Frontiers in Cell and Developmental Biology

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ISSN / EISSN : 2296-634X / 2296-634X
Published by: Frontiers Media SA (10.3389)
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Jinqi Lv, Simeng Zhang, Yang Liu, Ce Li, Tianshu Guo, Shuairan Zhang, ZeNan Li, Zihan Jiao, Haina Sun, Ye Zhang, et al.
Frontiers in Cell and Developmental Biology, Volume 9; https://doi.org/10.3389/fcell.2021.688949

Abstract:
The median survival time of patients with advanced gastric cancer (GC) who received radiotherapy and chemotherapy was <1 year. Epithelial–mesenchymal transformation (EMT) gives GC cells the ability to invade, which is an essential biological mechanism in the progression of GC. The long non-coding RNA (lncRNA)-based competitive endogenous RNA (ceRNA) system has been shown to play a key role in the GC-related EMT process. Although the AKT pathway is essential for EMT in GC, the relationship between AKT3 subtypes and EMT in GC is unclear. Here, we evaluated the underlying mechanism of ceRNA involving NR2F1-AS1/miR-190a/PHLDB2 in inducing EMT by promoting the expression and phosphorylation of AKT3. The results of bioinformatics analysis showed that the expression of NR2F1-AS1/miR-190a/PHLDB2 in GC was positively associated with the pathological features, staging, poor prognosis, and EMT process. We performed cell transfection, qRT-PCR, western blot, cell viability assay, TUNEL assay, Transwell assay, cell morphology observation, and double luciferase assay to confirm the regulation of NR2F1-AS1/miR-190a/PHLDB2 and its effect on EMT transformation. Finally, GSEA and GO/KEGG enrichment analysis identified that PI3K/AKT pathway was positively correlated to NR2F1-AS1/miR-190a/PHLDB2 expression. AKT3 knockout cells were co-transfected with PHLDB2-OE, and the findings revealed that AKT3 expression and phosphorylation were essential for the PHLDB2-mediated EMT process. Thus, our results showed that NR2F1-AS1/miR-190a/PHLDB2 promoted the phosphorylation of AKT3 to induce EMT in GC cells. This study provides a comprehensive understanding of the underlying mechanism involved in the EMT process as well as the identification of new EMT markers.
Haibo Du, Hao Zhou, Yixiao Sun, Xiaoyan Zhai, Zhengjun Chen, Yanfei Wang, Zhigang Xu
Frontiers in Cell and Developmental Biology, Volume 9; https://doi.org/10.3389/fcell.2021.765559

Abstract:
Stereocilia are actin-based cell protrusions on the apical surface of inner ear hair cells, playing a pivotal role in hearing and balancing sensation. The development and maintenance of stereocilia is tightly regulated and deficits in this process usually lead to hearing or balancing disorders. The Rho GTPase cell division cycle 42 (CDC42) is a key regulator of the actin cytoskeleton. It has been reported to localize in the hair cell stereocilia and play important roles in stereocilia maintenance. In the present work, we utilized hair cell-specific Cdc42 knockout mice and CDC42 inhibitor ML141 to explore the role of CDC42 in stereocilia development. Our data show that stereocilia height and width as well as stereocilia resorption are affected in Cdc42-deficient cochlear hair cells when examined at postnatal day 8 (P8). Moreover, ML141 treatment leads to planar cell polarity (PCP) deficits in neonatal hair cells. We also show that overexpression of a constitutively active mutant CDC42 in cochlear hair cells leads to enhanced stereocilia developmental deficits. In conclusion, the present data suggest that CDC42 plays a pivotal role in regulating hair cell stereocilia development.
Elena Della Bella, Stefania Pagani, Fernanda Martini,
Frontiers in Cell and Developmental Biology, Volume 9; https://doi.org/10.3389/fcell.2021.784791

