Frontiers in Cell and Developmental Biology
ISSN / EISSN : 2296-634X / 2296-634X
Published by: Frontiers Media SA (10.3389)
Total articles ≅ 4,387
Latest articles in this journal
Frontiers in Cell and Developmental Biology, Volume 9; doi:10.3389/fcell.2021.696619
Background The use of medicinal plant ingredients is one of the goals of developing potential drugs for treating depression. Compelling evidence suggests that anti-inflammatory medicines may block the occurrence of depression. We studied the effect of a natural compound, emodin, on the development of psychosocial stress-induced depression and the underlying mechanisms. Methods Chronic unpredicted mild stress (CUMS) for 7 weeks was performed to replicate psychosocial stress in rats. The sucrose preference test, force swimming test, and open field test were used to evaluate their behaviors. The differentially expressed proteins in the hippocampus were analyzed using proteomics. Nissl staining and Golgi staining were used to detect the loss of neurons and synapses, immunohistochemical staining was used to detect the activation of microglia, and the enzyme-linked immunosorbent assay was used to detect the levels of pro-inflammatory cytokines. Western blotting, immunofluorescence, and quantitative polymerase chain reaction were also performed. Results Hippocampal inflammation with up-regulated 5-lipoxygenase (5-LO) was observed in the depressed rats after CUMS exposure. The upregulation of 5-LO was caused by decreased miR-139-5p. To observe the effect of emodin, we screened out depression-susceptible (DeS) rats during CUMS and treated them with emodin (80 mg/kg/day). Two weeks later, emodin prevented the depression behaviors in DeS rats along with a series of pathological changes in their hippocampi, such as loss of neurons and spines, microglial activation, increased interleukin-1β and tumor necrosis factor-α, and the activation of 5-LO. Furthermore, we demonstrated that emodin inhibited its excess inflammatory response, possibly by targeting miR-139-5p/5-LO and modulating glycogen synthase kinase 3β and nuclear factor erythroid 2-related factor 2. Conclusion These results provide important evidence that emodin may be a candidate agent for the treatment of depression and established a key role of miR-139-5p/5-LO in the inflammation of depression.
Frontiers in Cell and Developmental Biology, Volume 9; doi:10.3389/fcell.2021.697939
Due to a grim prognosis, there is an urgent need to detect pancreatic ductal adenocarcinoma (PDAC) prior to metastasis. However, reliable diagnostic imaging methods or biomarkers for PDAC or its precursor lesions are still scarce. ADAM8, a metalloprotease-disintegrin, is highly expressed in PDAC tissue and negatively correlates with patient survival. The aim of our study was to determine the ability of ADAM8-positive extracellular vesicles (EVs) and cargo microRNAs (miRNAs) to discriminate precursor lesions or PDAC from healthy controls. In order to investigate enrichment of ADAM8 on EVs, these were isolated from serum of patients with PDAC (n = 52), precursor lesions (n = 7) and healthy individuals (n = 20). Nanoparticle Tracking Analysis and electron microscopy indicated successful preparation of EVs that were analyzed for ADAM8 by FACS. Additionally, EV cargo analyses of miRNAs from the same serum samples revealed the presence of miR-720 and miR-451 by qPCR and was validated in 20 additional PDAC samples. Statistical analyses included Wilcoxon rank test and ROC curves. FACS analysis detected significant enrichment of ADAM8 in EVs from patients with PDAC or precursor lesions compared to healthy individuals (p = 0.0005). ADAM8-dependent co-variates, miR-451 and miR-720 were also diagnostic, as patients with PDAC had significantly higher serum levels of miR-451 and lower serum levels of miR-720 than healthy controls and reached high sensitivity and specificity (AUC = 0.93 and 1.00, respectively) to discriminate PDAC from healthy control. Thus, detection of ADAM8-positive EVs and related cargo miR-720 and miR-451 may constitute a specific biomarker set for screening individuals at risk for PDAC.
