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International Journal of Molecular... Mar 2023Pancreatic cancer is one of the most lethal malignant diseases due to its high invasiveness, early metastatic properties, rapid disease progression, and typically late... (Review)
Review
Pancreatic cancer is one of the most lethal malignant diseases due to its high invasiveness, early metastatic properties, rapid disease progression, and typically late diagnosis. Notably, the capacity for pancreatic cancer cells to undergo epithelial-mesenchymal transition (EMT) is key to their tumorigenic and metastatic potential, and is a feature that can explain the therapeutic resistance of such cancers to treatment. Epigenetic modifications are a central molecular feature of EMT, for which histone modifications are most prevalent. The modification of histones is a dynamic process typically carried out by pairs of reverse catalytic enzymes, and the functions of these enzymes are increasingly relevant to our improved understanding of cancer. In this review, we discuss the mechanisms through which histone-modifying enzymes regulate EMT in pancreatic cancer.
Topics: Humans; Histone Code; Epithelial-Mesenchymal Transition; Pancreatic Neoplasms; Histones; Epigenesis, Genetic; Mesoderm
PubMed: 36902253
DOI: 10.3390/ijms24054820 -
Cell and Tissue Research Apr 2014Vascularization is essential for organ and tissue development. Teeth develop through interactions between epithelium and mesenchyme. The developing capillaries in the...
Vascularization is essential for organ and tissue development. Teeth develop through interactions between epithelium and mesenchyme. The developing capillaries in the enamel organ, the dental epithelial structure, occur simultaneously by mechanisms of vasculogenesis and angiogenesis at the onset of dentinogenesis. The vascular neoformation in the dental mesenchyme has been reported to start from the cap stage. However, the mechanisms of vascularization in the dental mesenchyme remain unknown. In the hope of understanding the mechanisms of the formation of dental mesenchymal vasculature, mouse lower molar germs from embryonic day (E) 13.5 to E16.5 were processed for immunostaining of CD31 and CD34, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) and transmission electron microscopy (TEM). In addition, the role of apoptosis for the vascularization in dental mesenchyme was examined by in vitro culture of E14.0 lower molars in the presence of the apoptosis inhibitor (z-VAD-fmk) and a subsequent subrenal culture. Our results showed that CD31- and CD34-positive cells progressively entered the central part of the dental papilla from the peridental mesenchyme. For TEM, angioblasts, young capillaries with thick endothelium and endothelial cells containing vacuoles were observed in peripheral dental mesenchyme, suggesting vasculogenesis was taking place. The presence of lateral sprouting, cytoplasmic filopodia and transluminal bridges in the dental papilla suggested angiogenesis was also occurring. Inhibition of apoptosis delayed the angiogenic vascularization of the dental papilla. Therefore, these data demonstrated that molar mesenchyme is progressively vascularized by mechanisms of both vasculogenesis and angiogenesis and apoptosis partially contributes to the vascularization of the dental papilla.
Topics: Amino Acid Chloromethyl Ketones; Animals; Antigens, CD34; Apoptosis; Capillaries; Fluorescent Antibody Technique; In Situ Nick-End Labeling; Mesoderm; Mice; Mice, Inbred ICR; Molar; Neovascularization, Physiologic; Platelet Endothelial Cell Adhesion Molecule-1; Protein Transport; Tooth Germ; Vascular Endothelial Growth Factor A
PubMed: 24477797
DOI: 10.1007/s00441-013-1785-5 -
Nature Communications Sep 2018Organogenesis requires the complex interactions of multiple cell lineages that coordinate their expansion, differentiation, and maturation over time. Here, we profile...
Organogenesis requires the complex interactions of multiple cell lineages that coordinate their expansion, differentiation, and maturation over time. Here, we profile the cell types within the epithelial and mesenchymal compartments of the murine pancreas across developmental time using a combination of single-cell RNA sequencing, immunofluorescence, in situ hybridization, and genetic lineage tracing. We identify previously underappreciated cellular heterogeneity of the developing mesenchyme and reconstruct potential lineage relationships among the pancreatic mesothelium and mesenchymal cell types. Within the epithelium, we find a previously undescribed endocrine progenitor population, as well as an analogous population in both human fetal tissue and human embryonic stem cells differentiating toward a pancreatic beta cell fate. Further, we identify candidate transcriptional regulators along the differentiation trajectory of this population toward the alpha or beta cell lineages. This work establishes a roadmap of pancreatic development and demonstrates the broad utility of this approach for understanding lineage dynamics in developing organs.
