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Cells
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Regulated Cell Death – Mechanisms and Biological Implications
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Regulated Cell Death – Mechanisms and Biological Implications

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

Deadline for manuscript submissions: closed (15 September 2022) | Viewed by 21754

Special Issue Editors

Dr. Enrico Radaelli

E-Mail Website
Guest Editor
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 3900 Delancey Street, MJR-VHUP, Room 4006, Philadelphia, PA 19104-6051, USA
Interests: veterinary pathology; comparative pathology; histopathology; digital pathology; image analysis; animal models of human disease; genetically engineered mice; humanized mice; histochemistry; immunohistochemistry; in situ hybridization; immunofluorescence
Dr. Igor E. Brodsky

E-Mail Website
Guest Editor
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Interests: pyroptosis; caspase-1; caspase-8; apoptosis; RIPK1; cell death; bacterial infection; Salmonella; Yersinia; inflammasome; NF-κB signaling; TNF; intestinal inflammation; sepsis

Special Issue Information

Dear Colleagues,

While the term apoptosis to describe programmed cell death first entered the scientific literature in 1972, the process of cell death in physiologic settings was largely considered passive and unregulated, with apoptosis being the only known example of a defined cell death ‘program’. However, over the past 15 years, there have been considerable advancements in our understanding of cell death, including the discovery of novel pathways governing distinct cell death modalities. Within organisms, cells that are exposed to extreme physicochemical or mechanical stressors undergo uncontrollable structural breakdown referred to as “accidental cell death” (ACD). Conversely, “regulated cell death” (RCD) is now known to encompass a number of processes, including apoptosis but also other forms of cell death. These involve specific signaling cascades and molecularly defined effector mechanisms leading to different types of cell demise that can be modulated pharmacologically or genetically. RCD is thus implicated not only in fundamental processes such as organogenesis and tissue remodeling, removal of unnecessary structures or cells, and regulation of cell numbers. RCD can also be triggered by exogenous perturbations of the intracellular or extracellular microenvironment when the adaptive processes that respond to stress fail. Emerging RCD modalities that have been recognized include necroptosis, parthanatos, pyroptosis, ferroptosis, and NETosis.

The recent breakthroughs in the study of cell death have sparked an unprecedented interest in this field of research. The Cells journal is therefore issuing a call for papers for a Special Issue on the topic of “Regulated Cell Death—Mechanisms and Biological Implications” and encourages the submission of primary research papers. In that context, the journal welcomes original research contributions advancing our understanding of the basic mechanisms leading to different types of cell death, discovery of biomarkers and assays for the definition of different cell death modalities, and implications of RCD in diverse biological or pathological contexts. High-quality review articles exploring specific aspects of the cell death field will be also considered.

Interested authors are advised to send a short summary or prospectus to the journal before submitting a manuscript. The submission of the summaries will begin on 7th June 2021 and will close on 31st October 2021. Upon review, corresponding authors will be contacted via e-mail in regard to the status of their submissions and next steps.

Dr. Enrico Radaelli
Dr. Igor E. Brodsky
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

  • accidental cell death
  • anoikis
  • apoptosis
  • autophagic cell death
  • entosis
  • ferroptosis
  • immunogenic cell death
  • lysosomes
  • pathology
  • mitochondrial transmembrane permeability-driven necroptosis
  • necrosis
  • neutrophil extracellular traps
  • parthanatos
  • pyroptosis
  • regulated cell death

Published Papers (7 papers)

