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Seminars in Cell & Developmental Biology Aug 2019The liver is an indispensable organ for metabolism and drug detoxification. The liver consists of endoderm-derived hepatobiliary lineages and various mesoderm-derived... (Review)
Review
The liver is an indispensable organ for metabolism and drug detoxification. The liver consists of endoderm-derived hepatobiliary lineages and various mesoderm-derived cells, and interacts with the surrounding tissues and organs through the ventral mesentery. Liver development, from hepatic specification to liver maturation, requires close interactions with mesoderm-derived cells, such as mesothelial cells, hepatic stellate cells, mesenchymal cells, liver sinusoidal endothelial cells and hematopoietic cells. These cells affect liver development through precise signaling events and even direct physical contact. Through the use of new techniques, emerging studies have recently led to a deeper understanding of liver development and its related mechanisms, especially the roles of mesodermal cells in liver development. Based on these developments, the current protocols for in vitro hepatocyte-like cell induction and liver-like tissue construction have been optimized and are of great importance for the treatment of liver diseases. Here, we review the roles of mesoderm-derived cells in the processes of liver development, hepatocyte-like cell induction and liver-like tissue construction.
Topics: Animals; Humans; Liver; Mesoderm; Mice
PubMed: 30193996
DOI: 10.1016/j.semcdb.2018.09.003 -
Hepatology Communications Mar 2021The hepatic mesenchyme has been studied extensively in the context of liver fibrosis; however, much less is known regarding the role of mesenchymal cells during liver... (Review)
Review
The hepatic mesenchyme has been studied extensively in the context of liver fibrosis; however, much less is known regarding the role of mesenchymal cells during liver regeneration. As our knowledge of the cellular and molecular mechanisms driving hepatic regeneration deepens, the key role of the mesenchymal compartment during the regenerative response has been increasingly appreciated. Single-cell genomics approaches have recently uncovered both spatial and functional zonation of the hepatic mesenchyme in homeostasis and following liver injury. Here we discuss how the use of preclinical models, from in vivo mouse models to organoid-based systems, are helping to shape our understanding of the role of the mesenchyme during liver regeneration, and how these approaches should facilitate the precise identification of highly targeted, pro-regenerative therapies for patients with liver disease.
Topics: Animals; Cells, Cultured; Hepatic Stellate Cells; Humans; Liver; Liver Diseases; Liver Regeneration; Mesoderm; Mice
PubMed: 33681672
DOI: 10.1002/hep4.1628 -
Methods in Molecular Biology (Clifton,... 2021As our understanding of Epithelial Mesenchymal Transition (EMT) increases, the original binary concept of E versus M no longer fits with experimental evidence....
As our understanding of Epithelial Mesenchymal Transition (EMT) increases, the original binary concept of E versus M no longer fits with experimental evidence. Re-definition of the EMT paradigm as spectral transitions between a full epithelium and a full mesenchyme suggests the existence of a virtual infinity of intermediate cellular states. The new challenge is to develop technical tools needed to contextualize each of these states and identify biologically significant cellular mechanisms that could be targeted in combatting EMT-related diseases.
Topics: Cell Culture Techniques; Epithelial-Mesenchymal Transition; Epithelium; Humans; Mesoderm
PubMed: 32939711
DOI: 10.1007/978-1-0716-0779-4_5 -
Developmental Biology Jul 2020Initial limb chondrogenesis offers the first differentiated tissues that resemble the mature skeletal anatomy. It is a developmental progression of three tissues. The... (Review)
Review
Initial limb chondrogenesis offers the first differentiated tissues that resemble the mature skeletal anatomy. It is a developmental progression of three tissues. The limb begins with undifferentiated mesenchyme-1, some of which differentiates into condensations-2, and this tissue then transforms into cartilage-3. Each tissue is identified by physical characteristics of cell density, shape, and extracellular matrix composition. Tissue specific regimes of gene regulation underlie the diagnostic physical and chemical properties of these three tissues. These three tissue based regimes co-exist amid a background of other gene regulatory regimes within the same tissues and time-frame of limb development. The bio-molecular indicators of gene regulation reveal six identifiable patterns. Three of these patterns describe the unique bio-molecular indicators of each of the three tissues. A fourth pattern shares bio-molecular indicators between condensation and cartilage. Finally, a fifth pattern is composed of bio-molecular indicators that are found in undifferentiated mesenchyme prior to any condensation differentiation, then these bio-molecular indicators are upregulated in condensations and downregulated in undifferentiated mesenchyme. The undifferentiated mesenchyme that remains in between the condensations and cartilage, the interdigit, contains a unique set of bio-molecular indicators that exhibit dynamic behaviour during chondrogenesis and therefore argue for its own inclusion as a tissue in its own right and for more study into this process of differentiation.
