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Proceedings of the American Thoracic... Dec 2009The bronchial epithelium is the barrier to the external environment and plays a vital role in protection of the internal milieu of the lung. It functions within the... (Review)
Review
The bronchial epithelium is the barrier to the external environment and plays a vital role in protection of the internal milieu of the lung. It functions within the epithelial-mesenchymal trophic unit to control the local microenvironment and help maintain tissue homeostasis. However, in asthma, chronic perturbation of these homeostatic mechanisms leads to alterations in the structure of the airways, termed remodeling. Damage to the epithelium is now recognized to play a key role in driving airway remodeling. We have postulated that epithelial susceptibility to environmental stress and injury together with impaired repair responses results in generation of signals that act on the underlying mesenchyme to propagate and amplify inflammatory and remodeling responses in the submucosa. Many types of challenges to the epithelium, including pathogens, allergens, environmental pollutants, cigarette smoke, and even mechanical forces, can elicit production of mediators by the epithelium, which can be translated into remodeling responses by the mesenchyme. Several important mediators of remodeling have been identified, most notably transforming growth factor-beta, which is released from damaged/repairing epithelium or in response to inflammatory mediators, such as IL-13. The cross talk between the epithelium and the underlying mesenchyme to drive remodeling responses is considered in the context of subepithelial fibrosis and potential pathogenetic mechanisms linked to the asthma susceptibility gene, a disintegrin and metalloprotease (ADAM)33.
Topics: Airway Remodeling; Asthma; Bronchi; Humans; Mesoderm; Respiratory Mucosa; Transforming Growth Factors
PubMed: 20008875
DOI: 10.1513/pats.200907-067DP -
Hepatology (Baltimore, Md.) Dec 2009The outcome of liver injury is dictated by the effectiveness of repair. Successful repair (i.e., regeneration) results in replacement of dead epithelial cells with... (Review)
Review
The outcome of liver injury is dictated by the effectiveness of repair. Successful repair (i.e., regeneration) results in replacement of dead epithelial cells with healthy epithelial cells, and reconstructs normal hepatic structure and function. Liver regeneration is known to involve replication of surviving mature hepatocytes and bile duct cells. This review discusses recent evidence for other mechanisms that might also replace dead hepatic epithelial cells and repair liver damage, particularly during chronic injury. According to this theory, certain epithelial cells in developing livers and/or injured adult livers undergo epithelial-to-mesenchymal transition (EMT) and move into the hepatic mesenchyme where they exhibit fibroblastic features. Some of these epithelia-derived mesenchymal cells, however, may be capable of undergoing subsequent mesenchymal-to-epithelial transition (MET), reverting to epithelial cells that ultimately become hepatocytes or cholangiocytes. Although these concepts remain to be proven, the theory predicts that the balance between EMT and MET modulates the outcome of chronic liver injury. When EMT activity outstrips MET, repair is mainly fibrogenic, causing liver fibrosis. Conversely, predominance of MET favors more normal liver regeneration. In this review, we summarize evidence that certain resident liver cells are capable of EMTs in vitro and during chronic liver injury.
Topics: Animals; Cell Transdifferentiation; Epithelial Cells; Hepatocytes; Humans; Liver; Liver Cirrhosis; Liver Regeneration; Mesenchymal Stem Cells; Mesoderm
PubMed: 19824076
DOI: 10.1002/hep.23196 -
Cold Spring Harbor Perspectives in... Jan 2018Epithelia exist in the animal body since the onset of embryonic development; they generate tissue barriers and specify organs and glands. Through epithelial-mesenchymal... (Review)
Review
Epithelia exist in the animal body since the onset of embryonic development; they generate tissue barriers and specify organs and glands. Through epithelial-mesenchymal transitions (EMTs), epithelia generate mesenchymal cells that form new tissues and promote healing or disease manifestation when epithelial homeostasis is challenged physiologically or pathologically. Transforming growth factor-βs (TGF-βs), activins, bone morphogenetic proteins (BMPs), and growth and differentiation factors (GDFs) have been implicated in the regulation of epithelial differentiation. These TGF-β family ligands are expressed and secreted at sites where the epithelium interacts with the mesenchyme and provide paracrine queues from the mesenchyme to the neighboring epithelium, helping the specification of differentiated epithelial cell types within an organ. TGF-β ligands signal via Smads and cooperating kinase pathways and control the expression or activities of key transcription factors that promote either epithelial differentiation or mesenchymal transitions. In this review, we discuss evidence that illustrates how TGF-β family ligands contribute to epithelial differentiation and induce mesenchymal transitions, by focusing on the embryonic ectoderm and tissues that form the external mammalian body lining.
