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Mechanism of Cardiac and Neuronal Cell Fate Control

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Proliferation and Division".

Deadline for manuscript submissions: closed (15 November 2021) | Viewed by 27083

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Special Issue Editors

Dr. Jidong Fu

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Guest Editor

Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA
Interests: stem cell; differentiation; cardiac; physiology; arrhythmia; microRNA; epigentic reprogramming; regenerative medicine

Dr. Kyle Fink

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Guest Editor

Stem Cell Program, Institute for Regenerative Cures, MIND Institute, Neurology Department, School of Medicine, University of California, Davis, CA, USA
Interests: gene therapy; epigenetics; stem cell, CRISPR/Cas9; neurological disorder

Special Issue Information

Dear Colleagues,

In the last decade, developmental biology has been a rapidly developing field; the molecular mechanism of cell fate control during development has been being investigated with great achievements. This advanced knowledge, learnt from the development of the embryo, has been applied to develop promising therapeutic approaches for regenerative medicine in different diseases, including heart and neurological diseases. This Special Issue explores the new discoveries of cardiac and neuronal cell fate control, and state-of-the-art research models and applications of mechanisms of cell fate control for cardiac and neurological diseases. Potential topics of reviews and research articles include, but are not limited to, the following:

Mechanism of cardiac and neuronal cell fate control during embryo development
Cardiac and neuronal differentiation of stem cells
Mechanism of cardiac and neuronal regeneration
Epigenetic reprogramming of cell fates
Cell fate transdifferentiation in diseases
Extracellular factors regulate cell fates and regeneration
Signalling pathways in regulation of cell fate control
In vivo and in vitro models of investigating cell fate control
Therapeutic approaches/applications of cardiac and neuronal regenerative medicine through regulating cell fate

Dr. Jidong Fu
Dr. Kyle Fink
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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

Cell fate decision
Development
Differentiation
Transdifferentiation
Regeneration
Stem cells
Extracellular factor

Published Papers (7 papers)

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Research

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14 pages, 4680 KiB

Open AccessArticle

Prompt Graft Cooling Enhances Cardioprotection during Heart Transplantation Procedures through the Regulation of Mitophagy

by Zhichao Wu, Jialiang Liang, Wei Huang, Lin Jiang, Christian Paul, Bonnie Lin, Junmeng Zheng and Yigang Wang

Cells 2021, 10(11), 2912; https://doi.org/10.3390/cells10112912 - 27 Oct 2021

Cited by 1 | Viewed by 1901

Abstract

A complete and prompt cardiac arrest using a cold cardioplegic solution is routinely used in heart transplantation to protect the graft function. However, warm ischemic time is still inevitable during the procedure to isolate donor hearts in the clinical setting. Our knowledge of the mechanism changes prevented by cold storage, and how warm ischemia damages donor hearts, is extremely poor. The potential consequences of this inevitable warm ischemic time to grafts, and the underlying potential protective mechanism of prompt graft cooling, have been studied in order to explore an advanced graft protection strategy. To this end, a surgical procedure, including 10–15 min warm ischemic time during procurement, was performed in mouse models to mimic the clinical situation (Group I), and compared to a group of mice that had the procurement performed with prompt cooling procedures (Group II). The myocardial morphologic changes (including ultrastructure) were then assessed by electron and optical microscopy after 6 h of cold preservation. Furthermore, syngeneic heart transplantation was performed after 6 h of cold preservation to measure the graft heart function. An electron microscopy showed extensive damage, including hypercontracted myofibers with contraction bands, and damaged mitochondria that released mitochondrial contents in Group I mice, while similar patterns of damage were not observed in the mice from Group II. The results from both the electron microscopy and immunoblotting verified that cardiac mitophagy (protective mitochondrial autophagy) was present in the mice from Group II, but was absent in the mice from Group I. Moreover, the mice from Group II demonstrated faster rebeating times and higher beating scores, as compared to the mice from Group I. The pressure catheter system results indicated that the graft heart function was significantly more improved in the mice from Group II than in those from Group I, as demonstrated by the left ventricle systolic pressure (31.96 ± 6.54 vs. 26.12 ± 8.87 mmHg), the +dp/dt (815.6 ± 215.4 vs. 693.9 ± 153.8 mmHg/s), and the -dp/dt: (492.4 ± 92.98 vs. 418.5 ± 118.9 mmHg/s). In conclusion, the warm ischemic time during the procedure impaired the graft function and destroyed the activation of mitophagy. Thus, appropriate mitophagy activation has emerged as a promising therapeutic target that may be essential for graft protection and functional improvement during heart transplantation. Full article

(This article belongs to the Special Issue Mechanism of Cardiac and Neuronal Cell Fate Control)

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20 pages, 8284 KiB

Open AccessArticle

The Spatiotemporal Expression of Notch1 and Numb and Their Functional Interaction during Cardiac Morphogenesis

by Lianjie Miao, Yangyang Lu, Anika Nusrat, Hala Y. Abdelnasser, Sayantap Datta, Bin Zhou, Robert J. Schwartz and Mingfu Wu