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Research

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18 pages, 4402 KiB  
Article
Genomewide m6A Mapping Uncovers Dynamic Changes in the m6A Epitranscriptome of Cisplatin-Treated Apoptotic HeLa Cells
by Azime Akçaöz Alasar, Özge Tüncel, Ayşe Bengisu Gelmez, Buket Sağlam, İpek Erdoğan Vatansever and Bünyamin Akgül
Cells 2022, 11(23), 3905; https://doi.org/10.3390/cells11233905 - 02 Dec 2022
Cited by 4 | Viewed by 2240
Abstract
Cisplatin (CP), which is a conventional cancer chemotherapeutic drug, induces apoptosis by modulating a diverse array of gene regulatory mechanisms. However, cisplatin-mediated changes in the m6A methylome are unknown. We employed an m6A miCLIP-seq approach to investigate the effect [...] Read more.
Cisplatin (CP), which is a conventional cancer chemotherapeutic drug, induces apoptosis by modulating a diverse array of gene regulatory mechanisms. However, cisplatin-mediated changes in the m6A methylome are unknown. We employed an m6A miCLIP-seq approach to investigate the effect of m6A methylation marks under cisplatin-mediated apoptotic conditions on HeLa cells. Our high-resolution approach revealed numerous m6A marks on 972 target mRNAs with an enrichment on 132 apoptotic mRNAs. We tracked the fate of differentially methylated candidate mRNAs under METTL3 knockdown and cisplatin treatment conditions. Polysome profile analyses revealed perturbations in the translational efficiency of PMAIP1 and PHLDA1 transcripts. Congruently, PMAIP1 amounts were dependent on METTL3. Additionally, cisplatin-mediated apoptosis was sensitized by METTL3 knockdown. These results suggest that apoptotic pathways are modulated by m6A methylation events and that the METTL3–PMAIP1 axis modulates cisplatin-mediated apoptosis in HeLa cells. Full article
(This article belongs to the Special Issue Regulated Cell Death – Mechanisms and Biological Implications)
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17 pages, 4012 KiB  
Article
New Insights into Mechanisms of Ferroptosis Associated with Immune Infiltration in Neonatal Hypoxic-Ischemic Brain Damage
by Shangbin Li, Li Wan, Jingfei Sun, Weichen Yan, Jie Wang, Xiong Gao, Changjun Ren and Ling Hao
Cells 2022, 11(23), 3778; https://doi.org/10.3390/cells11233778 - 25 Nov 2022
Cited by 3 | Viewed by 1735
Abstract
Background: The mechanisms underlying ferroptosis in neonatal hypoxic-ischemic brain damage (HIBD) remain unclear. Method: Four microarray datasets were collected from the GEO database (three mRNA datasets GSE23317, GSE144456, and GSE112137, and one miRNA microarray dataset GSE184939). Weighted gene co-expression network analysis (WGCNA) was [...] Read more.
Background: The mechanisms underlying ferroptosis in neonatal hypoxic-ischemic brain damage (HIBD) remain unclear. Method: Four microarray datasets were collected from the GEO database (three mRNA datasets GSE23317, GSE144456, and GSE112137, and one miRNA microarray dataset GSE184939). Weighted gene co-expression network analysis (WGCNA) was used to identify modules of HIBD-related genes. The ferroptosis-related genes were extracted from FerrDb, of which closely correlated to HIBD were obtained after the intersection with existing HIBD’s DEGs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, as well as protein–protein interaction (PPI) network analysis were subsequently conducted. Cytoscape was used to identify central genes. Immune cell infiltration analysis was performed by the CIBERSORT algorithm. Result: Fifty-six ferroptosis-related differentially expressed genes (FRDEGs) were screened, mainly related to ferroptosis, autophagy, hypoxia response, metabolic pathways, and immune inflammation. The seven optimal hub FRDEGs were obtained by intersecting with key modules of WGCNA. Then, the expression levels of the seven optimal hub FRDEGs were validated in the GSE144456 and GSE112137 datasets, and the ferroptosis-related mRNA-miRNA network was established. In addition, this study revealed immune cell infiltration in the HIBD cerebral cortex and the interaction between immune cells. Moreover, notably, specific FRDEGs were strongly positively correlated with immune function. Conclusions: The mechanism of ferroptosis is intricate and closely related to neonatal HIBD. Therefore, targeting ferroptosis-related gene therapy and immunotherapy may have therapeutic prospects for neonatal HIBD. Full article
(This article belongs to the Special Issue Regulated Cell Death – Mechanisms and Biological Implications)
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17 pages, 4633 KiB  
Article