Abstract:
Editorial on the Research Topic The Epigenetics in Osteogenic and Chondrogenic Differentiation of Mesenchymal Stem Cells Throughout the lifespan, mesenchymal stem cells (MSCs) provide tissue formation, growth, homeostasis, and renewal. From their discovery (Friedenstein et al., 1968), MSCs have been isolated from different tissues and their properties and abilities have been deeply explored (Pittenger et al., 2019). The intensive investigations have shown the complexity of the mechanisms which control self-renewal, differentiation into different cell phenotypes including bone and cartilage cells and senescence (Zhou et al., 2020). Because of their unique properties, MSCs are attractive tools for cell-based therapy in tissue engineering and regenerative medicine of hard connective tissues. It is now known that MSC differentiation into the osteogenic or chondrogenic lineage is a multistep process, highly regulated by a plethora of specific signaling molecules of the extracellular matrix or produced by neighboring cells, involving multiple extracellular signaling pathways and a complex gene expression regulation (Sagaradze et al., 2020; Chan et al., 2021). A further complexity grade in the regulation of MSCs differentiation is due to several epigenetic mechanisms which have attracted great interest over the last decade. These epigenetic factors or regulators include modifications of histones, adenosine triphosphate (ATP)-dependent chromatin remodeling complexes, DNA methylation, and different classes of non-coding RNAs (ncRNAs) which modulate the expression of a gene by changing the availability of DNA sequences for DNA-binding proteins, inhibiting translation, or cleaving the complementary target messenger RNAs (Iaquinta et al., 2021). The increasing knowledge in the field of epigenetics stimulated this Research Topic, which aims to collect data showing the impact of epigenetics in osteogenic and chondrogenic differentiation of MSCs. The Topic titled “The Epigenetics in Osteogenic and Chondrogenic Differentiation of Mesenchymal Stem Cells” includes comprehensive reviews focused on different critical epigenetic mechanisms involved in MSC differentiation, as well as original research papers. The contribution by Montecino et al. introduces to general mechanisms and molecular complexes which regulate chromatin organization in mammals, thus playing an essential role to differentially control the access to coding genomic sequences. Also, the authors collect recent data demonstrating the role of these epigenetic mechanisms in controlling gene transcription and describe how they contribute to osteogenic differentiation regulating the transcription of RUNX2 and SP7 genes, the key osteogenic transcription factors. Another fundamental aspect of the epigenetic regulation of MSC osteogenic differentiation is the regulation of gene expression by several classes of noncoding RNAs. Indeed, it is well-established that both miRNAs and long ncRNAs (lncRNAs) are essential players in gene expression, although their interplay is less known. Lanzillotti et al. provide an exhaustive description of in vitro and in vivo results concerning the crosstalk between lncRNAs and miRNAs in MSC osteogenic differentiation and their connection with specific components of the osteogenic signaling pathways. Data collected reveal a complex interplay which deserves further investigations. Other regulatory components of RNA stability are RNA binding proteins which act as modulators of gene expression. Among them, Kota et al. have focused on Elavl1 (embryonic lethal-abnormal vision like 1) a highly conserved component of ELAV family proteins with high affinities for U- and AU- rich elements (ARE) containing RNAs. In their study the authors show that Elavl1 is involved in osteogenic differentiation of mouse bone marrow derived mesenchymal stem cells (BMSCs), as Elavl1 knockdown stimulates osteogenic differentiation, in association to the increased stability and expression levels of different mRNAs coding for extracellular matrix components and regulatory enzymes. The issue of ncRNAs in the modulation of MSC chondrogenic differentiation is addressed in the study by Jiang et al. who investigated the possible function of Super-Enhancer lncRNAs (SE-lncRNAs), a subset of ncRNA transcribed from super-enhancers (Wang et al., 2020). A global picture on potential interconnections among signaling pathways, SE-lncRNAs, and mRNAs associated to the chondrogenic differentiation of BMSCs is shown. The article represents an example of current technologies including microarray and bioinformatic analysis to achieve a bulk of data helpful in identifying possible new chondrogenic key regulators. The essential role of histone modifications in the regulation of chondrocyte fate, cartilage development and pathologies has been discussed in the contribution by Wan et al. The review mainly focuses on histone-modifying proteins including acetyltransferases (HATs), histone lysine methyltransferases (KMTs), and demethylases (KDMs) and histone deacetylases (HDACs), as well as the effector proteins that recognize modified histones, regulating chondrocyte fate and functions. Emerging evidence shows specific histone changes associated with the expression of key chondrocyte marker genes such as SOX9 and collagen type II and with cartilage pathologies such as osteoarthritis (OA). Interestingly, the work also describes in vitro and in vivo data concerning the effects of small molecules and drugs able to modify histone signals, introducing to the potential of novel therapeutic approaches for OA and articular cartilage repair or regeneration. Another intriguing aspect of epigenetics regulation has been reported in the paper by Zhang et al. The authors investigated potential changes of chromatin accessibility under cyclic stretch. Although biophysical stimuli including electromagnetic fields and mechanical forces are known stimulators of MSC...
Beate Gündel, Xinyuan Liu, Matthias Löhr,
Frontiers in Cell and Developmental Biology, Volume 9; https://doi.org/10.3389/fcell.2021.741162

Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is one of the most overlooked cancers despite its dismal median survival time of 6 months. The biggest challenges in improving patient survival are late diagnosis due to lack of diagnostic markers, and limited treatment options due to almost complete therapy resistance. The past decades of research identified the dense stroma and the complex interplay/crosstalk between the cancer- and the different stromal cells as the main culprits for the slow progress in improving patient outcome. For better ex vivo simulation of this complex tumor microenvironment the models used in PDAC research likewise need to become more diverse. Depending on the focus of the investigation, several in vitro and in vivo models for PDAC have been established in the past years. Particularly, 3D cell culture such as spheroids and organoids have become more frequently used. This review aims to examine current PDAC in vitro models, their inherent limitations, and their successful implementations in research.
Franciele Faccio Busatto, Sofiane Y. Mersaoui, Yilun Sun, Yves Pommier, Jean-Yves Masson,
Frontiers in Cell and Developmental Biology, Volume 9; https://doi.org/10.3389/fcell.2021.727836