Cells 2021, 10(9), 2192; https://doi.org/10.3390/cells10092192 - 25 Aug 2021

Cited by 7 | Viewed by 3294

Abstract

Numb family proteins (NFPs), including Numb and Numblike (Numbl), are commonly known for their role as cell fate determinants for multiple types of progenitor cells, mainly due to their function as Notch inhibitors. Previous studies have shown that myocardial NFP double knockout (MDKO) hearts display an up-regulated Notch activation and various defects in cardiac progenitor cell differentiation and cardiac morphogenesis. Whether enhanced Notch activation causes these defects in MDKO is not fully clear. To answer the question, we examined the spatiotemporal patterns of Notch1 expression, Notch activation, and Numb expression in the murine embryonic hearts using multiple approaches including RNAScope, and Numb and Notch reporter mouse lines. To further interrogate the interaction between NFPs and Notch signaling activation, we deleted both Notch1 or RBPJk alleles in the MDKO. We examined and compared the phenotypes of Notch1 knockout, NFPs double knockout, Notch1; Numb; Numbl and RBPJk; Numb; Numbl triple knockouts. Our study showed that Notch1 is expressed and activated in the myocardium at several stages, and Numb is enriched in the epicardium and did not show the asymmetric distribution in the myocardium. Cardiac-specific Notch1 deletion causes multiple structural defects and embryonic lethality. Notch1 or RBPJk deletion in MDKO did not rescue the structural defects in the MDKO but partially rescued the defects of cardiac progenitor cell differentiation, cardiomyocyte proliferation, and trabecular morphogenesis. Our study concludes that NFPs regulate progenitor cell differentiation, cardiomyocyte proliferation, and trabecular morphogenesis partially through Notch1 and play more roles than inhibiting Notch1 signaling during cardiac morphogenesis. Full article

(This article belongs to the Special Issue Mechanism of Cardiac and Neuronal Cell Fate Control)

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15 pages, 5665 KiB

Open AccessFeature PaperArticle

Inhibition of CREB-CBP Signaling Improves Fibroblast Plasticity for Direct Cardiac Reprogramming

by Emre Bektik, Yu Sun, Adrienne T. Dennis, Phraew Sakon, Dandan Yang, Isabelle Deschênes and Ji-Dong Fu

Cells 2021, 10(7), 1572; https://doi.org/10.3390/cells10071572 - 22 Jun 2021

Cited by 7 | Viewed by 3094

Abstract

Direct cardiac reprogramming of fibroblasts into induced cardiomyocytes (iCMs) is a promising approach but remains a challenge in heart regeneration. Efforts have focused on improving the efficiency by understanding fundamental mechanisms. One major challenge is that the plasticity of cultured fibroblast varies batch to batch with unknown mechanisms. Here, we noticed a portion of in vitro cultured fibroblasts have been activated to differentiate into myofibroblasts, marked by the expression of αSMA, even in primary cell cultures. Both forskolin, which increases cAMP levels, and TGFβ inhibitor SB431542 can efficiently suppress myofibroblast differentiation of cultured fibroblasts. However, SB431542 improved but forskolin blocked iCM reprogramming of fibroblasts that were infected with retroviruses of Gata4, Mef2c, and Tbx5 (GMT). Moreover, inhibitors of cAMP downstream signaling pathways, PKA or CREB-CBP, significantly improved the efficiency of reprogramming. Consistently, inhibition of p38/MAPK, another upstream regulator of CREB-CBP, also improved reprogramming efficiency. We then investigated if inhibition of these signaling pathways in primary cultured fibroblasts could improve their plasticity for reprogramming and found that preconditioning of cultured fibroblasts with CREB-CBP inhibitor significantly improved the cellular plasticity of fibroblasts to be reprogrammed, yielding ~2-fold more iCMs than untreated control cells. In conclusion, suppression of CREB-CBP signaling improves fibroblast plasticity for direct cardiac reprogramming. Full article

(This article belongs to the Special Issue Mechanism of Cardiac and Neuronal Cell Fate Control)

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Graphical abstract

9 pages, 3858 KiB

Open AccessCommunication

Chamber-Specific Protein Expression during Direct Cardiac Reprogramming

by Zhentao Zhang, Jesse Villalpando, Wenhui Zhang and Young-Jae Nam

Cells 2021, 10(6), 1513; https://doi.org/10.3390/cells10061513 - 16 Jun 2021

Cited by 6 | Viewed by 1923

Abstract

Forced expression of core cardiogenic transcription factors can directly reprogram fibroblasts to induced cardiomyocyte-like cells (iCMs) in vitro and in vivo. This cardiac reprogramming approach provides a proof of concept for induced heart regeneration by converting a fibroblast fate to a cardiomyocyte fate. However, it remains elusive whether chamber-specific cardiomyocytes can be generated by cardiac reprogramming. Therefore, we assessed the ability of the cardiac reprogramming approach for chamber specification in vitro and in vivo. We found that in vivo cardiac reprogramming post-myocardial infarction exclusively induces a ventricular-like phenotype, while a major fraction of iCMs generated in vitro failed to determine their chamber identities. Our results suggest that in vivo cardiac reprogramming may have an inherent advantage of generating chamber-matched new cardiomyocytes as a potential heart regenerative approach. Full article

