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Philosophical Transactions of the Royal... Dec 2016Self-assembly of two important components of the cytoskeleton of eukaryotic cells, actin microfilaments and microtubules (MTs) results in polar filaments of one... (Review)
Review
Self-assembly of two important components of the cytoskeleton of eukaryotic cells, actin microfilaments and microtubules (MTs) results in polar filaments of one chirality. As is true for bacterial flagella, in actin microfilaments, screw direction is important for assembly processes and motility. For MTs, polar orientation within the cell is paramount. The alignment of these elements in the cell cytoplasm gives rise to emergent properties, including the potential for cell differentiation and specialization. Complex MTs with a characteristic chirality are found in basal bodies and centrioles; this chirality is preserved in cilia. In motile cilia, it is reflected in the direction of the effective stroke. The positioning of the basal body or cilia on the cell surface depends on polarity proteins. In evolution, survival depends on global polarity information relayed to the cell in part by orientation of the MT and actin filament cytoskeletons and the chirality of the basal body to determine left and right coordinates within a defined anterior-posterior cell and tissue axis.This article is part of the themed issue 'Provocative questions in left-right asymmetry'.
Topics: Actin Cytoskeleton; Biological Evolution; Cytoskeleton; Eukaryotic Cells; Microtubules
PubMed: 27821520
DOI: 10.1098/rstb.2015.0408 -
Current Opinion in Cell Biology Dec 2020The mammalian skin is equipped with a highly dynamic stratified epithelium. The maintenance and regeneration of this epithelium is supported by basally located... (Review)
Review
The mammalian skin is equipped with a highly dynamic stratified epithelium. The maintenance and regeneration of this epithelium is supported by basally located keratinocytes, which display stem cell properties, including lifelong proliferative potential and the ability to undergo diverse differentiation trajectories. Keratinocytes support not just the surface of the skin, called the epidermis, but also a range of ectodermal structures including hair follicles, sebaceous glands, and sweat glands. Recent studies have shed light on the hitherto underappreciated heterogeneity of keratinocytes by employing state-of-the-art imaging technologies and single-cell genomic approaches. In this mini review, we highlight major recent discoveries that illuminate the dynamics and cellular mechanisms that govern keratinocyte differentiation in the live mammalian skin and discuss the broader implications of these findings for our understanding of epithelial and stem cell biology in general.
Topics: Animals; Cell Differentiation; Epidermal Cells; Hair Follicle; Humans; Keratinocytes; Models, Biological; Stem Cells
PubMed: 33091828
DOI: 10.1016/j.ceb.2020.09.004 -
Neuroscience Bulletin Apr 2021Mouse cortical radial glial cells (RGCs) are primary neural stem cells that give rise to cortical oligodendrocytes, astrocytes, and olfactory bulb (OB) GABAergic...
Mouse cortical radial glial cells (RGCs) are primary neural stem cells that give rise to cortical oligodendrocytes, astrocytes, and olfactory bulb (OB) GABAergic interneurons in late embryogenesis. There are fundamental gaps in understanding how these diverse cell subtypes are generated. Here, by combining single-cell RNA-Seq with intersectional lineage analyses, we show that beginning at around E16.5, neocortical RGCs start to generate ASCL1EGFR apical multipotent intermediate progenitors (MIPCs), which then differentiate into basal MIPCs that express ASCL1, EGFR, OLIG2, and MKI67. These basal MIPCs undergo several rounds of divisions to generate most of the cortical oligodendrocytes and astrocytes and a subpopulation of OB interneurons. Finally, single-cell ATAC-Seq supported our model for the genetic logic underlying the specification and differentiation of cortical glial cells and OB interneurons. Taken together, this work reveals the process of cortical radial glial cell lineage progression and the developmental origins of cortical astrocytes and oligodendrocytes.
Topics: Animals; Cell Differentiation; Mice; Neural Stem Cells; Neurogenesis; Neuroglia; Oligodendroglia
PubMed: 33606177
DOI: 10.1007/s12264-021-00640-9 -
Current Opinion in Cell Biology Oct 2018Cell extrusion drives most epithelial cell death while maintaining a functional epithelial barrier. To extrude, a cell produces a lipid signal that triggers the... (Review)
Review
Cell extrusion drives most epithelial cell death while maintaining a functional epithelial barrier. To extrude, a cell produces a lipid signal that triggers the neighboring cells to reorganize actin and myosin basally to squeeze the extruding cell out apically from the barrier. More studies continue to reveal other signals and mechanisms controlling apical extrusion. New developmental studies are uncovering mechanisms controlling basal extrusion, or ingression, which occurs when apical extrusion is defective or during de-differentiation in development. Here, we review recent advances in epithelial extrusion, focusing particularly on forces exerted upon extruding cells and their various later fates ranging from cell death, normal development, and cancer.