Topics: Animals; Cell Differentiation; Epidermis; Epithelial-Mesenchymal Transition; Epithelium; Feathers; Hair Follicle; Humans; Mesoderm; Neural Crest; Signal Transduction; Tooth; Transforming Growth Factor beta
PubMed: 28246184
DOI: 10.1101/cshperspect.a022194 -
Discovery Medicine May 2010While asthma is an inflammatory disorder of the conducting airways, most frequently therapeutics directed specifically at components of these pathways have had limited... (Review)
Review
While asthma is an inflammatory disorder of the conducting airways, most frequently therapeutics directed specifically at components of these pathways have had limited or no success in the clinic. Part of the problem lies in over-reliance on simple animal models of antigen sensitization and challenge to select therapeutic candidates, and partly because allergic mechanisms have been studied out of context of the formed elements that make up the structure of the airways such as the epithelium and underlying vasculature and mesenchyme. This review covers recent experience with some new therapeutics that include biologics and concludes by presenting a new paradigm for the disease that embraces heterogeneity and greater consideration of the role played by functionally active structural components. Since asthma was originally described in terms of reversible airflow obstruction, this moves away from placing inflammation at the center of the disease more towards a parallel involvement of the epithelial mesenchymal trophic unit to provide the context within which the inflammatory response occurs.
Topics: Asthma; Epithelium; Humans; Mesoderm; Time Factors
PubMed: 20515612
DOI: No ID Found -
Mechanisms of Development Feb 2015During fin morphogenesis, several mesenchyme condensations occur to give rise to the dermal skeleton. Although each of them seems to create distinctive and unique... (Review)
Review
During fin morphogenesis, several mesenchyme condensations occur to give rise to the dermal skeleton. Although each of them seems to create distinctive and unique structures, they all follow the premises of the same morphogenetic principle. Holmgren's principle of delamination was first proposed to describe the morphogenesis of skeletal elements of the cranium, but Jarvik extended it to the development of the fin exoskeleton. Since then, some cellular or molecular explanations, such as the "flypaper" model (Thorogood et al.), or the evolutionary description by Moss, have tried to clarify this topic. In this article, we review new data from zebrafish studies to meet these criteria described by Holmgren and other authors. The variety of cell lineages involved in these skeletogenic condensations sheds light on an open discussion of the contributions of mesoderm- versus neural crest-derived cell lineages to the development of the head and trunk skeleton. Moreover, we discuss emerging molecular studies that are disclosing conserved regulatory mechanisms for dermal skeletogenesis and similarities during fin development and regeneration, which may have important implications in the potential use of the zebrafish fin as a model for regenerative medicine.
Topics: Animal Fins; Animals; Humans; Mesoderm; Models, Animal; Morphogenesis; Regeneration; Skull
PubMed: 25460362
DOI: 10.1016/j.mod.2014.11.002 -
Developmental Biology Mar 2018The murine pancreas buds from the ventral embryonic endoderm at approximately 8.75 dpc and a second pancreas bud emerges from the dorsal endoderm by 9.0 dpc. Although it...