Necrostatin-1 Alleviates Lung Ischemia-Reperfusion Injury via Inhibiting Necroptosis and Apoptosis of Lung Epithelial Cells
by Lingjun Dong, Fuxiang Liang, Zhiling Lou, Yangfan Li, Jinsheng Li, Yaling Chen, Jingjing Ding, Bin Jiang, Chuanqiang Wu, Huan Yu, Yafei Liu, Weiping Zhang, Yunbi Lu and Ming Wu
Cells 2022, 11(19), 3139; https://doi.org/10.3390/cells11193139 - 06 Oct 2022
Cited by 11 | Viewed by 2140
Abstract
Lung ischemia-reperfusion injury (LIRI) is associated with many diseases, including primary graft dysfunction after lung transplantation, and has no specific and effective therapies. Necroptosis contributes to the pathogenesis of ischemia-reperfusion injury. Necrostatin-1 (Nec-1), the necroptosis inhibitor targeting RIPK1, has been reported to alleviate [...] Read more.
Lung ischemia-reperfusion injury (LIRI) is associated with many diseases, including primary graft dysfunction after lung transplantation, and has no specific and effective therapies. Necroptosis contributes to the pathogenesis of ischemia-reperfusion injury. Necrostatin-1 (Nec-1), the necroptosis inhibitor targeting RIPK1, has been reported to alleviate ischemia-reperfusion injury in various organs. However, the underlying mechanism of Nec-1 in LIRI remains unclear. In this paper, an in vivo LIRI model was built up by left lung hilar clamping in mice, and an in vitro cold ischemia-reperfusion (CI/R) model using BEAS-2B cells was applied to mimic the lung transplantation setting. We found Nec-1 significantly alleviated ischemia-reperfusion-induced lung injury, cytokine releasing, and necroptosis of epithelial cells in mouse lungs. In vitro, Nec-1 also mitigated CI/R-induced cell death and inflammatory responses in BEAS-2B cells, and these protective effects were achieved by simultaneously inhibiting the formation of necrosome and RIPK1-dependent apoptosis. However, Nec-1 decreased the necrosome number but increased the apoptosis level in lung tissues after ischemia reperfusion. We further clarified that Nec-1 could also attenuate lung injury by promoting neutrophil apoptosis from flow cytometry. In conclusion, Nec-1 alleviated lung ischemia-reperfusion injury by inhibiting necroptosis and apoptosis of epithelial cells and promoting the apoptosis of neutrophils. Thus, Nec-1 could be a promising medication against primary graft dysfunction after lung transplantation. Full article
(This article belongs to the Special Issue Regulated Cell Death – Mechanisms and Biological Implications)
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13 pages, 3202 KiB  
Article
The Pro-Survival Oct4/Stat1/Mcl-1 Axis Is Associated with Poor Prognosis in Lung Adenocarcinoma Patients
by Yu-Chu Su, Yi-Cheng Chen, Yau-Lin Tseng, Gia-Shing Shieh, Pensee Wu, Ai-Li Shiau and Chao-Liang Wu
Cells 2021, 10(10), 2642; https://doi.org/10.3390/cells10102642 - 03 Oct 2021
Cited by 3 | Viewed by 2131
Abstract
The embryonic stem cell marker Oct4 is expressed in several human cancers and is positively correlated with a poor outcome in cancer patients. However, its physiological role in cancer progression remains poorly understood. Tumor cells block apoptosis to escape cell death so that [...] Read more.
The embryonic stem cell marker Oct4 is expressed in several human cancers and is positively correlated with a poor outcome in cancer patients. However, its physiological role in cancer progression remains poorly understood. Tumor cells block apoptosis to escape cell death so that they can proliferate indefinitely, leading to ineffective therapy for cancer patients. In this study, we investigated whether Oct4 regulates the apoptosis pathway and contributes to poor prognosis in patients with lung adenocarcinoma. Our results revealed that Oct4 expression is correlated with Stat1 expression in lung adenocarcinoma patients and Oct4 is directly bound to the Stat1 promoter to transactivate Stat1 in lung adenocarcinoma cells. Expression of the Stat1 downstream gene Mcl-1 increased in Oct4-overexpressing cancer cells, while Stat1 knockdown in Oct4-overexpressing cancer cells sensitized them to cisplatin-induced apoptosis. Furthermore, Oct4 promoted Stat1 expression and tumor growth, whereas silencing of Stat1 reduced Oct4-induced tumor growth in human lung tumor xenograft models. Taken together, we demonstrate that Oct4 is a pro-survival factor by inducing Stat1 expression and that the Oct4/Stat1/Mcl-1 axis may be a potential therapeutic target for lung adenocarcinoma. Full article
(This article belongs to the Special Issue Regulated Cell Death – Mechanisms and Biological Implications)
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Review