Frontiers in Cell and Developmental Biology, Volume 9; doi:10.3389/fcell.2021.671736
Uterine Corpus Endometrial Carcinoma (UCEC) is the most common gynecological cancer. Here, we have investigated the significance of immune-related genes in predicting the prognosis and response of UCEC patients to immunotherapy and chemotherapy. Based on the Cancer Genome Atlas (TCGA) database, the single-sample gene-set enrichment analysis (ssGSEA) scores was utilized to obtain enrichment of 29 immune signatures. Univariate, multivariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses were performed to generate an immune-related prognostic signature (IRPS). The biological functions of IRPS-associated genes were evaluated using GSEA, Tumor Immune Estimation Resource (TIMER) Database analysis, Mutation analysis, Immunophenoscore (IPS) analysis, Gene Expression Profiling Interactive Analysis (GEPIA), Genomics of Drug Sensitivity in Cancer (GDSC) and Immune Cell Abundance Identifier (ImmuCellAI). Potential small molecule drugs for UCEC were predicted using the connectivity map (Cmap). The mRNA and protein expression levels of IRPS-associated genes were tested via quantitative real-time PCR (qPCR) and immunohistology. Two immune-related genes (CCL13 and KLRC1) were identified to construct the IRPS. Both genes were related to the prognosis of UCEC patients (P < 0.05). The IRPS could distinguish patients with different prognosis and was closely associated with the infiltration of several types of immune cells. Our findings showed that patients with low IRPS benefited more from immunotherapy and developed stronger response to several chemotherapies, which was also confirmed by the results of ImmuCellAI. Finally, we identified three small molecular drugs that might improve the prognosis of patients with high IRPS. IRPS can be utilized to predict the prognosis of UCEC patients and provide valuable information about their therapeutic response to immunotherapy and chemotherapy.
Frontiers in Cell and Developmental Biology, Volume 9; doi:10.3389/fcell.2021.679637
The exact relationships and detailed mechanisms between autophagy and necroptosis remain obscure. Here, we demonstrated the link between accumulated autophagosome and necroptosis by intervening with autophagic flux. We first confirmed that the LC3 interacting region (LIR) domain is present in the protein sequences of RIPK1 and RIPK3. Mutual effects among LC3, RIPK1, and RIPK3 have been identified in myocardium and cardiomyocytes. Direct LC3-RIPK1 and LC3-RIPK3 interactions were confirmed by pull-down assays, and their interactions were deleted after LIR domain mutation. Moreover, after disrupting autophagic flux under normoxia with bafilomycin A1 treatment, or with LC3 or ATG5 overexpression adenovirus, RIPK1, RIPK3, p-RIPK3, and p-MLKL levels increased, suggesting necroptosis activation. Severe disruptions in autophagic flux were observed under hypoxia and bafilomycin A1 co-treated cardiomyocytes and myocardium and led to more significant activation of necroptosis. Conversely, after alleviating hypoxia-induced autophagic flux impairment with LC3 or ATG5 knockdown adenovirus, the effects of hypoxia on RIPK1 and RIPK3 levels were reduced, which resulted in decreased p-RIPK3 and p-MLKL. Furthermore, necroptosis was inhibited by siRNAs against RIPK1 and RIPK3 under hypoxia or normoxia. Based on our results, LIR domain mediated LC3-RIPK1 and LC3-RIPK3 interaction. Besides, autophagosome accumulation under hypoxia lead to necrosome formation and, in turn, necroptosis, while when autophagic flux was uninterrupted, RIPK1 and RIPK3 were cleared through an autophagy-related pathway which inhibited necroptosis. These findings provide novel insights for the role of LC3 in regulating cardiomyocyte necroptosis, indicating its therapeutic potential in the prevention and treatment of hypoxic myocardial injury and other hypoxia-related diseases.