Topics: Actins; Animals; Biomechanical Phenomena; Disease; Epithelial Cells; Humans; Myosins; Nervous System
PubMed: 29727745
DOI: 10.1016/j.ceb.2018.04.007 -
Journal of Mammary Gland Biology and... Dec 2021Mammary gland is an outstanding system to study the regulatory mechanisms governing adult epithelial stem cell activity. Stem cells in the basal layer of the mammary...
Mammary gland is an outstanding system to study the regulatory mechanisms governing adult epithelial stem cell activity. Stem cells in the basal layer of the mammary gland fuel the morphogenesis and regeneration of a complex epithelial network during development and upon transplantation. The self-renewal of basal stem/progenitor cells is subjected to regulation by both cell-intrinsic and extrinsic mechanisms. Nfatc1 is a transcription factor that regulates breast tumorigenesis and metastasis, but its role in mammary epithelial development and stem cell function has not been investigated. Here we show that Nfatc1 is expressed in a small subset of mammary basal epithelial cells and its epithelial-specific deletion results in mild defects in side branching and basal-luminal cell balance. Moreover, Nfatc1-deficient basal cells exhibit reduced colony forming ability in vitro and somewhat compromised regenerative potential upon transplantation. Thus, our study provides evidence for a detectable yet non-essential role of Nfatc1 in mammary epithelial morphogenesis and basal stem/progenitor cell self-renewal.
Topics: Animals; Cell Differentiation; Epithelial Cells; Mammary Glands, Animal; Morphogenesis; Stem Cells; Transcription Factors
PubMed: 34932179
DOI: 10.1007/s10911-021-09502-6 -
Experimental Cell Research Jun 2015Epithelial cells are important building blocks of most tissues and the corner stone of tissue architectures that allow directional transport of nutrients, ions and waste... (Review)
Review
Epithelial cells are important building blocks of most tissues and the corner stone of tissue architectures that allow directional transport of nutrients, ions and waste products in and out of the body. In tissues composed of millions of cells every individual cell needs to make right decisions when to differentiate, migrate, divide or die. Tight control of such fundamental cell-level processes ensures proper tissue morphogenesis, homeostasis and function. Cellular decisions are guided by biochemical and mechanical cues from their immediate microenvironment that consists of the extracellular matrix (ECM), neighboring cells and soluble factors. Generation of two distinct surfaces one facing the outside world (the apical domain) and the other contacting the neighboring cells and basal ECM (basolateral domain) is the most fundamental property of epithelial cells. The cues from the ECM are of particular importance in this process and communication between the cells and the ECM is largely mediated by transmembrane ECM receptors. Integrins constitute the largest family of such receptors binding to the ECM. Integrins have been shown to be essential for the establishment of initial polarity cues that define the position of the basal domain and thereby govern the orientation of the forming apico-basal axis. In this review I will discuss the multifaceted roles of integrins in epithelial cells with a particular focus on recent developments unveiling the specific functions of the different integrin heterodimers in regulating epithelial cell polarization and morphogenesis.
Topics: Animals; Cell Polarity; Epithelial Cells; Extracellular Matrix; Humans; Integrins; Signal Transduction
PubMed: 25597426
DOI: 10.1016/j.yexcr.2015.01.003 -
Nature Communications Aug 2020How stem cells give rise to epidermis is unclear despite the crucial role the epidermis plays in barrier and appendage formation. Here we use single cell-RNA sequencing...
How stem cells give rise to epidermis is unclear despite the crucial role the epidermis plays in barrier and appendage formation. Here we use single cell-RNA sequencing to interrogate basal stem cell heterogeneity of human interfollicular epidermis and find four spatially distinct stem cell populations at the top and bottom of rete ridges and transitional positions between the basal and suprabasal epidermal layers. Cell-cell communication modeling suggests that basal cell populations serve as crucial signaling hubs to maintain epidermal communication. Combining pseudotime, RNA velocity, and cellular entropy analyses point to a hierarchical differentiation lineage supporting multi-stem cell interfollicular epidermal homeostasis models and suggest that transitional basal stem cells are stable states essential for proper stratification. Finally, alterations in differentially expressed transitional basal stem cell genes result in severe thinning of human skin equivalents, validating their essential role in epidermal homeostasis and reinforcing the critical nature of basal stem cell heterogeneity.
Topics: Cell Communication; Cell Differentiation; Cell Lineage; Epidermal Cells; Epidermis; Foreskin; Gene Expression Profiling; Gene Expression Regulation; Homeostasis; Humans; Infant, Newborn; Keratinocytes; Male; Models, Biological; Signal Transduction; Stem Cells
PubMed: 32843640
DOI: 10.1038/s41467-020-18075-7 -
Annals of the New York Academy of... Oct 2022Epithelial cells are polarized with defined apical tight junctions (TJs), lateral adherens junctions (AJs), and basal integrin-matrix interactions. However, it is...
