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Cell Oct 2018Intestinal mesenchymal cells play essential roles in epithelial homeostasis, matrix remodeling, immunity, and inflammation. But the extent of heterogeneity within the...
Intestinal mesenchymal cells play essential roles in epithelial homeostasis, matrix remodeling, immunity, and inflammation. But the extent of heterogeneity within the colonic mesenchyme in these processes remains unknown. Using unbiased single-cell profiling of over 16,500 colonic mesenchymal cells, we reveal four subsets of fibroblasts expressing divergent transcriptional regulators and functional pathways, in addition to pericytes and myofibroblasts. We identified a niche population located in proximity to epithelial crypts expressing SOX6, F3 (CD142), and WNT genes essential for colonic epithelial stem cell function. In colitis, we observed dysregulation of this niche and emergence of an activated mesenchymal population. This subset expressed TNF superfamily member 14 (TNFSF14), fibroblastic reticular cell-associated genes, IL-33, and Lysyl oxidases. Further, it induced factors that impaired epithelial proliferation and maturation and contributed to oxidative stress and disease severity in vivo. Our work defines how the colonic mesenchyme remodels to fuel inflammation and barrier dysfunction in IBD.
Topics: Animals; Cell Proliferation; Colitis; Colon; Epithelial Cells; Fibroblasts; Genetic Heterogeneity; Homeostasis; Humans; Inflammation; Inflammatory Bowel Diseases; Intestinal Mucosa; Intestines; Mesenchymal Stem Cells; Mesoderm; Mice; Mice, Inbred C57BL; Myofibroblasts; Pericytes; RAW 264.7 Cells; SOXD Transcription Factors; Single-Cell Analysis; Thromboplastin; Tumor Necrosis Factor Ligand Superfamily Member 14; Wnt Signaling Pathway
PubMed: 30270042
DOI: 10.1016/j.cell.2018.08.067 -
Cell Research Feb 2009During development and in the context of different morphogenetic events, epithelial cells undergo a process called epithelial to mesenchymal transition or... (Review)
Review
During development and in the context of different morphogenetic events, epithelial cells undergo a process called epithelial to mesenchymal transition or transdifferentiation (EMT). In this process, the cells lose their epithelial characteristics, including their polarity and specialized cell-cell contacts, and acquire a migratory behavior, allowing them to move away from their epithelial cell community and to integrate into surrounding tissue, even at remote locations. EMT illustrates the differentiation plasticity during development and is complemented by another process, called mesenchymal to epithelial transition (MET). While being an integral process during development, EMT is also recapitulated under pathological conditions, prominently in fibrosis and in invasion and metastasis of carcinomas. Accordingly, EMT is considered as an important step in tumor progression. TGF-beta signaling has been shown to play an important role in EMT. In fact, adding TGF-beta to epithelial cells in culture is a convenient way to induce EMT in various epithelial cells. Although much less characterized, epithelial plasticity can also be regulated by TGF-beta-related bone morphogenetic proteins (BMPs), and BMPs have been shown to induce EMT or MET depending on the developmental context. In this review, we will discuss the induction of EMT in response to TGF-beta, and focus on the underlying signaling and transcription mechanisms.
Topics: Bone Morphogenetic Proteins; Cell Transdifferentiation; Epithelial Cells; Mesoderm; Signal Transduction; Smad Proteins; Transcription Factors; Transforming Growth Factor beta
PubMed: 19153598
DOI: 10.1038/cr.2009.5 -
Cell Reports Jul 2022After gut tube patterning in early embryos, the cellular and molecular changes of developing stomach and intestine remain largely unknown. Here, combining single-cell...
After gut tube patterning in early embryos, the cellular and molecular changes of developing stomach and intestine remain largely unknown. Here, combining single-cell RNA sequencing and spatial RNA sequencing, we construct a spatiotemporal transcriptomic landscape of the mouse stomach and intestine during embryonic days E9.5-E15.5. Several subpopulations are identified, including Lox stomach mesenchyme, Aldh1a3 small-intestinal mesenchyme, and Adamdec1 large-intestinal mesenchyme. The regionalization and heterogeneity of both the epithelium and the mesenchyme can be traced back to E9.5. The spatiotemporal distributions of cell clusters and the mesenchymal-epithelial interaction analysis indicate that a coordinated development of the epithelium and mesenchyme contribute to the stomach regionalization, intestine segmentation, and villus formation. Using the gut tube-derived organoids, we find that the cell fate of the foregut and hindgut can be switched by the regional niche factors, including fibroblast growth factors (FGFs) and retinoic acid (RA). This work lays a foundation for further dissection of the mechanisms governing this process.
