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1.
Stem Cells ; 34(3): 720-31, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26865184

ABSTRACT

It has been suggested that multipotent stem cells with neural crest (NC) origin persist into adulthood in oral mucosa. However their exact localization and role in normal homeostasis is unknown. In this study, we discovered that Lgr5 is expressed in NC cells during embryonic development, which give rise to the dormant stem cells in the adult tongue and oral mucosa. Those Lgr5 positive oral stromal stem cells display properties of NC stem cells including clonal growth and multipotent differentiation. RNA sequencing revealed that adult Lgr5+ oral stromal stem cells express high number of neural crest related markers like Sox9, Twist1, Snai1, Myc, Ets1, Crabp1, Epha2, and Itgb1. Using lineage-tracing experiments, we show that these cells persist more than a year in the ventral tongue and some areas of the oral mucosa and give rise to stromal progeny. In vivo transplantation demonstrated that these cells reconstitute the stroma. Our studies show for the first time that Lgr5 is expressed in the NC cells at embryonic day 9.5 (E9.5) and is maintained during embryonic development and postnataly in the stroma of the ventral tongue, and some areas of the oral mucosa and that Lgr5+ cells participate in the maintenance of the stroma.


Subject(s)
Cell Differentiation/genetics , Embryonic Development/genetics , Multipotent Stem Cells/metabolism , Receptors, G-Protein-Coupled/biosynthesis , Animals , Cell Lineage/genetics , High-Throughput Nucleotide Sequencing , Mice , Mouth/cytology , Mouth/growth & development , Multipotent Stem Cells/cytology , Neural Crest/cytology , Neural Crest/growth & development , Neural Stem Cells/cytology , Neural Stem Cells/metabolism , Receptors, G-Protein-Coupled/genetics
2.
Cell Commun Adhes ; 21(3): 141-7, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24787376

ABSTRACT

The skin forms a life-sustaining barrier between the organism and physical environment. The physical barrier of skin is mainly localized in the stratum corneum (SC); however, nucleated epidermis also contributes to the barrier through tight, gap, and adherens junctions (AJs), as well as through desmosomes and cytoskeletal elements. Many inflammatory diseases, such as atopic dermatitis (AD) and psoriasis, are associated with barrier dysfunction. It is becoming increasingly clear that the skin barrier function is not only affected by inflammatory signals but that defects in structural components of the barrier may be the initiating event for inflammatory diseases. This view is supported by findings that mutations in filaggrin, a key structural epidermal barrier protein, cause the inflammatory skin disease AD, and that a loss of AJ components, namely epidermal p120 catenin or α-catenin results in skin inflammation.


Subject(s)
Inflammation/metabolism , Intercellular Junctions/metabolism , Skin Diseases/metabolism , Catenins/metabolism , Filaggrin Proteins , Humans , Inflammation/pathology , Intermediate Filament Proteins/genetics , Intermediate Filament Proteins/metabolism , Skin Diseases/pathology
3.
Stem Cells ; 32(8): 2267-77, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24715701

ABSTRACT

Adult stem cells (SCs) are important to maintain homeostasis of tissues including several mini-organs like hair follicles and sweat glands. However, the existence of stem cells in minor salivary glands (SGs) is largely unexplored. In vivo histone2B green fluorescent protein pulse chase strategy has allowed us to identify slow-cycling, label-retaining cells (LRCs) of minor SGs that preferentially localize in the basal layer of the lower excretory duct with a few in the acini. Engraftment of isolated SG LRC in vivo demonstrated their potential to differentiate into keratin 5 (basal layer marker) and keratin 8 (luminal layer marker)-positive structures. Transcriptional analysis revealed activation of TGFß1 target genes in SG LRC and BMP signaling in SG progenitors. We also provide evidence that minor SGSCs are sensitive to tobacco-derived tumor-inducing agent and give rise to tumors resembling low grade adenoma. Our data highlight for the first time the existence of minor SG LRCs with stem cells characteristic and emphasize the role of transforming growth factor beta (TGFß) pathway in their maintenance.


Subject(s)
Adult Stem Cells/cytology , Cell Separation/methods , Salivary Glands, Minor/cytology , Animals , Flow Cytometry , Fluorescent Antibody Technique , Immunohistochemistry , Mice , Mice, Transgenic , Oligonucleotide Array Sequence Analysis , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction
4.
Diabetologia ; 57(2): 352-61, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24162585

ABSTRACT

AIMS/HYPOTHESIS: Adult beta cells have a diminished ability to proliferate. Phosphatase and tensin homologue (PTEN) is a lipid phosphatase that antagonises the function of the mitogenic phosphatidylinositol 3-kinase (PI3K) pathway. The objective of this study was to understand the role of PTEN and PI3K signalling in the maintenance of beta cells postnatally. METHODS: We developed a Pten (lox/lox); Rosa26 (lacZ); RIP-CreER (+) model that permitted us to induce Pten deletion by treatment with tamoxifen in mature animals. We evaluated islet mass and function as well as beta cell proliferation in 3- and 12-month-old mice treated with tamoxifen (Pten deleted) vs mice treated with vehicle (Pten control). RESULTS: Deletion of Pten in juvenile (3-month-old) beta cells significantly induced their proliferation and increased islet mass. The expansion of islet mass occurred concomitantly with the enhanced ability of the Pten-deleted mice to maintain euglycaemia in response to streptozotocin treatment. In older mice (>12 months of age), deletion of Pten similarly increased islet mass and beta cell proliferation. This novel finding suggests that PTEN-regulated mechanisms may override the age-onset diminished ability of beta cells to respond to mitogenic stimulation. We also found that proteins regulating G1/S cell-cycle transition, such as cyclin D1, cyclin D2, p27 and p16, were altered when PTEN was lost, suggesting that they may play a role in PTEN/PI3K-regulated beta cell proliferation in adult tissue. CONCLUSIONS/INTERPRETATION: The signals regulated by the PTEN/PI3K pathway are important for postnatal maintenance of beta cells and regulation of their proliferation in adult tissues.


Subject(s)
Aging/pathology , Diabetes Mellitus, Experimental/pathology , Insulin-Secreting Cells/metabolism , PTEN Phosphohydrolase/metabolism , Animals , Cell Cycle , Cell Death , Cell Proliferation , DNA Methylation , Diabetes Mellitus, Experimental/metabolism , Down-Regulation/genetics , Gene Deletion , Homeostasis , Male , Mice , Mice, Mutant Strains , PTEN Phosphohydrolase/deficiency , Signal Transduction , Up-Regulation
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