Frontiers in Cell and Developmental Biology, Volume 9; doi:10.3389/fcell.2021.699212
Osteosarcoma is the most common malignant bone tumor, and although there has been significant progress in its management, metastases often herald incurable disease. Here we defined genes differentially expressed between primary and metastatic osteosarcoma as metastasis-related genes (MRGs) and used them to construct a novel six-MRG prognostic signature for overall survival of patients with osteosarcoma. Validation in internal and external datasets confirmed satisfactory accuracy and generalizability of the prognostic model, and a nomogram based on the signature and clinical variables was constructed to aid clinical decision-making. Of the six MRGs, FHIT is a well-documented tumor suppressor gene that is poorly defined in osteosarcoma. Consistent with tumor suppressor function, FHIT was downregulated in osteosarcoma cells and human osteosarcoma samples. FHIT overexpression inhibited osteosarcoma proliferation, migration, and invasion both in vitro and in vivo. Mechanistically, FHIT overexpression upregulate the epithelial marker E-cadherin while repressing the mesenchymal markers N-cadherin and vimentin. Our six-MRG signature represents a novel and clinically useful prognostic biomarker for patients with osteosarcoma, and FHIT might represent a therapeutic target by reversing epithelial to mesenchymal transition.
Frontiers in Cell and Developmental Biology, Volume 9; doi:10.3389/fcell.2021.706375
Human papillomavirus (HPV) integration is the major contributor to cervical cancer (CC) development by inducing structural variations (SVs) in the human genome. SVs are directly associated with the three-dimensional (3D) genome structure leading to cancer development. The detection of SVs is not a trivial task, and several genome-wide techniques have greatly helped in the identification of SVs in the cancerous genome. However, in cervical cancer, precise prediction of SVs mainly translocations and their effects on 3D-genome and gene expression still need to be explored. Here, we have used high-throughput chromosome conformation capture (Hi-C) data of cervical cancer to detect the SVs, especially the translocations, and validated it through whole-genome sequencing (WGS) data. We found that the cervical cancer 3D-genome architecture rearranges itself as compared to that in the normal tissue, and 24% of the total genome switches their A/B compartments. Moreover, translocation detection from Hi-C data showed the presence of high-resolution t(4;7) (q13.1; q31.32) and t(1;16) (q21.2; q22.1) translocations, which disrupted the expression of the genes located at and nearby positions. Enrichment analysis suggested that the disrupted genes were mainly involved in controlling cervical cancer-related pathways. In summary, we detect the novel SVs through Hi-C data and unfold the association among genome-reorganization, translocations, and gene expression regulation. The results help understand the underlying pathogenicity mechanism of SVs in cervical cancer development and identify the targeted therapeutics against cervical cancer.
Frontiers in Cell and Developmental Biology, Volume 9; doi:10.3389/fcell.2021.729155
Editorial on the Research Topic A Hippo's View: From Molecular Basis to Translational Medicine Initially identified in Drosophila, the major components of the Hippo pathway including the core kinase cascade, downstream effector and nuclear transcription factor are evolutionarily conserved, resulting in extensive studies from many investigators in the past decades. The Hippo pathway is now recognized as a key player in organ size control via primarily stimulating programmed cell death and restricting cell proliferation (Halder and Johnson, 2011; Yu et al., 2015; Zheng and Pan, 2019). The Hippo pathway regulates cell proliferation, survival and differentiation in response to a wide range of extracellular cues including growth factors, mitogenic hormones, metabolic inputs, and perceived physical signals from cell microenvironment, suggesting its crucial role in normal physiology. Moreover, Hippo signaling dysregulation has been linked to various human diseases like developmental anomalies, impaired immunity, cancer development, cancer metastasis and drug resistance. Therefore, elucidating the molecular basis of Hippo pathway regulation and underlying mechanism will not only provide novel insights into many fundamental processes in physiology, but also foster the development of therapeutic strategies for translational medicine. Here, we prepare a special