Topics: Animals; Cartilage; Cell Differentiation; Chondrogenesis; Extracellular Matrix; Gene Expression Regulation, Developmental; Limb Buds; Mesoderm; Proteoglycans
PubMed: 32417169
DOI: 10.1016/j.ydbio.2020.04.009 -
Developmental Dynamics : An Official... Jan 2017Reciprocal epithelial-mesenchymal communications are critical throughout lung development, dictating branching morphogenesis and cell specification. Numerous signaling...
BACKGROUND
Reciprocal epithelial-mesenchymal communications are critical throughout lung development, dictating branching morphogenesis and cell specification. Numerous signaling molecules are involved in these interactions, but the way epithelial-mesenchymal crosstalk is coordinated remains unclear. The ERK/MAPK pathway transduces several important signals in lung formation. Epithelial inactivation of both Mek genes, encoding ERK/MAPK kinases, causes lung agenesis and death. Conversely, Mek mutation in mesenchyme results in lung hypoplasia, trachea cartilage malformations, kyphosis, omphalocele, and death. Considering the negative impact of kyphosis and omphalocele on intrathoracic space and, consequently, on lung growth, the exact role of ERK/MAPK pathway in lung mesenchyme remains unresolved.
RESULTS
To address the role of the ERK/MAPK pathway in lung mesenchyme in absence of kyphosis and omphalocele, we used the Tbx4 deleter mouse line, which acts specifically in lung mesenchyme. These Mek mutants did not develop kyphosis and omphalocele but they presented lung hypoplasia, tracheal defects, and neonatal death. Tracheal cartilage anomalies suggested a role for the ERK/MAPK pathway in the control of chondrocyte hypertrophy. Moreover, expression data indicated potential interactions between the ERK/MAPK and canonical Wnt pathways during lung formation.
CONCLUSIONS
Lung development necessitates a functional ERK/MAPK pathway in the lung mesenchymal layer in order to coordinate efficient epithelial-mesenchymal interactions. Developmental Dynamics 246:72-82, 2017. © 2016 Wiley Periodicals, Inc.
Topics: Animals; Cell Communication; Chondrocytes; Epithelium; Lung; MAP Kinase Signaling System; Mesoderm; Mice; Mutation; Organogenesis; Trachea; Wnt Signaling Pathway
PubMed: 27748998
DOI: 10.1002/dvdy.24464 -
PLoS Genetics Feb 2014The cranial bones and dermis differentiate from mesenchyme beneath the surface ectoderm. Fate selection in cranial mesenchyme requires the canonical Wnt effector...
The cranial bones and dermis differentiate from mesenchyme beneath the surface ectoderm. Fate selection in cranial mesenchyme requires the canonical Wnt effector molecule β-catenin, but the relative contribution of Wnt ligand sources in this process remains unknown. Here we show Wnt ligands are expressed in cranial surface ectoderm and underlying supraorbital mesenchyme during dermal and osteoblast fate selection. Using conditional genetics, we eliminate secretion of all Wnt ligands from cranial surface ectoderm or undifferentiated mesenchyme, to uncover distinct roles for ectoderm- and mesenchyme-derived Wnts. Ectoderm Wnt ligands induce osteoblast and dermal fibroblast progenitor specification while initiating expression of a subset of mesenchymal Wnts. Mesenchyme Wnt ligands are subsequently essential during differentiation of dermal and osteoblast progenitors. Finally, ectoderm-derived Wnt ligands provide an inductive cue to the cranial mesenchyme for the fate selection of dermal fibroblast and osteoblast lineages. Thus two sources of Wnt ligands perform distinct functions during osteoblast and dermal fibroblast formation.
Topics: Animals; Cell Differentiation; Ectoderm; Gene Expression Regulation, Developmental; Ligands; Mesoderm; Mice; Osteoblasts; Signal Transduction; Skull; Stem Cells; Wnt Proteins; beta Catenin
PubMed: 24586192
DOI: 10.1371/journal.pgen.1004152 -
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 -
Journal of Visualized Experiments : JoVE Jan 2013The central nervous system is derived from the neural plate that undergoes a series of complex morphogenetic movements resulting in formation of the neural tube in a...
