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Advances in Experimental Medicine and... 2023The structure of the mammalian lung controls the flow of air through the airways and into the distal alveolar region where gas exchange occurs. Specialized cells in the...
The structure of the mammalian lung controls the flow of air through the airways and into the distal alveolar region where gas exchange occurs. Specialized cells in the lung mesenchyme produce the extracellular matrix (ECM) and growth factors required for lung structure. Historically, characterizing the mesenchymal cell subtypes was challenging due to their ambiguous morphology, overlapping expression of protein markers, and limited cell-surface molecules needed for isolation. The recent development of single-cell RNA sequencing (scRNA-seq) complemented with genetic mouse models demonstrated that the lung mesenchyme comprises transcriptionally and functionally heterogeneous cell-types. Bioengineering approaches that model tissue structure clarify the function and regulation of mesenchymal cell types. These experimental approaches demonstrate the unique abilities of fibroblasts in mechanosignaling, mechanical force generation, ECM production, and tissue regeneration. This chapter will review the cell biology of the lung mesenchyme and experimental approaches to study their function.
Topics: Mice; Animals; Lung; Extracellular Matrix; Fibroblasts; Intercellular Signaling Peptides and Proteins; Mesoderm; Mammals
PubMed: 37195530
DOI: 10.1007/978-3-031-26625-6_8 -
Cells & Development Dec 2021In vertebrate embryos the presomitic mesoderm becomes progressively segmented into somites at the anterior end while extending along the anterior-posterior axis. A...
In vertebrate embryos the presomitic mesoderm becomes progressively segmented into somites at the anterior end while extending along the anterior-posterior axis. A commonly adopted model to explain how this tissue elongates is that of posterior growth, driven in part by the addition of new cells from uncommitted progenitor populations in the tailbud. However, in zebrafish, much of somitogenesis is associated with an absence of overall volume increase, and posterior progenitors do not contribute new cells until the final stages of somitogenesis. Here, we perform a comprehensive 3D morphometric analysis of the paraxial mesoderm and reveal that extension is linked to a volumetric decrease and an increase in cell density. We also find that individual cells decrease in volume over successive somite stages. Live cell tracking confirms that much of this tissue deformation occurs within the presomitic mesoderm progenitor zone and is associated with non-directional rearrangement. Taken together, we propose a compaction-extension mechanism of tissue elongation that highlights the need to better understand the role tissue intrinsic and extrinsic forces in regulating morphogenesis.
Topics: Animals; Embryonic Development; Mesoderm; Morphogenesis; Somites; Zebrafish
PubMed: 34597846
DOI: 10.1016/j.cdev.2021.203748 -
DNA and Cell Biology Oct 2023Fibroblast growth factor (FGF) signaling is conserved from cnidaria to mammals (Ornitz and Itoh, 2022) and it regulates several critical processes such as... (Review)
Review
Fibroblast growth factor (FGF) signaling is conserved from cnidaria to mammals (Ornitz and Itoh, 2022) and it regulates several critical processes such as differentiation, proliferation, apoptosis, cell migration, and embryonic development. One pivotal process FGF signaling controls is the division of vertebrate paraxial mesoderm into repeated segmented units called somites (i.e., somitogenesis). Somite segmentation occurs periodically and sequentially in a head-to-tail manner, and lays down the plan for compartmentalized development of the vertebrate body axis (Gomez , 2008). These somites later give rise to vertebrae, tendons, and skeletal muscle. Somite segments form sequentially from the anterior end of the presomitic mesoderm (PSM). The periodicity of somite segmentation is conferred by the segmentation clock, comprising oscillatory expression of Hairy and enhancer-of-split (Her/Hes) genes in the PSM. The positional information for somite boundaries is instructed by the double phosphorylated extracellular signal-regulated kinase (ppERK) gradient, which is the relevant readout of FGF signaling during somitogenesis (Sawada , 2001; Delfini , 2005; Simsek and Ozbudak, 2018; Simsek , 2023). In this review, we summarize the crosstalk between the segmentation clock and FGF/ppERK gradient and discuss how that leads to periodic somite boundary formation. We also draw attention to outstanding questions regarding the interconnected roles of the segmentation clock and ppERK gradient, and close with suggested future directions of study.
Topics: Animals; Fibroblast Growth Factors; Somites; Mesoderm; Signal Transduction; Embryonic Development; Gene Expression Regulation, Developmental; Mammals
PubMed: 37462914
DOI: 10.1089/dna.2023.0226 -
Cell Reports Aug 2022Embryonic stem cells (ESCs) can adopt lineage-specific gene-expression programs by stepwise exposure to defined factors, resulting in the generation of functional cell...