Topics: Animals; Cell Differentiation; Endoderm; Epithelium; Intestine, Small; Mesoderm; Mice
PubMed: 35830795
DOI: 10.1016/j.celrep.2022.111053 -
Cell Sep 2017The lung is an architecturally complex organ comprising a heterogeneous mixture of various epithelial and mesenchymal lineages. We use single-cell RNA sequencing and...
The lung is an architecturally complex organ comprising a heterogeneous mixture of various epithelial and mesenchymal lineages. We use single-cell RNA sequencing and signaling lineage reporters to generate a spatial and transcriptional map of the lung mesenchyme. We find that each mesenchymal lineage has a distinct spatial address and transcriptional profile leading to unique niche regulatory functions. The mesenchymal alveolar niche cell is Wnt responsive, expresses Pdgfrα, and is critical for alveolar epithelial cell growth and self-renewal. In contrast, the Axin2+ myofibrogenic progenitor cell preferentially generates pathologically deleterious myofibroblasts after injury. Analysis of the secretome and receptome of the alveolar niche reveals functional pathways that mediate growth and self-renewal of alveolar type 2 progenitor cells, including IL-6/Stat3, Bmp, and Fgf signaling. These studies define the cellular and molecular framework of lung mesenchymal niches and reveal the functional importance of developmental pathways in promoting self-renewal versus a pathological response to tissue injury.
Topics: Algorithms; Animals; Epithelial Cells; Fibrosis; Gene Expression Profiling; Lung; Lung Injury; Mesoderm; Mice; Organoids; Paracrine Communication; Regeneration; Signal Transduction; Single-Cell Analysis; Stem Cells
PubMed: 28886382
DOI: 10.1016/j.cell.2017.07.034 -
The Journal of Clinical Investigation Jul 2023Mesenchymal cells are uniquely located at the interface between the epithelial lining and the stroma, allowing them to act as a signaling hub among diverse cellular... (Review)
Review
Mesenchymal cells are uniquely located at the interface between the epithelial lining and the stroma, allowing them to act as a signaling hub among diverse cellular compartments of the lung. During embryonic and postnatal lung development, mesenchyme-derived signals instruct epithelial budding, branching morphogenesis, and subsequent structural and functional maturation. Later during adult life, the mesenchyme plays divergent roles wherein its balanced activation promotes epithelial repair after injury while its aberrant activation can lead to pathological remodeling and fibrosis that are associated with multiple chronic pulmonary diseases, including bronchopulmonary dysplasia, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease. In this Review, we discuss the involvement of the lung mesenchyme in various morphogenic, neomorphogenic, and dysmorphogenic aspects of lung biology and health, with special emphasis on lung fibroblast subsets and smooth muscle cells, intercellular communication, and intrinsic mesenchymal mechanisms that drive such physiological and pathophysiological events throughout development, homeostasis, injury repair, regeneration, and aging.
