ABSTRACT
Pancreatic ductal adenocarcinoma (PDA) is partly initiated through the transdifferentiation of acinar cells to metaplastic ducts that act as precursors of neoplasia and cancer. Tuft cells are solitary chemosensory cells not found in the normal pancreas but arise in metaplasia and neoplasia, diminishing as neoplastic lesions progress to carcinoma. Metaplastic tuft cells (mTCs) function to suppress tumor progression through communication with the tumor microenvironment, but their fate during progression is unknown. To determine the fate of mTCs during PDA progression, we have created a lineage tracing model that uses a tamoxifen-inducible tuft-cell specific Pou2f3CreERT/+ driver to induce transgene expression, including the lineage tracer tdTomato or the oncogene Myc. mTC lineage trace models of pancreatic neoplasia and carcinoma were used to follow mTC fate. We found that mTCs, in the carcinoma model, transdifferentiate into neural-like progenitor cells (NRPs), a cell type associated with poor survival in PDA patients. Using conditional knock-out and overexpression systems, we found that Myc activity in mTCs is necessary and sufficient to induce this Tuft-to-Neuroendocrine-Transition (TNT).
ABSTRACT
The olfactory neuroepithelium serves as a sensory organ for odors and forms part of the nasal mucosal barrier. Olfactory sensory neurons are surrounded and supported by epithelial cells. Among them, microvillous cells (MVCs) are strategically positioned at the apical surface, but their specific functions are enigmatic, and their relationship to the other specialized epithelial cells is unclear. Here, we establish that the family of MVCs comprises tuft cells and ionocytes in both mice and humans. Integrating analysis of the respiratory and olfactory epithelia, we define the distinct receptor expression of TRPM5+ tuft-MVCs compared with GÉ-gustducinhigh respiratory tuft cells and characterize a previously undescribed population of glandular DCLK1+ tuft cells. To establish how allergen sensing by tuft-MVCs might direct olfactory mucosal responses, we used an integrated single-cell transcriptional and protein analysis. Inhalation of Alternaria induced mucosal epithelial effector molecules including Chil4 and a distinct pathway leading to proliferation of the quiescent olfactory horizontal basal stem cell (HBC) pool, both triggered in the absence of olfactory apoptosis. Alternaria- and ATP-elicited HBC proliferation was dependent on TRPM5+ tuft-MVCs, identifying these specialized epithelial cells as regulators of olfactory stem cell responses. Together, our data provide high-resolution characterization of nasal tuft cell heterogeneity and identify a function of TRPM5+ tuft-MVCs in directing the olfactory mucosal response to allergens.
Subject(s)
Olfactory Mucosa , Tuft Cells , Humans , Mice , Animals , Olfactory Mucosa/metabolism , Nasal Mucosa , Epithelial Cells/metabolism , Cell Proliferation , Doublecortin-Like KinasesABSTRACT
Noventa e oito pacientes portadores de conjuntivite viral aguda que procuraram a Clínica de Oftalmologia da Escola Paulista de Medicina no período de fevereiro de 1983 a fevereiro de 1984 foram avaliados clínica e laboratorialmente. De acordo com o exame oftalmológico, os pacientes foram classificados como portadores de ceratoconjuntivite epidêmica, febre faringoconjuntival, conjuntivite folicular aguda inespecífica e conjuntivite hemorrágica aguda. Amostras pareadas de soro obtidas na fase aguda e na convalescença do processo infeccioso foram avaliados quanto à presença de anticorpos contra adenovírus e enterovírus 70 pelas técnicas de fixaçäo de complemento e neutralizaçäo, respectivamente. Observou-se diagnóstico sorológico positivo para adenovírus e enterovírus 70 em 5% e 51% dos casos, respectivamente, enquanto que em 44% dos casos näo houve conversäo sorológica para ambos os tipos de vírus. Casos esporádicos foram diagnosticados até 9 meses antes da epidemia. Os pacientes apresentaram quadro clínico semelhante ao de outras epidemias, com hemorragia subconjuntival, ceratite e linfadenopatia