Embryonic stem cells (ESCs) can adopt lineage-specific gene-expression programs by stepwise exposure to defined factors, resulting in the generation of functional cell types. Bulk and single-cell-based assays were employed to catalog gene expression, histone modifications, chromatin conformation, and accessibility transitions in ESC populations and individual cells acquiring a presomitic mesoderm fate and undergoing further specification toward myogenic and neurogenic lineages. These assays identified cis-regulatory regions and transcription factors presiding over gene-expression programs occurring at defined ESC transitions and revealed the presence of heterogeneous cell populations within discrete ESC developmental stages. The datasets were employed to identify previously unappreciated genomic elements directing the initial activation of Pax7 and myogenic and neurogenic gene-expression programs. This study provides a resource for the discovery of genomic and transcriptional features of pluripotent, mesoderm-induced ESCs and ESC-derived cell lineages.
Topics: Cell Differentiation; Embryonic Stem Cells; Gene Expression Regulation, Developmental; Mesoderm; Regulatory Sequences, Nucleic Acid; Transcriptome
PubMed: 35977485
DOI: 10.1016/j.celrep.2022.111219 -
The EMBO Journal Apr 2022Mesoderm arises at gastrulation and contributes to both the mouse embryo proper and its extra-embryonic membranes. Two-photon live imaging of embryos bearing a keratin...
Mesoderm arises at gastrulation and contributes to both the mouse embryo proper and its extra-embryonic membranes. Two-photon live imaging of embryos bearing a keratin reporter allowed recording filament nucleation and elongation in the extra-embryonic region. Upon separation of amniotic and exocoelomic cavities, keratin 8 formed apical cables co-aligned across multiple cells in the amnion, allantois, and blood islands. An influence of substrate rigidity and composition on cell behavior and keratin content was observed in mesoderm explants. Embryos lacking all keratin filaments displayed a deflated extra-embryonic cavity, a narrow thick amnion, and a short allantois. Single-cell RNA sequencing of sorted mesoderm cells and micro-dissected amnion, chorion, and allantois, provided an atlas of transcriptomes with germ layer and regional information. It defined the cytoskeleton and adhesion expression profile of mesoderm-derived keratin 8-enriched cells lining the exocoelomic cavity. Those findings indicate a novel role for keratin filaments in the expansion of extra-embryonic structures and suggest mechanisms of mesoderm adaptation to the environment.
Topics: Animals; Embryo, Mammalian; Extraembryonic Membranes; Gastrulation; Keratins; Mesoderm; Mice
PubMed: 35266581
DOI: 10.15252/embj.2021108747 -
Nature Communications Aug 2020Visceral organs, such as the lungs, stomach and liver, are derived from the fetal foregut through a series of inductive interactions between the definitive endoderm (DE)...
Visceral organs, such as the lungs, stomach and liver, are derived from the fetal foregut through a series of inductive interactions between the definitive endoderm (DE) and the surrounding splanchnic mesoderm (SM). While DE patterning is fairly well studied, the paracrine signaling controlling SM regionalization and how this is coordinated with epithelial identity is obscure. Here, we use single cell transcriptomics to generate a high-resolution cell state map of the embryonic mouse foregut. This identifies a diversity of SM cell types that develop in close register with the organ-specific epithelium. We infer a spatiotemporal signaling network of endoderm-mesoderm interactions that orchestrate foregut organogenesis. We validate key predictions with mouse genetics, showing the importance of endoderm-derived signals in mesoderm patterning. Finally, leveraging these signaling interactions, we generate different SM subtypes from human pluripotent stem cells (hPSCs), which previously have been elusive. The single cell data can be explored at: https://research.cchmc.org/ZornLab-singlecell .
Topics: Animals; Cell Lineage; Digestive System; Endoderm; Gene Expression Profiling; Gene Expression Regulation, Developmental; Gene Regulatory Networks; Humans; Internet; Mesoderm; Mice, Inbred C57BL; Organogenesis; Signal Transduction; Single-Cell Analysis; Transcription Factors
PubMed: 32855417
DOI: 10.1038/s41467-020-17968-x -
Science Advances Jan 2024Spatiotemporal patterns widely occur in biological, chemical, and physical systems. Particularly, embryonic development displays a diverse gamut of repetitive patterns... (Review)
Review
Spatiotemporal patterns widely occur in biological, chemical, and physical systems. Particularly, embryonic development displays a diverse gamut of repetitive patterns established in many tissues and organs. Branching treelike structures in lungs, kidneys, livers, pancreases, and mammary glands as well as digits and bones in appendages, teeth, and palates are just a few examples. A fascinating instance of repetitive patterning is the sequential segmentation of the primary body axis, which is conserved in all vertebrates and many arthropods and annelids. In these species, the body axis elongates at the posterior end of the embryo containing an unsegmented tissue. Meanwhile, segments sequentially bud off from the anterior end of the unsegmented tissue, laying down an exquisite repetitive pattern and creating a segmented body plan. In vertebrates, the paraxial mesoderm is sequentially divided into somites. In this review, we will discuss the most prominent models, the most puzzling experimental data, and outstanding questions in vertebrate somite segmentation.