Topics: Animals; Cell Differentiation; Cell Line; Cell Lineage; Epithelium; Gene Expression Regulation, Developmental; Human Embryonic Stem Cells; Humans; In Situ Hybridization; Mesoderm; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Fluorescence; Pancreas; Reverse Transcriptase Polymerase Chain Reaction; Single-Cell Analysis
PubMed: 30254276
DOI: 10.1038/s41467-018-06176-3 -
Developmental Biology Oct 2007The kidney develops by cycles of ureteric bud branching and nephron formation. The cycles begin and are sustained by reciprocal inductive interactions and feedback...
The kidney develops by cycles of ureteric bud branching and nephron formation. The cycles begin and are sustained by reciprocal inductive interactions and feedback between ureteric bud tips and the surrounding mesenchyme. Understanding how the cycles end is important because it controls nephron number. During the period when nephrogenesis ends in mice, we examined the morphology, gene expression, and function of the domains that control branching and nephrogenesis. We found that the nephrogenic mesenchyme, which is required for continued branching, was gone by the third postnatal day. This was associated with an accelerated rate of new nephron formation in the absence of apoptosis. At the same time, the tips of the ureteric bud branches lost the typical appearance of an ampulla and lost Wnt11 expression, consistent with the absence of the capping mesenchyme. Surprisingly, expression of Wnt9b, a gene necessary for mesenchyme induction, continued. We then tested the postnatal day three bud branch tip and showed that it maintained its ability both to promote survival of metanephric mesenchyme and to induce nephrogenesis in culture. These results suggest that the sequence of events leading to disruption of the cycle of branching morphogenesis and nephrogenesis began with the loss of mesenchyme that resulted from its conversion into nephrons.
Topics: Animals; Animals, Newborn; Kidney; Mesoderm; Mice; Morphogenesis; Nephrons; Tissue Culture Techniques; Ureter; Wnt Proteins
PubMed: 17826763
DOI: 10.1016/j.ydbio.2007.08.021 -
Developmental Cell Jun 2008The epithelial-mesenchymal transition is a highly conserved cellular program that allows polarized, immotile epithelial cells to convert to motile mesenchymal cells.... (Review)
Review
The epithelial-mesenchymal transition is a highly conserved cellular program that allows polarized, immotile epithelial cells to convert to motile mesenchymal cells. This important process was initially recognized during several critical stages of embryonic development and has more recently been implicated in promoting carcinoma invasion and metastasis. In this review, we summarize and compare major signaling pathways that regulate the epithelial-mesenchymal transitions during both development and tumor metastasis. Studies in both fields are critical for our molecular understanding of cell migration and morphogenesis.
Topics: Animals; Cell Movement; Embryonic Development; Epithelial Cells; Humans; Mesoderm; Models, Biological; Neoplasm Metastasis; Neoplasms; Signal Transduction
PubMed: 18539112
DOI: 10.1016/j.devcel.2008.05.009 -
Current Biology : CB Sep 1998The mammalian lung, like many other organs, develops by branching morphogenesis of an epithelium [1]. Development initiates with evagination of two ventral buds of... (Review)
Review
The mammalian lung, like many other organs, develops by branching morphogenesis of an epithelium [1]. Development initiates with evagination of two ventral buds of foregut endoderm into the underlying splanchnic mesoderm. As the buds extend, they send out lateral branches at precise, invariant positions, establishing the primary airways and the lobes of each lung. Dichotomous branching leads to further extension of the airways. Grafting studies have demonstrated the importance of bronchial mesenchyme in inducing epithelial branching, but the significance of epithelial signaling has largely been unstudied. The morphogen Sonic hedgehog (Shh) is widely expressed in the foregut endoderm and is specifically upregulated in the distal epithelium of the lung where branching is occurring [2]. Ectopic expression of Shh disrupts branching and increases proliferation, suggesting that local Shh signaling regulates lung development [2]. We report here that Shh is essential for development of the respiratory system. In Shh null mutants, we found that the trachea and esophagus do not separate properly and the lungs form a rudimentary sac due to failure of branching and growth after formation of the primary lung buds. Interestingly, normal proximo-distal differentiation of the airway epithelium occurred, indicating that Shh is not needed for differentiation events. In addition, the transcription of several mesenchymally expressed downstream targets of Shh is abolished. These results highlight the importance of epithelially derived Shh in regulating branching morphogenesis of the lung.
