiovascular cell programming, disease modeling and cell based therapy, written by scientists active in the field.

Prof. Dr. Robert David
Guest Editor

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

cardiovascular diseases
iPSCs (induced pluripotent stem cells)
ESCs
adult stem cells
autologous cell therapy
cardiovascular organoids
cardiovascular disease modeling
drug discovery
direct reprogramming
forward programming
cardiovascular repair
cell targeting

Published Papers (3 papers)

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Research

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20 pages, 3207 KiB

Open AccessArticle

Recombinant Adeno-Associated Viral Vector-Mediated Gene Transfer of hTBX18 Generates Pacemaker Cells from Ventricular Cardiomyocytes

by Melad Farraha, Renuka Rao, Sindhu Igoor, Thi Y. L. Le, Michael A. Barry, Christopher Davey, Cindy Kok, James J.H. Chong and Eddy Kizana

Int. J. Mol. Sci. 2022, 23(16), 9230; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169230 - 17 Aug 2022

Cited by 2 | Viewed by 1625

Abstract

Sinoatrial node dysfunction can manifest as bradycardia, leading to symptoms of syncope and sudden cardiac death. Electronic pacemakers are the current standard of care but are limited due to a lack of biological chronotropic control, cost of revision surgeries, and risk of lead- and device-related complications. We therefore aimed to develop a biological alternative to electronic devices by using a clinically relevant gene therapy vector to demonstrate conversion of cardiomyocytes into sinoatrial node-like cells in an in vitro context. Neonatal rat ventricular myocytes were transduced with recombinant adeno-associated virus vector 6 encoding either hTBX18 or green fluorescent protein and maintained for 3 weeks. At the endpoint, qPCR, Western blot analysis and immunocytochemistry were used to assess for reprogramming into pacemaker cells. Cell morphology and Arclight action potentials were imaged via confocal microscopy. Compared to GFP, hTBX18-transduced cells showed that hTBX18, HCN4 and Cx45 were upregulated. Cx43 was significantly downregulated, while sarcomeric α-actinin remained unchanged. Cardiomyocytes transduced with hTBX18 acquired the tapering morphology of native pacemaker cells, as compared to the block-like, striated appearance of ventricular cardiomyocytes. Analysis of the action potentials showed phase 4 depolarization and a significant decrease in the APD50 of the hTBX18-transduced cells. We have demonstrated that rAAV-hTBX18 gene transfer to ventricular myocytes results in morphological, molecular, physiological, and functional changes, recapitulating the pacemaker phenotype in an in vitro setting. The generation of these induced pacemaker-like cells using a clinically relevant vector opens new prospects for biological pacemaker development. Full article

(This article belongs to the Special Issue Cell Programming for Cardiovascular Disease Modeling and Therapy 2.0)

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16 pages, 3041 KiB

Open AccessArticle

Missense Mutations in Desmoplakin Plakin Repeat Domains Have Dramatic Effects on Domain Structure and Function

by Fiyaz Mohammed, Elena Odintsova and Martyn Chidgey

Int. J. Mol. Sci. 2022, 23(1), 529; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010529 - 04 Jan 2022

Cited by 1 | Viewed by 1809

Abstract

Plakin repeat domains (PRDs) are globular modules that mediate the interaction of plakin proteins with the intermediate filament (IF) cytoskeleton. These associations are vital for maintaining tissue integrity in cardiac muscle and epithelial tissues. PRDs are subject to mutations that give rise to cardiomyopathies such as arrhythmogenic right ventricular cardiomyopathy, characterised by ventricular arrhythmias and associated with an increased risk of sudden heart failure, and skin blistering diseases. Herein, we have examined the functional and structural effects of 12 disease-linked missense mutations, identified from the human gene mutation database, on the PRDs of the desmosomal protein desmoplakin. Five mutations (G2056R and E2193K in PRD-A, G2338R and G2375R in PRD-B and G2647D in PRD-C) rendered their respective PRD proteins either fully or partially insoluble following expression in bacterial cells. Each of the residues affected are conserved across plakin family members, inferring a crucial role in maintaining the structural integrity of the PRD. In transfected HeLa cells, the mutation G2375R adversely affected the targeting of a desmoplakin C-terminal construct containing all three PRDs to vimentin IFs. The deletion of PRD-B and PRD-C from the construct compromised its targeting to vimentin. Bioinformatic and structural modelling approaches provided multiple mechanisms by which the disease-causing mutations could potentially destabilise PRD structure and compromise cytoskeletal linkages. Overall, our data highlight potential molecular mechanisms underlying pathogenic missense mutations and could pave the way for informing novel curative interventions targeting cardiomyopathies and skin blistering disorders. Full article

(This article belongs to the Special Issue Cell Programming for Cardiovascular Disease Modeling and Therapy 2.0)

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Review

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28 pages, 708 KiB

Open AccessReview

Cell-Based and Selected Cell-Free Therapies for Myocardial Infarction: How Do They Compare to the Current Treatment Options?

by Mária Csöbönyeiová, Nikoleta Beerová, Martin Klein, Michaela Debreová-Čeháková and Ľuboš Danišovič

Int. J. Mol. Sci. 2022, 23(18), 10314; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810314 - 07 Sep 2022

Cited by 8 | Viewed by 3646

Abstract

Because of cardiomyocyte death or dysfunction frequently caused by myocardial infarction (MI), heart failure is a leading cause of morbidity and mortality in modern society. Paradoxically, only limited and non-curative therapies for heart failure or MI are currently available. As a result, over the past two decades research has focused on developing cell-based approaches promoting the regeneration of infarcted tissue. Cell-based therapies for myocardial regeneration include powerful candidates, such as multipotent stem cells (mesenchymal stem cells (MSCs), bone-marrow-derived stem cells, endothelial progenitor cells, and hematopoietic stem cells) and induced pluripotent stem cells (iPSCs). These possess unique properties, such as potency to differentiate into desired cell types, proliferation capacity, and patient specificity. Preclinical and clinical studies have demonstrated modest improvement in the myocardial regeneration and reduced infarcted areas upon transplantation of pluripotent or multipotent stem cells. Another cell population that need to be considered as a potential source for cardiac regeneration are telocytes found in different organs, including the heart. Their therapeutic effect has been studied in various heart pathologies, such as MI, arrhythmias, or atrial amyloidosis. The most recent cell-free therapeutic tool relies on the cardioprotective effect of complex cargo carried by small membrane-bound vesicles—exosomes—released from stem cells via exocytosis. The MSC/iPSC-derived exosomes could be considered a novel exosome-based therapy for cardiovascular diseases thanks to their unique content. There are also other cell-free approaches, e.g., gene therapy, or acellular cardiac patches. Therefore, our review provides the most recent insights into the novel strategies for myocardial repair based on the regenerative potential of different cell types and cell-free approaches. Full article

(This article belongs to the Special Issue Cell Programming for Cardiovascular Disease Modeling and Therapy 2.0)

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