Research Topic issue to provide an overview of the up-to-date research findings on this exciting and burgeoning filed. While various intracellular and extracellular signals have been discovered to regulate the Hippo pathway, the current focus in the field is how these signals converge on the Hippo pathway for growth control and tissue homeostasis. In this issue, Cai et al. reviewed how the Hippo pathway effectors YAP and TAZ are modulated under different mechanical cues. Given the fundamental roles of YAP and TAZ in mechanotransduction, the authors discussed the potential pathological roles of YAP/TAZ in several human diseases involving mechanical cues, such as pulmonary hypertension, atherosclerosis, cardiac hypertrophy, fibrosis, musculoskeletal disorder, and cancer. Calcium (Ca2+) functions as an essential intracellular messenger in a number of cellular signaling events (Clapham, 2007). Wei and Li summarized the molecular mechanisms for the Ca2+-mediated regulation of the Hippo pathway, underscoring the important role of Ca2+-mediated actin reset (CaAR) in this process. Uncovering additional effectors for Ca2+ signaling with relevance to the Hippo pathway will enrich our understanding of the Hippo pathway regulation from a new perspective. The tissue architecture-related cell polarity, cell-cell junctions and cell-extracellular matrix (ECM) interaction are known regulators of the Hippo pathway. Using Drosophila wing discs as a model, Wang et al. identified Wallenda (Wnd) (MAP3K13 in human) as a new player in the cell polarity-mediated Hippo pathway regulation. Wnd is involved in this process through nemo-like kinase, Nmo (NLK in human), and such Wnd-Nmo axis in regulating the Hippo pathway is shown conserved in evolution. Thus, it will be interesting to further examine whether dysregulation of these newly discovered regulators would cause cell polarity-associated human diseases like cancer. Although the Hippo pathway kinase cascade transduces many upstream signaling events to YAP and TAZ, mechanisms that modulate YAP and TAZ activities independent of the Hippo kinase cascade do exist. In this Research Topic issue, Cho and Jiang authoritatively highlighted the recent findings of such “non-canonical” regulation for YAP and TAZ. These mechanisms highlight the complex regulation of the Hippo pathway, connect the Hippo pathway with other key cellular signaling events, and reveal novel therapeutic strategies for future investigations. To resolve the complex regulation of the Hippo pathway, extensive efforts have been made to identify new Hippo pathway regulators. In line with it, Pipchuk and Yang described the application of luciferase-based biosensors to the Hippo pathway study. The authors discussed several assays using split luciferase complementation systems that have been successfully used for identifying new Hippo pathway regulators, highlighting the advantage of this luciferase-based biosensor method in studying real-time protein-protein interaction in live cells. Although the Hippo pathway is known for its crucial role in organ size control, recent studies have extended it to other biological processes, such as embryogenesis, stem cell regulation and tissue regeneration. Here, Zhao et al. reviewed the emerging findings of the Hippo pathway in neural crest (NC) development. This work summarized the critical role of the Hippo pathway in many aspects of NC development, including NC initiation, migration, proliferation, survival and differentiation, as well as the NC-related diseases caused by the dysregulated Hippo signaling. In terms with organogenesis. Wu et al. described how the Hippo pathway acts in pancreatic development. This review highlighted the role of the Hippo pathway in progenitor cell maintenance and normal proper cell polarization/branching during pancreatic organogenesis and morphogenesis, which involve the crosstalk with several key developmental signaling pathways, such as Notch, Wnt, and PI3K-Akt. Given the critical role of the Hippo pathway in numerous physiological processes, its dysregulation has been linked to many human diseases such as cancer. For example, the Hippo pathway is implicated to control cancer stem cell expansion and maintenance against cancer development (Park et al., 2018). To reveal the underlying mechanisms, Shen et al. investigated the Hippo pathway effector TAZ in breast cancer stem cells (BCSCs) and revealed the Cyclin D1-CDK4/CDK6 axis as downstream effector for the TAZ-driven breast tumorigenesis. This work suggests a possible vulnerability for BCSCs as well as a new...