The central nervous system is derived from the neural plate that undergoes a series of complex morphogenetic movements resulting in formation of the neural tube in a process known as neurulation. During neurulation, morphogenesis of the mesenchyme that underlies the neural plate is believed to drive neural fold elevation. The cranial mesenchyme is comprised of the paraxial mesoderm and neural crest cells. The cells of the cranial mesenchyme form a pourous meshwork composed of stellate shaped cells and intermingling extracellular matrix (ECM) strands that support the neural folds. During neurulation, the cranial mesenchyme undergoes stereotypical rearrangements resulting in its expansion and these movements are believed to provide a driving force for neural fold elevation. However, the pathways and cellular behaviors that drive cranial mesenchyme morphogenesis remain poorly studied. Interactions between the ECM and the cells of the cranial mesenchyme underly these cell behaviors. Here we describe a simple ex vivo explant assay devised to characterize the behaviors of these cells. This assay is amendable to pharmacological manipulations to dissect the signaling pathways involved and live imaging analyses to further characterize the behavior of these cells. We present a representative experiment demonstrating the utility of this assay in characterizing the migratory properties of the cranial mesenchyme on a variety of ECM components.
Topics: Animals; Embryology; Female; Mesoderm; Mice; Neural Tube; Organ Culture Techniques; Pregnancy; Skull
PubMed: 23381592
DOI: 10.3791/4245 -
Methods in Molecular Biology (Clifton,... 2014High-density micromass cultures of embryonic mesenchymal cells have proved to be an invaluable model for studying the entire chondrogenic program, from precartilaginous...
High-density micromass cultures of embryonic mesenchymal cells have proved to be an invaluable model for studying the entire chondrogenic program, from precartilaginous condensations through to chondrocyte hypertrophy. This culture model also provides a powerful system in which to explore the function of various factors in the commitment and differentiation of mesenchymal cells to the chondrogenic lineage. In this regard, micromass cultures provide a consistent and robust model for investigating the effects of genetic manipulations on skeletal phenotypes and for delineating their molecular basis. In this methods chapter, the derivation and use of micromass cultures from murine limb buds are described, but these techniques are also applicable to other organisms and mesenchymal cell sources.
Topics: Animals; Cell Culture Techniques; Chondrogenesis; Female; Gene Expression; Histocytochemistry; Limb Buds; Mesoderm; Mice; Pregnancy; Transfection
PubMed: 24482179
DOI: 10.1007/978-1-62703-989-5_19 -
Acta Anatomica 1995Epithelium is the tissue phenotype of early embryos and primitive adults of the chordate phylum. A second tissue type, however, is produced by epithelial-mesenchymal... (Review)
Review
Epithelium is the tissue phenotype of early embryos and primitive adults of the chordate phylum. A second tissue type, however, is produced by epithelial-mesenchymal transformation (EMT) in higher chordates, such as vertebrata. Mesenchymal cells have the ability, which true epithelia do not, to invade and migrate through the extracellular matrix (ECM) to create dramatic cell transpositions. The first-formed or primary mesenchymal cells in amniote vertebrates migrate from the primitive streak to differentiate into the mesodermal and endodermal epithelia. Definitive mesenchyme with connective tissue and muscle potentials arises from the epithelial mesoderm at about the same time as the neural crest mesenchyme forms from the ectoderm. Later on in embryogenesis. EMT is used to remodel unwanted epithelia, such as that of the palate medial edges. We discuss the mechanisms by which epithelial cells transform into mesenchyme and vice versa. On the one hand, cells activate putative mesenchymal master genes, turn off epithelial genes, and acquire motility machinery that allows them to interact in 3 dimensions (3D) with ECM via actin cortex while sliding their endoplasm into their new front ends. On the other hand, primary mesenchymal cells can reactivate epithelial regulatory genes, such as E-cadherin, turn off the motility machinery for invading ECM, and reexpress apical-basal polarity. We review the genes, such as FSP1, src, ras, and fos, that are activated in cells transforming to mesenchyme and the genes their neighbors activate to induce EMT, such as those for TGF beta, NT-3, and sonic hedgehog. Suspension in 3D collagen gels can induce adult epithelium to undergo EMT; alpha 5 beta 1 integrin is activated on surfaces in contact with collagen, including apical surfaces that do not normally express integrins. In vivo, it is possible that pathological manipulations of a cell's environment likewise induce EMT. Of the examples we give, the creation of invasive metastatic carcinoma cells by EMT is the most fearful. Interestingly, transfection of either metastatic cells or normal embryonic fibroblasts with the E-cadherin gene converts them to the epithelial phenotype. It may be possible in the future to manipulate the tissue phenotype of diseased cells to the advantage of the animal.
Topics: Animals; Cadherins; Cell Transformation, Neoplastic; Embryonic Induction; Epithelial Cells; Epithelium; Extracellular Matrix; Fibroblasts; Gene Expression Regulation, Developmental; Genes, Regulator; Integrin beta1; Mesoderm; Mice; Organ Culture Techniques; Receptors, Fibronectin
PubMed: 8714286
DOI: 10.1159/000147748