Abstract:
Topoisomerase 2 (TOP2) inhibitors are drugs widely used in the treatment of different types of cancer. Processing of their induced-lesions create double-strand breaks (DSBs) in the DNA, which is the main toxic mechanism of topoisomerase inhibitors to kill cancer cells. It was established that the Nucleotide Excision Repair pathway respond to TOP2-induced lesions, mainly through the Cockayne Syndrome B (CSB) protein. In this paper, we further define the mechanism and type of lesions induced by TOP2 inhibitors when CSB is abrogated. In the absence of TOP2, but not during pharmacological inhibition, an increase in R-Loops was detected. We also observed that CSB knockdown provokes the accumulation of DSBs induced by TOP2 inhibitors. Consistent with a functional interplay, interaction between CSB and TOP2 occurred after TOP2 inhibition. This was corroborated with in vitro DNA cleavage assays where CSB stimulated the activity of TOP2. Altogether, our results show that TOP2 is stimulated by the CSB protein and prevents the accumulation of R-loops/DSBs linked to genomic instability.
Franziska Trnka, Christian Hoffmann, Han Wang, Roberto Sansevrino, Branislava Rankovic, Benjamin R. Rost, Dietmar Schmitz, H. Broder Schmidt,
Frontiers in Cell and Developmental Biology, Volume 9; https://doi.org/10.3389/fcell.2021.716919

Abstract:
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to the death of upper and lower motor neurons. While most cases of ALS are sporadic, some of the familial forms of the disease are caused by mutations in the gene encoding for the RNA-binding protein FUS. Under physiological conditions, FUS readily phase separates into liquid-like droplets in vivo and in vitro. ALS-associated mutations interfere with this process and often result in solid-like aggregates rather than fluid condensates. Yet, whether cells recognize and triage aberrant condensates remains poorly understood, posing a major barrier to the development of novel ALS treatments. Using a combination of ALS-associated FUS mutations, optogenetic manipulation of FUS condensation, chemically induced stress, and pH-sensitive reporters of organelle acidity, we systematically characterized the cause-effect relationship between the material state of FUS condensates and the sequestering of lysosomes. From our data, we can derive three conclusions. First, regardless of whether we use wild-type or mutant FUS, expression levels (i.e., high concentrations) play a dominant role in determining the fraction of cells having soluble or aggregated FUS. Second, chemically induced FUS aggregates recruit LAMP1-positive structures. Third, mature, acidic lysosomes accumulate only at FUS aggregates but not at liquid-condensates. Together, our data suggest that lysosome-degradation machinery actively distinguishes between fluid and solid condensates. Unraveling these aberrant interactions and testing strategies to manipulate the autophagosome-lysosome axis provides valuable clues for disease intervention.
Weipu Mao, Keyi Wang, Si Sun, Jianping Wu, Ming Chen, , Ming Luo
Frontiers in Cell and Developmental Biology, Volume 9; https://doi.org/10.3389/fcell.2021.738364

Abstract:
Background: Inhibitors of DNA-binding (ID) proteins are important regulators of cell proliferation and differentiation. The aim of this study was to evaluated the role of ID proteins in bladder cancer (BCa) and related molecular mechanisms.Methods: The TCGA database was analyzed for the expression and clinical significance of ID proteins. The expression of ID2 was determined by qRT-PCR, immunohistochemical staining and western blot. The role of ID2 was determined by CCK-8, colony formation, wound healing, transwell and xenograft tumor assays, and the potential mechanism of ID2 in BCa was investigated by RNA sequencing.Results: ID2 expression was significantly downregulated in TCGA database and clinical samples, and high ID2 expression was associated with low-grade tumor staging and correlated with better overall survival, disease specific survival (DSS) and progress free interval (PFI). In vivo and in vitro experiments showed that knockdown of ID2 promoted proliferation, migration, invasion and metastasis of BCa cells, while overexpression of ID2 significantly inhibited cell proliferation, migration, invasion and metastasis. Mechanistically, ID2 acts as a tumor suppressor through PI3K/AKT signaling pathway to inhibit the progression and metastasis of BCa.Conclusion: Our results suggest that ID2 exerts tumor suppressive effects in BCa through PI3K/AKT signaling pathway, and altered ID2 expression can be used as a biomarker of BCa progression and metastasis.
, Artur A. Indzhykulian, David P. Corey
Frontiers in Cell and Developmental Biology, Volume 9; https://doi.org/10.3389/fcell.2021.744248