The murine pancreas buds from the ventral embryonic endoderm at approximately 8.75 dpc and a second pancreas bud emerges from the dorsal endoderm by 9.0 dpc. Although it is clear that secreted signals from adjacent mesoderm-derived sources are required for both the appropriate emergence and further refinement of the pancreatic endoderm, neither the exact signals nor the requisite tissue sources have been defined in mammalian systems. Herein we use DiI fate mapping of cultured murine embryos to identify the embryonic sources of both the early inductive and later condensed pancreatic mesenchyme. Despite being capable of supporting pancreas induction from dorsal endoderm in co-culture experiments, we find that in the context of the developing embryo, the dorsal aortae as well as the paraxial, intermediate, and lateral mesoderm derivatives only transiently associate with the dorsal pancreas bud, producing descendants that are decidedly anterior to the pancreas bud. Unlike these other mesoderm derivatives, the axial (notochord) descendants maintain association with the dorsal pre-pancreatic endoderm and early pancreas bud. This fate mapping data points to the notochord as the likely inductive source in vivo while also revealing dynamic morphogenetic movements displayed by individual mesodermal subtypes. Because none of the mesoderm examined above produced the pancreatic mesenchyme that condenses around the induced bud to support exocrine and endocrine differentiation, we also sought to identify the mesodermal origins of this mesenchyme. We identify a portion of the coelomic mesoderm that contributes to the condensed pancreatic mesenchyme. In conclusion, we identify a portion of the notochord as a likely source of the signals required to induce and maintain the early dorsal pancreas bud, demonstrate that the coelomic mesothelium contributes to the dorsal and ventral pancreatic mesenchyme, and provide insight into the dynamic morphological rearrangements of mesoderm-derived tissues during early organogenesis stages of mammalian development.
Topics: Animals; Embryo, Mammalian; Mesoderm; Mice; Organogenesis; Pancreas
PubMed: 29329912
DOI: 10.1016/j.ydbio.2018.01.003 -
Birth Defects Research. Part A,... Oct 2012The central nervous system is derived from the neural plate, which undergoes a series of complex morphogenetic events resulting in formation of the neural tube in a... (Review)
Review
The central nervous system is derived from the neural plate, which undergoes a series of complex morphogenetic events resulting in formation of the neural tube in a process known as neurulation. The cellular behaviors driving neurulation in the cranial region involve forces generated by the neural tissue itself as well as the surrounding epithelium and mesenchyme. Of interest, the cranial mesenchyme underlying the neural plate undergoes stereotypical rearrangements hypothesized to drive elevation of the neural folds. As the neural folds rise, the hyaluronate-rich extracellular matrix greatly expands resulting in increased space between individual cranial mesenchyme cells. Based on inhibitor studies, expansion of the extracellular matrix has been implicated in driving neural fold elevation; however, because the surrounding neural and epidermal ectoderm were also affected by inhibitor exposure, these studies are inconclusive. Similarly, treatment of neurulating embryos with teratogenic doses of retinoic acid results in altered organization of the cranial mesenchyme, but alterations in surrounding tissues are also observed. The strongest evidence for a critical role for the cranial mesenchyme in neural fold elevation comes from studies of genes expressed exclusively in the cranial mesenchyme that when mutated result in exencephaly associated with abnormal organization of the cranial mesenchyme. Twist is the best studied of these and is expressed in both the paraxial mesoderm and neural crest derived cranial mesenchyme. In this article, we review the evidence implicating the cranial mesenchyme in providing a driving force for neural fold elevation to evaluate whether there are sufficient data to support this hypothesis.
Topics: Animals; Humans; Mesoderm; Models, Biological; Morphogenesis; Neural Crest; Neural Tube Defects; Neurulation; Skull; Tretinoin
PubMed: 22945385
DOI: 10.1002/bdra.23073 -
Cell Research Jan 2012This article reviews the molecular structure, expression pattern, physiological function, pathological roles and molecular mechanisms of Twist1 in development, genetic... (Review)
Review
This article reviews the molecular structure, expression pattern, physiological function, pathological roles and molecular mechanisms of Twist1 in development, genetic disease and cancer. Twist1 is a basic helix-loop-helix domain-containing transcription factor. It forms homo- or hetero-dimers in order to bind the Nde1 E-box element and activate or repress its target genes. During development, Twist1 is essential for mesoderm specification and differentiation. Heterozygous loss-of-function mutations of the human Twist1 gene cause several diseases including the Saethre-Chotzen syndrome. The Twist1-null mouse embryos die with unclosed cranial neural tubes and defective head mesenchyme, somites and limb buds. Twist1 is expressed in breast, liver, prostate, gastric and other types of cancers, and its expression is usually associated with invasive and metastatic cancer phenotypes. In cancer cells, Twist1 is upregulated by multiple factors including SRC-1, STAT3, MSX2, HIF-1α, integrin-linked kinase and NF-κB. Twist1 significantly enhances epithelial-mesenchymal transition (EMT) and cancer cell migration and invasion, hence promoting cancer metastasis. Twist1 promotes EMT in part by directly repressing E-cadherin expression by recruiting the nucleosome remodeling and deacetylase complex for gene repression and by upregulating Bmi1, AKT2, YB-1, etc. Emerging evidence also suggests that Twist1 plays a role in expansion and chemotherapeutic resistance of cancer stem cells. Further understanding of the mechanisms by which Twist1 promotes metastasis and identification of Twist1 functional modulators may hold promise for developing new strategies to inhibit EMT and cancer metastasis.