Topics: Animals; Body Patterning; Somites; Mesoderm; Vertebrates; Embryonic Development; Gene Expression Regulation, Developmental
PubMed: 38277458
DOI: 10.1126/sciadv.adk8937 -
Development (Cambridge, England) Nov 2023Tissue interactions are essential for guiding organ development and regeneration. Hair follicle formation relies on inductive signalling between two tissues, the...
Tissue interactions are essential for guiding organ development and regeneration. Hair follicle formation relies on inductive signalling between two tissues, the embryonic surface epithelium and the adjacent mesenchyme. Although previous research has highlighted the hair-inducing potential of the mesenchymal component of the hair follicle - the dermal papilla and its precursor, the dermal condensate - the source and nature of the primary inductive signal before dermal condensate formation have remained elusive. Here, we performed epithelial-mesenchymal tissue recombination experiments using hair-forming back skin and glabrous plantar skin from mouse embryos to unveil that the back skin mesenchyme is inductive even before dermal condensate formation. Moreover, the naïve, unpatterned mesenchyme was sufficient to trigger hair follicle formation even in the oral epithelium. Building on previous knowledge, we explored the hair-inductive ability of the Wnt agonist R-spondin 1 and a Bmp receptor inhibitor in embryonic skin explants. Although R-spondin 1 instigated precocious placode-specific transcriptional responses, it was insufficient for hair follicle induction, either alone or in combination with Bmp receptor inhibition. Our findings pave the way for identifying the hair follicle-inducing cue.
Topics: Mice; Animals; Hair Follicle; Hair; Skin; Mesoderm; Bone Morphogenetic Protein Receptors
PubMed: 37982496
DOI: 10.1242/dev.202140 -
Nature Communications Jul 2020Human embryogenesis is hallmarked by two phases of yolk sac development. The primate hypoblast gives rise to a transient primary yolk sac, which is rapidly superseded by... (Review)
Review
Human embryogenesis is hallmarked by two phases of yolk sac development. The primate hypoblast gives rise to a transient primary yolk sac, which is rapidly superseded by a secondary yolk sac during gastrulation. Moreover, primate embryos form extraembryonic mesoderm prior to gastrulation, in contrast to mouse. The function of the primary yolk sac and the origin of extraembryonic mesoderm remain unclear. Here, we hypothesise that the hypoblast-derived primary yolk sac serves as a source for early extraembryonic mesoderm, which is supplemented with mesoderm from the gastrulating embryo. We discuss the intricate relationship between the yolk sac and the primate embryo and highlight the pivotal role of the yolk sac as a multifunctional hub for haematopoiesis, germ cell development and nutritional supply.
Topics: Animals; Cell Differentiation; Embryonic Development; Embryonic Germ Cells; Hematopoiesis; Mesoderm; Primates; Yolk Sac
PubMed: 32724077
DOI: 10.1038/s41467-020-17575-w -
Developmental Cell Jun 2023Mesenchymal-epithelial transitions are fundamental drivers of development and disease, but how these behaviors generate epithelial structure is not well understood....
Mesenchymal-epithelial transitions are fundamental drivers of development and disease, but how these behaviors generate epithelial structure is not well understood. Here, we show that mesenchymal-epithelial transitions promote epithelial organization in the mouse node and notochordal plate through the assembly and radial intercalation of three-dimensional rosettes. Axial mesoderm rosettes acquire junctional and apical polarity, develop a central lumen, and dynamically expand, coalesce, and radially intercalate into the surface epithelium, converting mesenchymal-epithelial transitions into higher-order tissue structure. In mouse Par3 mutants, axial mesoderm rosettes establish central tight junction polarity but fail to form an expanded apical domain and lumen. These defects are associated with altered rosette dynamics, delayed radial intercalation, and formation of a small, fragmented surface epithelial structure. These results demonstrate that three-dimensional rosette behaviors translate mesenchymal-epithelial transitions into collective radial intercalation and epithelial formation, providing a strategy for building epithelial sheets from individual self-organizing units in the mammalian embryo.
Topics: Animals; Mice; Mesoderm; Epithelium; Cell Differentiation; Embryo, Mammalian; Morphogenesis; Mammals
PubMed: 37080203
DOI: 10.1016/j.devcel.2023.03.018