Topics: Infant, Newborn; Humans; Lung; Pulmonary Disease, Chronic Obstructive; Fibrosis; Regeneration; Mesoderm; Epithelial Cells
PubMed: 37463440
DOI: 10.1172/JCI170498 -
Annals of the American Thoracic Society Mar 2015The extracellular matrix (ECM) of the lung serves as both a scaffold for resident cells and a mechanical support for respiratory function. The ECM is deposited during... (Review)
Review
The extracellular matrix (ECM) of the lung serves as both a scaffold for resident cells and a mechanical support for respiratory function. The ECM is deposited during development and undergoes continuous turnover and maintenance during organ growth and homeostasis. Cells of the mesenchyme, including the tissue resident fibroblast, take a leading role in depositing and organizing the matrix and do so in an anatomically distinct fashion, with differing composition, organization, and mechanical properties within the airways, vessels, and alveoli of the lung. Recent technological advancements have allowed the lung's ECM biochemical composition and mechanical properties to be studied with improved resolution, thereby identifying novel disease-related changes in ECM characteristics. In parallel, efforts to study cells seeded on normal and disease-derived matrices have illustrated the powerful role the ECM can play in altering key functions of lung resident cells. The mechanical properties of the matrix have been identified as an important modifier of cell-matrix adhesions, with matrices of pathologic stiffness promoting profibrotic signaling and cell function. Ongoing work is identifying both mechanically activated pathways in mesenchymal cells and disease-related ECM molecules that biochemically regulate cell function. Uncovering the control systems by which cells respond to and regulate the matrix, and the failures in these systems that underlie aberrant repair, remains a major challenge. Progress in this area will be an essential element in efforts to engineer functional lung tissue for regenerative approaches and will be key to identifying new therapeutic strategies for lung diseases characterized by disturbed matrix architecture.
Topics: Extracellular Matrix; Fibroblasts; Humans; Mechanotransduction, Cellular; Mesoderm; Pulmonary Fibrosis
PubMed: 25830830
DOI: 10.1513/AnnalsATS.201407-320MG -
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 -
Differentiation; Research in Biological... 2016This paper reviews the importance of mesenchymal-epithelial interactions in development and gives detailed technical protocols for investigating these interactions.... (Review)
Review
This paper reviews the importance of mesenchymal-epithelial interactions in development and gives detailed technical protocols for investigating these interactions. Successful analysis of mesenchymal-epithelial interactions requires knowing the ages in which embryonic, neonatal and adult organs can be separated into mesenchymal and epithelial tissues. Methods for separation of mesenchymal and epithelial tissues and preparation of tissue recombinants are described.
Topics: Animals; Cell Differentiation; Cellular Reprogramming; Epithelium; Humans; Mesoderm; Mice; Organogenesis
PubMed: 26610327
DOI: 10.1016/j.diff.2015.10.006 -
Current Opinion in Genetics &... Jun 2015Each of the steps of respiratory system development relies on intricate interactions and coordinated development of the lung epithelium and mesenchyme. In the past, more... (Review)
Review
Each of the steps of respiratory system development relies on intricate interactions and coordinated development of the lung epithelium and mesenchyme. In the past, more attention has been paid to the epithelium than the mesenchyme. The mesenchyme is a source of specification and morphogenetic signals as well as a host of surprisingly complex cell lineages that are crucial for normal lung development and function. This review highlights recent research focusing on the mesenchyme that has revealed genetic and epigenetic mechanisms of its development in the context of other cell layers during respiratory lineage specification, branching morphogenesis, epithelial differentiation, lineage distinction, vascular development, and alveolar maturation.
Topics: Animals; Cell Differentiation; Cell Lineage; Epigenesis, Genetic; Humans; Lung; Mesoderm; Mice; Models, Biological; Morphogenesis; Respiratory Mucosa
PubMed: 25796078
DOI: 10.1016/j.gde.2015.01.011 -
Seminars in Cell & Developmental Biology Apr 2020Convergent extension is a fundamental morphogenetic process that underlies not only the generation of the elongated vertebrate body plan from the initially radially... (Review)
Review
Convergent extension is a fundamental morphogenetic process that underlies not only the generation of the elongated vertebrate body plan from the initially radially symmetrical embryo, but also the specific shape changes characteristic of many individual tissues. These tissue shape changes are the result of specific cell behaviors, coordinated in time and space, and affected by the physical properties of the tissue. While mediolateral cell intercalation is the classic cellular mechanism for producing tissue convergence and extension, other cell behaviors can also provide similar tissue-scale distortions or can modulate the effects of mediolateral cell intercalation to sculpt a specific shape. Regulation of regional tissue morphogenesis through planar polarization of the variety of underlying cell behaviors is well-recognized, but as yet is not well understood at the molecular level. Here, we review recent advances in understanding the cellular basis for convergence and extension and its regulation.
Topics: Animals; Embryo, Mammalian; Mesoderm; Morphogenesis
PubMed: 31734039
DOI: 10.1016/j.semcdb.2019.11.002