Frontiers in Cell and Developmental Biology, Volume 9; doi:10.3389/fcell.2021.654210
The skin is the largest organ of the human body, and its dysfunction is related to many diseases. There is a need to find new potential effective therapies for some skin conditions such as inflammatory diseases, wound healing, or hair restoration. Mesenchymal stromal cell (MSC)-conditioned medium (CM) provides a potential opportunity in the treatment of skin disease. Thus, the objective of this review is to evaluate the uses of MSC-CM for treating skin diseases in both animal and human models. A systematic review was conducted regarding the use of MSC-CM for treating skin conditions. One hundred one studies were analyzed. MSC-CM was evaluated in wound healing (55), hypertrophic scars (9), flap reperfusion (4), hair restoration (15), skin rejuvenation (15), and inflammatory skin diseases (3). MSC-CM was obtained from different MSC sources, mainly adipose tissue, bone marrow, and umbilical cord blood. MSC-CM was tested intravenously, intraperitoneally, subcutaneously, intradermally or intralesionally injected or topically applied. MSC-CM was used in both animals and humans. MSC-CM improved wound healing, hair restoration, skin rejuvenation, atopic dermatitis, and psoriasis in both animals and humans. MSC-CM also decreased hypertrophic scars and flap ischemia in animal models. In conclusion, MSC-CM is a promising therapy for skin conditions. Further studies are needed to corroborate safety and effectiveness and to standardize CM manufacturing.
Frontiers in Cell and Developmental Biology, Volume 9; doi:10.3389/fcell.2021.702068
The inner/apical surface of the embryonic brain wall is important as a major site for cell production by neural progenitor cells (NPCs). We compared the mechanical properties of the apical surfaces of two neighboring but morphologically distinct cerebral wall regions in mice from embryonic day (E) E12–E14. Through indentation measurement using atomic force microscopy (AFM), we first found that Young’s modulus was higher at a concave-shaped apical surface of the pallium than at a convex-shaped apical surface of the ganglionic eminence (GE). Further AFM analysis suggested that contribution of actomyosin as revealed with apical surface softening by blebbistatin and stiffness of dissociated NPCs were both comparable between pallium and GE, not accounting for the differential apical surface stiffness. We then found that the density of apices of NPCs was greater, with denser F-actin meshwork, in the apically stiffer pallium than in GE. A similar correlation was found between the decreasing density between E12 and E14 of NPC apices and the declining apical surface stiffness in the same period in both the pallium and the GE. Thus, one plausible explanation for the observed difference (pallium > GE) in apical surface stiffness may be differential densification of NPC apices. In laser ablation onto the apical surface, the convex-shaped GE apical surface showed quicker recoils of edges than the pallial apical surface did, with a milder inhibition of recoiling by blebbistatin than in pallium. This greater pre-stress in GE may provide an indication of how the initially apically concave wall then becomes an apically convex “eminence.”
Frontiers in Cell and Developmental Biology, Volume 9; doi:10.3389/fcell.2021.724948
A Corrigendum on WNT5B in Physiology and Disease by Suthon, S., Perkins, R. S., Bryja, V., Miranda-Carboni, G. A., and Krum, S. A. (2021). Front. Cell Dev. Biol. 9:667581. doi: 10.3389/fcell.2021.667581 In the original article, there were two errors. (1) Our information on Wnt modification and secretion was out of date. Mouse Wnts are not palmitoleated on cysteines—that was an error in mutational analysis by Karl Willert. All the cysteines in Wnt are engaged in disulfide bonds (DOI 10.1126/science.1222879, 10.1074/jbc.m114.575027). However, a new reference describes WNT palmitoylation in zebrafish WNT3A (Dhasmana et al., 2021). (2) The WLS protein binds to Wnt in the ER, not the Golgi. The Golgi localization of WLS was also an error due to the use of