Salivary glands regenerate after radiation injury through SOX2-mediated secretory cell replacement

Salivary gland acinar cells are routinely destroyed during radiation treatment for head and neck cancer that results in a lifetime of hyposalivation and co-morbidities. A potential regenerative strategy for replacing injured tissue is the reactivation of endogenous stem cells by targeted therapeutics. However, the identity of these cells, whether they are capable of regenerating the tissue, and the mechanisms by which they are regulated are unknown. Using in vivo and ex vivo models, in combination with genetic lineage tracing and human tissue, we discover a SOX2+ stem cell population essential to acinar cell maintenance that is capable of replenishing acini after radiation. Furthermore, we show that acinar cell replacement is nerve dependent and that addition of a muscarinic mimetic is sufficient to drive regeneration. Moreover, we show that SOX2 is diminished in irradiated human salivary gland, along with parasympathetic nerves, suggesting that tissue degeneration is due to loss of progenitors and their regulators. Thus, we establish a new paradigm that salivary glands can regenerate after genotoxic shock and do so through a SOX2 nerve-dependent mechanism

Multi-leptons with High Transverse Momentum at HERA

Events with at least two high transverse momentum leptons (electrons or muons) are studied using the H1 and ZEUS detectors at HERA with an integrated luminosity of 0.94 fb-1. The observed numbers of events are in general agreement with the Standard Model predictions. Seven di- and tri-lepton events are observed in e+p collision data with a scalar sum of the lepton transverse momenta above 100GeV while 1.94 ± 0.17 events are expected. Such events are not observed in e-p collisions for which 1.19 ± 0.12 are predicted. Total visible and differential di-electron and di-muon photoproduction cross sections are extracted in a restricted phase space dominated by photon-photon collisions. © SISSA 2009

Events with an Isolated Lepton and Missing Transverse Momentum and Measurement of W Production at HERA

A search for events containing an isolated electron or muon and missing transverse momentum produced in e±p collisions is performed with the H1 and ZEUS detectors at HERA. The data were taken in the period 1994-2007 and correspond to an integrated luminosity of 0.98 fb-1. The observed event yields are in good overall agreement with the Standard Model prediction, which is dominated by single W production. In the e+p data, at large hadronic transverse momentum PTX \u3c 25GeV, a total of 23 events are observed compared to a prediction of 14.0 ±1.9. The total single W boson production cross section is measured as 1.06 ± 0.16 (stat.) ± 0.07 (sys.) pb, in agreement with an Standard Model (SM) expectation of 1.26 ± 0.19 pb

NRG-ERBB3 signaling drives secretory acinus formation

Acini are essential for the secretory function of multiple exocrine organs. During acini formation, a cluster of epithelial end bud progenitors must undergo secretory program initiation, maturation and cell polarization to form a unit of single layered secretory cells enclosing a central lumen. Yet, how this complex process is regulated remains unknown. Using the developing salivary gland as a model, we reveal the EGF receptor ERBB3 as a master driver of acinus formation. We discovered ERBB3 to be enriched in end buds, and through conditional deletion of epithelial Erbb3, to be essential in multiple steps of secretory cell program initiation, cell maturation, expansion and polarization. Moreover, we demonstrate that addition of a single factor, ERBB3 ligand neuregulin-1, to isolated epithelia ex vivo is sufficient to recapitulate the complex outcomes of in vivo acinus formation in multiple exocrine organs. Finally, we reveal a new ERBB3-mTOR1/2 signaling link that governs the full formation of the secretory acinus

NRG-ERBB3 signaling drives secretory acinus formation

Acini are essential for the secretory function of multiple exocrine organs. During acini formation, a cluster of epithelial end bud progenitors must undergo secretory program initiation, maturation and cell polarization to form a unit of single layered secretory cells enclosing a central lumen. Yet, how this complex process is regulated remains unknown. Using the developing salivary gland as a model, we reveal the EGF receptor ERBB3 as a master driver of acinus formation. We discovered ERBB3 to be enriched in end buds, and through conditional deletion of epithelial Erbb3, to be essential in multiple steps of secretory cell program initiation, cell maturation, expansion and polarization. Moreover, we demonstrate that addition of a single factor, ERBB3 ligand neuregulin-1, to isolated epithelia ex vivo is sufficient to recapitulate the complex outcomes of in vivo acinus formation in multiple exocrine organs. Finally, we reveal a new ERBB3-mTOR1/2 signaling link that governs the full formation of the secretory acinus

Salivary gland development and disease.

Mammalian salivary glands synthesize and secrete saliva via a vast interconnected network of epithelial tubes attached to secretory end units. The extensive morphogenesis required to establish this organ is dependent on interactions between multiple cell types (epithelial, mesenchymal, endothelial, and neuronal) and the engagement of a wide range of signaling pathways. Here we describe critical regulators of salivary gland development and discuss how mutations in these impact human organogenesis. In particular, we explore the genetic contribution of growth factor pathways, nerve-derived factors and extracellular matrix molecules to salivary gland formation in mice and humans

Genetic and Morphological Comparisons of Lesser Celandine (Ficaria verna) Invasions Suggest Regionally Widespread Sexual Reproduction

Both asexual and sexual reproduction can provide important keys to the success of invasive species. A species with potential for both is lesser celandine (Ficaria verna), a European native with multiple subspecies that have been introduced in North America as ornamentals and escaped cultivation. Asexual reproduction via bulbils is prolific in many introduced populations of lesser celandine, with sexual reproduction reportedly rare. Although genetic and morphological diversity of European celandine has been studied, few have examined invasive North American populations. We aimed to document introduced genotypic and phenotypic diversity at a regional scale. We first compared sequence-related amplified polymorphism (SRAP) genotypes of 64 individuals collected from Columbus, Cincinnati, and Cleveland, OH. In a second experiment, we phenotyped 129 individuals from the same regions and from Louisville, KY, measuring traits in an outdoor common garden experiment. The SRAP markers were highly polymorphic and revealed surprising genetic differentiation. Genetic and trait variation were both structured across regions, but we also saw high variation within regions. Cleveland populations differed the most genetically and morphologically. Nearly every individual made asexual bulbils, and many individuals that flowered produced expanded achenes. Trait data suggested subspecies verna or ficariiformis occur in these regions. Genetic admixture within regions and within individuals, along with achene expansion, suggests sexual reproduction may be widespread. Sexual and asexual propagules may spread by different vectors, and our resistance analyses indicated water dispersal and habitat availability contribute to genetic structure. These findings suggest that celandine has substantial potential for further spread and evolutionary change