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19 pages, 1822 KiB  
Review
Lethal and Non-Lethal Functions of Caspases in the DNA Damage Response
by Karla E. Lopez and Lisa Bouchier-Hayes
Cells 2022, 11(12), 1887; https://doi.org/10.3390/cells11121887 - 10 Jun 2022
Cited by 12 | Viewed by 3049
Abstract
Members of the caspase family are well known for their roles in the initiation and execution of cell death. Due to their function in the removal of damaged cells that could otherwise become malignant, caspases are important players in the DNA damage response [...] Read more.
Members of the caspase family are well known for their roles in the initiation and execution of cell death. Due to their function in the removal of damaged cells that could otherwise become malignant, caspases are important players in the DNA damage response (DDR), a network of pathways that prevent genomic instability. However, emerging evidence of caspases positively or negatively impacting the accumulation of DNA damage in the absence of cell death demonstrates that caspases play a role in the DDR that is independent of their role in apoptosis. This review highlights the apoptotic and non-apoptotic roles of caspases in the DDR and how they can impact genomic stability and cancer treatment. Full article
(This article belongs to the Special Issue Regulated Cell Death – Mechanisms and Biological Implications)
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18 pages, 1629 KiB  
Review
Reovirus Activated Cell Death Pathways
by Carly DeAntoneo, Pranav Danthi and Siddharth Balachandran
Cells 2022, 11(11), 1757; https://doi.org/10.3390/cells11111757 - 27 May 2022
Cited by 8 | Viewed by 3616
Abstract
Mammalian orthoreoviruses (ReoV) are non-enveloped viruses with segmented double-stranded RNA genomes. In humans, ReoV are generally considered non-pathogenic, although members of this family have been proven to cause mild gastroenteritis in young children and may contribute to the development of inflammatory conditions, including [...] Read more.
Mammalian orthoreoviruses (ReoV) are non-enveloped viruses with segmented double-stranded RNA genomes. In humans, ReoV are generally considered non-pathogenic, although members of this family have been proven to cause mild gastroenteritis in young children and may contribute to the development of inflammatory conditions, including Celiac disease. Because of its low pathogenic potential and its ability to efficiently infect and kill transformed cells, the ReoV strain Type 3 Dearing (T3D) is clinical trials as an oncolytic agent. ReoV manifests its oncolytic effects in large part by infecting tumor cells and activating programmed cell death pathways (PCDs). It was previously believed that apoptosis was the dominant PCD pathway triggered by ReoV infection. However, new studies suggest that ReoV also activates other PCD pathways, such as autophagy, pyroptosis, and necroptosis. Necroptosis is a caspase-independent form of PCD reliant on receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and its substrate, the pseudokinase mixed-lineage kinase domain-like protein (MLKL). As necroptosis is highly inflammatory, ReoV-induced necroptosis may contribute to the oncolytic potential of this virus, not only by promoting necrotic lysis of the infected cell, but also by inflaming the surrounding tumor microenvironment and provoking beneficial anti-tumor immune responses. In this review, we summarize our current understanding of the ReoV replication cycle, the known and potential mechanisms by which ReoV induces PCD, and discuss the consequences of non-apoptotic cell death—particularly necroptosis—to ReoV pathogenesis and oncolysis. Full article
(This article belongs to the Special Issue Regulated Cell Death – Mechanisms and Biological Implications)
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38 pages, 2124 KiB  
Review
How Pyroptosis Contributes to Inflammation and Fibroblast-Macrophage Cross-Talk in Rheumatoid Arthritis
by Benjamin Demarco, Sara Danielli, Fabian A. Fischer and Jelena S. Bezbradica
Cells 2022, 11(8), 1307; https://doi.org/10.3390/cells11081307 - 12 Apr 2022
Cited by 10 | Viewed by 5730
Abstract
About thirty years ago, a new form of pro-inflammatory lytic cell death was observed and termed pyroptosis. Only in 2015, gasdermins were defined as molecules that create pores at the plasma membrane and drive pyroptosis. Today, we know that gasdermin-mediated death is an [...] Read more.
About thirty years ago, a new form of pro-inflammatory lytic cell death was observed and termed pyroptosis. Only in 2015, gasdermins were defined as molecules that create pores at the plasma membrane and drive pyroptosis. Today, we know that gasdermin-mediated death is an important antimicrobial defence mechanism in bacteria, yeast and mammals as it destroys the intracellular niche for pathogen replication. However, excessive and uncontrolled cell death also contributes to immunopathology in several chronic inflammatory diseases, including arthritis. In this review, we discuss recent findings where pyroptosis contributes to tissue damage and inflammation with a main focus on injury-induced and autoimmune arthritis. We also review novel functions and regulatory mechanisms of the pyroptotic executors gasdermins. Finally, we discuss possible models of how pyroptosis may contribute to the cross-talk between fibroblast and macrophages, and also how this cross-talk may regulate inflammation by modulating inflammasome activation and pyroptosis induction. Full article
(This article belongs to the Special Issue Regulated Cell Death – Mechanisms and Biological Implications)
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