an epitope tag on the c-terminus (10.1016/j.devcel.2014.03.016, 10.1016/j.cell.2020.11.038). A correction has been made to the introduction, paragraph number 2 The WNT family now contains 19 WNT genes, falling into 12 WNT subfamilies in mammalian genomes. All WNT genes encode proteins around 40 kDa in size and contain highly conserved cysteines (Miller, 2002; Clevers and Nusse, 2012). Mammalian WNT proteins are palmitoylated at conserved serine residues by a special palmitoyl transferase, Porcupine (PORCN), in the endoplasmic reticulum (Takada et al., 2006; Galli et al., 2007; Rios-Esteves et al., 2014). Zebrafish WNT3 is lipidated at both cysteine and serine residues (Dhasmana et al., 2021). The activity of PORCN is essential for the secretion of WNT ligands. Then, the seven-transmembrane protein Wntless/Evi (Wls) in the endoplasmic reticulum escorts mature hydrophobic WNT proteins to be secreted at the plasma membrane or released in exosomes, leading to both autocrine and paracrine effects (Banziger et al., 2006; Routledge and Scholpp, 2019). Accordingly, the following reference has been added to the original article: Dhasmana, D., Veerapathiran, S., Azbazdar, Y., Nelanuthala, A. V. S., Teh, C., Ozhan, G., et al. (2021). Wnt3 is lipidated at conserved cysteine and serine residues in zebrafish neural tissue. Front. Cell Dev. Biol. 9:671218. 10.3389/fcell.2021.671218 And the following reference has been removed from the original article: Willert, K., Brown, J. D., Danenberg, E., Duncan, A. W., Weissman, I. L., Reya, T., et al. (2003). Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature 423, 448–452. The authors apologize for these errors and state that this does not change the scientific conclusions of the article in any way. The original article has5 been updated. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Banziger, C., Soldini, D., Schutt, C., Zipperlen, P., Hausmann, G., and Basler, K. (2006). Wntless, a conserved membrane protein dedicated to the secretion of Wnt proteins from signaling cells. Cell. 125, 509–522. doi: 10.1016/j.cell.2006.02.049 PubMed Abstract | CrossRef Full Text | Google Scholar Clevers, H., and Nusse, R. (2012). Wnt/beta-catenin signaling and disease. Cell. 149, 1192–1205. Dhasmana, D., Veerapathiran, S., Azbazdar, Y., Nelanuthala, A. V. S., Teh, C., Ozhan, G., et al. (2021).Wnt3 is lipidated at conserved cysteine and serine residues in zebrafish neural tissue. Front. Cell Dev. Biol. 9:671218. doi: 10.3389/fcell.2021.671218 CrossRef Full Text | Google Scholar Galli, L. M., Barnes, T. L., Secrest, S. S., Kadowaki, T., and Burrus, L. W. (2007). Porcupine-mediated lipid-modification regulates the activity and distribution of Wnt proteins in the chick neural tube. Development. 134, 3339–3348. doi: 10.1242/dev.02881 PubMed Abstract | CrossRef Full Text | Google Scholar Miller, J. R. (2002). The Wnts. Genome Biol. 3:REVIEWS3001. Rios-Esteves, J., Haugen, B., and Resh, M. D. (2014). Identification of key residues and regions important for porcupine-mediated Wnt acylation. J. Biol. Chem. 289, 17009–17019. doi: 10.1074/jbc.m114.561209 PubMed Abstract | CrossRef Full Text | Google Scholar Routledge, D., and Scholpp, S. (2019). Mechanisms of intercellular Wnt transport. Development. 146:dev176073. doi: 10.1242/dev.176073 CrossRef Full Text | Google Scholar Takada, R., Satomi, Y., Kurata, T., Ueno, N., Norioka, S., Kondoh, H., et al. (2006). Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion. Dev. Cell. 11, 791–801. doi: 10.1016/j.devcel.2006.10.003 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: Wnt5B, Wnt signaling, development, cancer, Wnt5a Citation: Suthon S, Perkins RS, Bryja V, Miranda-Carboni GA and Krum SA (2021) Corrigendum: WNT5B in Physiology and Disease. Front. Cell Dev. Biol. 9:724948. doi: 10.3389/fcell.2021.724948 Received: 14 June 2021; Accepted: 23 June 2021; Published: 23 July 2021. Edited and reviewed by: Gunes Ozhan, Dokuz Eylül University, Turkey Copyright © 2021 Suthon, Perkins, Bryja, Miranda-Carboni and Krum. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Susan A. Krum, [email protected]