(This article belongs to the Special Issue Mechanism of Cardiac and Neuronal Cell Fate Control)

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Review

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27 pages, 1460 KiB

Open AccessReview

Harnessing the Power of Stem Cell Models to Study Shared Genetic Variants in Congenital Heart Diseases and Neurodevelopmental Disorders

by Xuyao Chang, Mingxia Gu and Jason Tchieu

Cells 2022, 11(3), 460; https://doi.org/10.3390/cells11030460 - 28 Jan 2022

Viewed by 3335

Abstract

Advances in human pluripotent stem cell (hPSC) technology allow one to deconstruct the human body into specific disease-relevant cell types or create functional units representing various organs. hPSC-based models present a unique opportunity for the study of co-occurring disorders where “cause and effect” can be addressed. Poor neurodevelopmental outcomes have been reported in children with congenital heart diseases (CHD). Intuitively, abnormal cardiac function or surgical intervention may stunt the developing brain, leading to neurodevelopmental disorders (NDD). However, recent work has uncovered several genetic variants within genes associated with the development of both the heart and brain that could also explain this co-occurrence. Given the scalability of hPSCs, straightforward genetic modification, and established differentiation strategies, it is now possible to investigate both CHD and NDD as independent events. We will first overview the potential for shared genetics in both heart and brain development. We will then summarize methods to differentiate both cardiac & neural cells and organoids from hPSCs that represent the developmental process of the heart and forebrain. Finally, we will highlight strategies to rapidly screen several genetic variants together to uncover potential phenotypes and how therapeutic advances could be achieved by hPSC-based models. Full article

(This article belongs to the Special Issue Mechanism of Cardiac and Neuronal Cell Fate Control)

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33 pages, 1424 KiB

Open AccessReview

Cell Transdifferentiation and Reprogramming in Disease Modeling: Insights into the Neuronal and Cardiac Disease Models and Current Translational Strategies

by Rajkumar Singh Kalra, Jaspreet Kaur Dhanjal, Mriganko Das, Birbal Singh and Rajesh Naithani

Cells 2021, 10(10), 2558; https://doi.org/10.3390/cells10102558 - 27 Sep 2021

Cited by 5 | Viewed by 5674

Abstract

Cell transdifferentiation and reprogramming approaches in recent times have enabled the manipulation of cell fate by enrolling exogenous/artificial controls. The chemical/small molecule and regulatory components of transcription machinery serve as potential tools to execute cell transdifferentiation and have thereby uncovered new avenues for disease modeling and drug discovery. At the advanced stage, one can believe these methods can pave the way to develop efficient and sensitive gene therapy and regenerative medicine approaches. As we are beginning to learn about the utility of cell transdifferentiation and reprogramming, speculations about its applications in translational therapeutics are being largely anticipated. Although clinicians and researchers are endeavoring to scale these processes, we lack a comprehensive understanding of their mechanism(s), and the promises these offer for targeted and personalized therapeutics are scarce. In the present report, we endeavored to provide a detailed review of the original concept, methods and modalities enrolled in the field of cellular transdifferentiation and reprogramming. A special focus is given to the neuronal and cardiac systems/diseases towards scaling their utility in disease modeling and drug discovery. Full article

(This article belongs to the Special Issue Mechanism of Cardiac and Neuronal Cell Fate Control)

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18 pages, 1270 KiB

Open AccessReview

Mitochondrial Biogenesis, Mitochondrial Dynamics, and Mitophagy in the Maturation of Cardiomyocytes

by Qianqian Ding, Yanxiang Qi and Suk-Ying Tsang

Cells 2021, 10(9), 2463; https://doi.org/10.3390/cells10092463 - 18 Sep 2021

Cited by 34 | Viewed by 6524

Abstract

Pluripotent stem cells (PSCs) can undergo unlimited self-renewal and can differentiate into all the cell types present in our body, including cardiomyocytes. Therefore, PSCs can be an excellent source of cardiomyocytes for future regenerative medicine and medical research studies. However, cardiomyocytes obtained from PSC differentiation culture are regarded as immature structurally, electrophysiologically, metabolically, and functionally. Mitochondria are organelles responsible for various cellular functions such as energy metabolism, different catabolic and anabolic processes, calcium fluxes, and various signaling pathways. Cells can respond to cellular needs to increase the mitochondrial mass by mitochondrial biogenesis. On the other hand, cells can also degrade mitochondria through mitophagy. Mitochondria are also dynamic organelles that undergo continuous fusion and fission events. In this review, we aim to summarize previous findings on the changes of mitochondrial biogenesis, mitophagy, and mitochondrial dynamics during the maturation of cardiomyocytes. In addition, we intend to summarize whether changes in these processes would affect the maturation of cardiomyocytes. Lastly, we aim to discuss unanswered questions in the field and to provide insights for the possible strategies of enhancing the maturation of PSC-derived cardiomyocytes. Full article

(This article belongs to the Special Issue Mechanism of Cardiac and Neuronal Cell Fate Control)

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