Abstract:
Hair cells—the sensory cells of the vertebrate inner ear—bear at their apical surfaces a bundle of actin-filled protrusions called stereocilia, which mediate the cells’ mechanosensitivity. Hereditary deafness is often associated with morphological disorganization of stereocilia bundles, with the absence or mislocalization within stereocilia of specific proteins. Thus, stereocilia bundles are closely examined to understand most animal models of hereditary hearing loss. Because stereocilia have a diameter less than a wavelength of light, light microscopy is not adequate to reveal subtle changes in morphology or protein localization. Instead, electron microscopy (EM) has proven essential for understanding stereocilia bundle development, maintenance, normal function, and dysfunction in disease. Here we review a set of EM imaging techniques commonly used to study stereocilia, including optimal sample preparation and best imaging practices. These include conventional and immunogold transmission electron microscopy (TEM) and scanning electron microscopy (SEM), as well as focused-ion-beam scanning electron microscopy (FIB-SEM), which enables 3-D serial reconstruction of resin-embedded biological structures at a resolution of a few nanometers. Parameters for optimal sample preparation, fixation, immunogold labeling, metal coating and imaging are discussed. Special attention is given to protein localization in stereocilia using immunogold labeling. Finally, we describe the advantages and limitations of these EM techniques and their suitability for different types of studies.
Carlos Camacho-Macorra, Marcos Sintes, Noemí Tabanera, Irene Grasa, ,
Frontiers in Cell and Developmental Biology, Volume 9; https://doi.org/10.3389/fcell.2021.767048

Abstract:
Hedgehog (Hh) signaling is a highly regulated molecular pathway implicated in many developmental and homeostatic events. Mutations in genes encoding primary components or regulators of the pathway cause an array of congenital malformations or postnatal pathologies, the extent of which is not yet fully defined. Mosmo (Modulator of Smoothened) is a modulator of the Hh pathway, which encodes a membrane tetraspan protein. Studies in cell lines have shown that Mosmo promotes the internalization and degradation of the Hh signaling transducer Smoothened (Smo), thereby down-modulating pathway activation. Whether this modulation is essential for vertebrate embryonic development remains poorly explored. Here, we have addressed this question and show that in zebrafish embryos, the two mosmo paralogs, mosmoa and mosmob, are expressed in the head mesenchyme and along the entire ventral neural tube. At the cellular level, Mosmoa localizes at the plasma membrane, cytoplasmic vesicles and primary cilium in both zebrafish and chick embryos. CRISPR/Cas9 mediated inactivation of both mosmoa and mosmob in zebrafish causes frontonasal hypoplasia and craniofacial skeleton defects, which become evident in the adult fish. We thus suggest that MOSMO is a candidate to explain uncharacterized forms of human congenital craniofacial malformations, such as those present in the 16p12.1 chromosomal deletion syndrome encompassing the MOSMO locus.
Jing Wang, Yuan-Wei Zhang, Nian-Jie Zhang, Shuo Yin, Du-Ji Ruan, Nian He, Xu Chen, Xue-Feng Yang
Frontiers in Cell and Developmental Biology, Volume 9; https://doi.org/10.3389/fcell.2021.759820

Abstract:
Recently, the effect of endocrine-disrupting chemicals on the cancer procession has been a concern. Nonylphenol (NP) is a common environmental estrogen that has been shown to enhance the proliferation of colorectal cancer (CRC) cells in our previous studies; however, the underlying mechanism remains unclear. In this study, we confirmed the increased concentration of NP in the serum of patients with CRC. RNA sequencing was used to explore the differentially expressed genes after NP exposure. We found 16 upregulated genes and 12 downregulated genes in COLO205 cells after NP treatment. Among these differentially expressed genes, we found that coiled-coil domain containing 80 (CCDC80) was downregulated by NP treatment and was associated with CRC progression. Further experiments revealed that the overexpression of CCDC80 significantly suppressed NP-induced cell proliferation and recovered the reduced cell apoptosis. Meanwhile, the overexpression of CCDC80 significantly inhibited the activation of ERK1/2 induced by NP treatment. ERK1/2 inhibitor (PD98059) treatment also suppressed NP-induced CRC cell growth, but the overexpression of CCDC80 did not enhance the effect of ERK1/2 inhibitor. Taken together, NP treatment significantly inhibited the expression of CCDC80, and the overexpression of CCDC80 suppressed NP-induced CRC cell growth by inhibiting the activation of ERK1/2. These results suggest that NP could induce CRC cell growth by influencing the expression of multiple genes. CCDC80 and ERK1/2 inhibitors may be suitable therapeutic targets in NP-related CRC progression.
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