Topics: Acrocephalosyndactylia; Amino Acid Sequence; Animals; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Mesoderm; Mice; Molecular Sequence Data; NF-kappa B; Neoplasms; Nuclear Proteins; Organogenesis; Protein Stability; Signal Transduction; Twist-Related Protein 1
PubMed: 21876555
DOI: 10.1038/cr.2011.144 -
Cellular and Molecular Life Sciences :... Oct 2018Mesenchymoangioblast (MB) is the earliest precursor for endothelial and mesenchymal cells originating from APLNRPDGFRαKDR mesoderm in human pluripotent stem cell... (Review)
Review
Mesenchymoangioblast (MB) is the earliest precursor for endothelial and mesenchymal cells originating from APLNRPDGFRαKDR mesoderm in human pluripotent stem cell cultures. MBs are identified based on their capacity to form FGF2-dependent compact spheroid colonies in a serum-free semisolid medium. MBs colonies are composed of PDGFRβCD271EMCNDLK1CD73 primitive mesenchymal cells which are generated through endothelial/angioblastic intermediates (cores) formed during first 3-4 days of clonogenic cultures. MB-derived primitive mesenchymal cells have potential to differentiate into mesenchymal stromal/stem cells (MSCs), pericytes, and smooth muscle cells. In this review, we summarize the specification and developmental potential of MBs, emphasize features that distinguish MBs from other mesenchymal progenitors described in the literature and discuss the value of these findings for identifying molecular pathways leading to MSC and vasculogenic cell specification, and developing cellular therapies using MB-derived progeny.
Topics: Autoimmune Diseases; Cell Lineage; Embryonic Development; Endothelial Cells; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mesoderm; Pluripotent Stem Cells; Spheroids, Cellular
PubMed: 29992471
DOI: 10.1007/s00018-018-2871-3 -
RNA Biology Dec 2017Epithelial-mesenchymal interactions are required to coordinate cell proliferation, patterning, and functional differentiation of multiple cell types in a developing... (Review)
Review
Epithelial-mesenchymal interactions are required to coordinate cell proliferation, patterning, and functional differentiation of multiple cell types in a developing organ. This exquisite coordination is dependent on various secreted molecules that provide developmental signals to mediate these tissue interactions. Recently, it was reported that mature mesenchymal-derived microRNAs (miRNAs) in the fetal mouse salivary gland are loaded into exosomes, and transported to the epithelium where they influence progenitor cell proliferation. The exosomal miRNAs regulated epithelial expression of genes involved in DNA methylation in progenitor cells to influence morphogenesis. Thus, exosomal miRNAs are mobile genetic signals that cross tissue boundaries within an organ. These findings raise many questions about how miRNA signals are initiated to coordinate organogenesis and whether they are master regulators of epithelial-mesenchymal interactions. The development of therapeutic applications using exosomal miRNAs for the regeneration of damaged adult organs is a promising area of research.
Topics: Animals; Biological Transport; Epithelial Cells; Epithelium; Exosomes; Extracellular Vesicles; Humans; Mesoderm; MicroRNAs; Molecular Diagnostic Techniques; Organogenesis; Salivary Glands; Signal Transduction
PubMed: 28816640
DOI: 10.1080/15476286.2017.1361098