Epithelial cells are polarized with defined apical tight junctions (TJs), lateral adherens junctions (AJs), and basal integrin-matrix interactions. However, it is increasingly recognized that resident cell junction proteins can be found in varying locations and with previously unrecognized functions. Our study here presents the nanoarchitecture and nanocolocalization of cell junction proteins in culture and tissue by stochastic optical reconstruction microscopy (STORM). The Z-axial view of noncancerous MDCK-II and PZ-HPV-7 cell-cell junctions resolved β-catenin and p120 localizations to TJs and AJs, with p120 apical to β-catenin and colocalizing with TJ protein claudin-7. More basally, p120 and β-catenin become colocalized. This topography was lost in isogenic Ras-transformed MDCK cells and cancerous PC3 cells, where p120 becomes basally localized in relation to β-catenin. Claudin-7 gene conditional knockout (cKO) in mice also have altered polarity of p120 relative to β-catenin, like that seen in normal-to-cancer cell phenotypic transformation. Additionally, claudin-7 cKO resulted in redistribution and relocalization of other cell junction proteins, including claudin-1, zonula occludens-1, integrin α2, epithelial cell adhesion molecule, and focal adhesion kinase (FAK); specifically, integrin α2 and FAK were observed at the apical-lateral compartment. Our data show that STORM reveals regional cellular junction nanoarchitecture previously uncharacterized, providing new insight into potential trans-compartmental modulation of protein functions.
Topics: Adherens Junctions; Animals; Cadherins; Claudin-1; Claudins; Epithelial Cell Adhesion Molecule; Epithelial Cells; Focal Adhesion Protein-Tyrosine Kinases; Integrin alpha2; Mice; Microscopy; Tight Junctions; beta Catenin
PubMed: 35819053
DOI: 10.1111/nyas.14855 -
Cells Jun 2022In idiopathic pulmonary fibrosis (IPF), keratin (KRT)17+/KRT5+ basal and KRT17+/KRT5- aberrant basaloid cells are atypically present within the alveolar space. We...
UNLABELLED
In idiopathic pulmonary fibrosis (IPF), keratin (KRT)17+/KRT5+ basal and KRT17+/KRT5- aberrant basaloid cells are atypically present within the alveolar space. We previously described the fibrosis-enriched outgrowth of alveolar basal cells from peripheral fibrotic lung tissue. Using single cell RNA sequencing (scRNA-seq), we here characterize the transcriptome of these cultured alveolar basal cells under different culture conditions.
METHODS
Fibrotic peripheral lung tissue pieces were placed in DMEM growth medium. Outgrown cells were analysed by scRNA-seq, TaqMan-PCR or immunofluorescence (IF) either directly or after medium change to an epithelial cell specific medium (Cnt-PR-A).
RESULTS
A fraction of alveolar basal cells cultured in DMEM growth medium showed close transcriptomic similarities to IPF basal cells. However, although they expressed KRT5, the transcriptome of the majority of cells matched best to the transcriptome of recently described KRT17+/KRT5- aberrant basaloid cells, co-expressing the canonical basal cell marker KRT17 and mesenchymal cell marker (VIM, FN1). A smaller fraction of cells matched best to secretory epithelial cells. Two differentiation gradients from basal to aberrant basaloid-like cells and basal to secretory epithelial-like cells were apparent. Interestingly, these differentiation paths seemed reversed when the cell culture medium was changed to Cnt-PR-A.
CONCLUSIONS
Our results suggest that cultured alveolar basal cells have the capacity to differentiate towards secretory epithelial-like cells and to aberrant basaloid-like cells. However, due to the persistent expression of KRT5, a complete differentiation towards aberrant basaloid cells did not seem to be achieved in our culture conditions. Importantly, differentiation seemed reversible by changing the cells microenvironment. Determining specific factors influencing these differentiation paths may help to define novel drug targets for IPF therapy.
Topics: Alveolar Epithelial Cells; Epithelial Cells; Humans; Idiopathic Pulmonary Fibrosis; Lung; Transcriptome
PubMed: 35681516
DOI: 10.3390/cells11111820 -
Nature Reviews. Cancer Jul 2014Metastasis is the leading cause of cancer-related deaths, but it is unclear how cancer cells escape their primary sites in epithelia and disseminate to other sites in... (Review)
Review
Metastasis is the leading cause of cancer-related deaths, but it is unclear how cancer cells escape their primary sites in epithelia and disseminate to other sites in the body. One emerging possibility is that transformed epithelial cells could invade the underlying tissue by a process called cell extrusion, which epithelia use to remove cells without disrupting their barrier function. Typically, during normal cell turnover, live cells extrude apically from the epithelium into the lumen and later die by anoikis; however, several oncogenic mutations shift cell extrusion basally, towards the tissue that the epithelium encases. Tumour cells with high levels of survival and motility signals could use basal extrusion to escape from the tissue and migrate to other sites within the body.
Topics: Cell Movement; Epithelial Cells; Humans; Neoplasm Invasiveness; Neoplasms
PubMed: 24943812
DOI: 10.1038/nrc3767