Topics: Animals; Embryonic Induction; Endoderm; Esophagus; Fetal Proteins; Gene Expression Regulation, Developmental; Hedgehog Proteins; Lung; Membrane Proteins; Mesoderm; Mice; Mice, Knockout; Morphogenesis; Patched Receptors; Proteins; Receptors, Cell Surface; Trachea; Trans-Activators
PubMed: 9768363
DOI: 10.1016/s0960-9822(98)70446-4 -
Developmental Dynamics : An Official... Sep 2019Second heart field cells and neural crest cells have been reported to participate in the morphogenesis of the pharyngeal arch arteries (PAAs); however, how the PAAs grow...
BACKGROUND
Second heart field cells and neural crest cells have been reported to participate in the morphogenesis of the pharyngeal arch arteries (PAAs); however, how the PAAs grow out and are separated from the aortic sac into left and right sections is unknown.
RESULTS
An Isl-1 positive pharyngeal mesenchyme protrusion in the aortic sac ventrally extends and fuses with the aortic sac wall to form a midsagittal septum that divides the aortic sac. The aortic sac division separates the left and right PAAs to form independent arteries. The midsagittal septum dividing the aortic sac has a different expression pattern from the aortic-pulmonary (AP) septum in which Isl-1 positive cells are absent. At 11 days post-conception (dpc) in a mouse embryo, the Isl-1 positive mesenchyme protrusion appears as a heart-shaped structure, in which subpopulations with Isl-1+ Tbx3+ and Isl-1+ Nkx2.5+ cells are included.
CONCLUSIONS
The aortic sac is a dynamic structure that is continuously divided during the migration from the pharyngeal mesenchyme to the pericardial cavity. The separation of the aortic sac is not complete until the AP septum divides the aortic sac into the ascending aorta and pulmonary trunk. Moreover, the midsagittal septum and the AP septum are distinct structures.
Topics: Animals; Aorta; Arteries; Branchial Region; Embryo, Mammalian; Heart; LIM-Homeodomain Proteins; Mesoderm; Mice; Morphogenesis; Transcription Factors
PubMed: 31175693
DOI: 10.1002/dvdy.68 -
PLoS Biology Sep 2011The developing pancreatic epithelium gives rise to all endocrine and exocrine cells of the mature organ. During organogenesis, the epithelial cells receive essential...
The developing pancreatic epithelium gives rise to all endocrine and exocrine cells of the mature organ. During organogenesis, the epithelial cells receive essential signals from the overlying mesenchyme. Previous studies, focusing on ex vivo tissue explants or complete knockout mice, have identified an important role for the mesenchyme in regulating the expansion of progenitor cells in the early pancreas epithelium. However, due to the lack of genetic tools directing expression specifically to the mesenchyme, the potential roles of this supporting tissue in vivo, especially in guiding later stages of pancreas organogenesis, have not been elucidated. We employed transgenic tools and fetal surgical techniques to ablate mesenchyme via Cre-mediated mesenchymal expression of Diphtheria Toxin (DT) at the onset of pancreas formation, and at later developmental stages via in utero injection of DT into transgenic mice expressing the Diphtheria Toxin receptor (DTR) in this tissue. Our results demonstrate that mesenchymal cells regulate pancreatic growth and branching at both early and late developmental stages by supporting proliferation of precursors and differentiated cells, respectively. Interestingly, while cell differentiation was not affected, the expansion of both the endocrine and exocrine compartments was equally impaired. To further elucidate signals required for mesenchymal cell function, we eliminated β-catenin signaling and determined that it is a critical pathway in regulating mesenchyme survival and growth. Our study presents the first in vivo evidence that the embryonic mesenchyme provides critical signals to the epithelium throughout pancreas organogenesis. The findings are novel and relevant as they indicate a critical role for the mesenchyme during late expansion of endocrine and exocrine compartments. In addition, our results provide a molecular mechanism for mesenchymal expansion and survival by identifying β-catenin signaling as an essential mediator of this process. These results have implications for developing strategies to expand pancreas progenitors and β-cells for clinical transplantation.
Topics: Animals; Diphtheria Toxin; Embryo, Mammalian; Epithelium; Gene Expression Regulation, Developmental; Mesoderm; Mice; Mice, Knockout; Organogenesis; Pancreas
PubMed: 21909240
DOI: 10.1371/journal.pbio.1001143 -
Developmental Biology Apr 2021Mice possess two types of teeth that differ in their cusp patterns; incisors have one cusp and molars have multiple cusps. The patterning of these two types of teeth...
Mice possess two types of teeth that differ in their cusp patterns; incisors have one cusp and molars have multiple cusps. The patterning of these two types of teeth relies on fine-tuning of the reciprocal molecular signaling between dental epithelial and mesenchymal tissues during embryonic development. The AP-2 transcription factors, particularly Tfap2a and Tfap2b, are essential components of such epithelial-mesenchymal signaling interactions that coordinate craniofacial development in mice and other vertebrates, but little is known about their roles in the regulation of tooth development and shape. Here we demonstrate that incisors and molars differ in their temporal and spatial expression of Tfap2a and Tfap2b. At the bud stage, Tfap2a is expressed in both the epithelium and mesenchyme of the incisors and molars, but Tfap2b expression is restricted to the molar mesenchyme, only later appearing in the incisor epithelium. Tissue-specific deletions show that loss of the epithelial domain of Tfap2a and Tfap2b affects the number and spatial arrangement of the incisors, notably resulting in duplicated lower incisors. In contrast, deletion of these two genes in the mesenchymal domain has little effect on tooth development. Collectively these results implicate epithelial expression of Tfap2a and Tfap2b in regulating the extent of the dental lamina associated with patterning the incisors and suggest that these genes contribute to morphological differences between anterior (incisor) and posterior (molar) teeth within the mammalian dentition.
Topics: Alleles; Animals; Animals, Genetically Modified; Epithelium; Female; Gene Deletion; Incisor; Male; Mesoderm; Mice; Molar; Odontogenesis; Signal Transduction; Tooth Germ; Transcription Factor AP-2
PubMed: 33460639
DOI: 10.1016/j.ydbio.2020.12.017 -
Tissue Engineering. Part B, Reviews Feb 2011Oral mucosa consists of two tissue layers, the superficial epithelium and the underlying lamina propria. Together, oral mucosa functions as a barrier against exogenous... (Review)
Review
Oral mucosa consists of two tissue layers, the superficial epithelium and the underlying lamina propria. Together, oral mucosa functions as a barrier against exogenous substances and pathogens. In development, interactions of stem/progenitor cells of the epithelium and mesenchyme are crucial to the morphogenesis of oral mucosa. Previous work in oral mucosa regeneration has yielded important clues for several meritorious proof-of-concept approaches. Tissue engineering offers a broad array of novel tools for oral mucosa regeneration with reduced donor site trauma and accelerated clinical translation. However, the developmental concept of epithelial-mesenchymal interactions (EMIs) is rarely considered in oral mucosa regeneration. EMIs in postnatal oral mucosa regeneration likely will not be a simple recapitulation of prenatal oral mucosa development. Biomaterial scaffolds play an indispensible role for oral mucosa regeneration and should provide a conducive environment for pivotal EMIs. Autocrine and paracrine factors, either exogenously delivered or innately produced, have rarely been and should be harnessed to promote oral mucosa regeneration. This review focuses on a working concept of epithelial and mesenchymal interactions in oral mucosa regeneration.
Topics: Animals; Cell Communication; Concept Formation; Epithelial Cells; Humans; Mesoderm; Mouth Mucosa; Regeneration; Stem Cells; Tissue Engineering
PubMed: 21062224
DOI: 10.1089/ten.TEB.2010.0489