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1.
Exp Cell Res ; 372(2): 141-149, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30268759

RESUMO

Distal airway stem cells (DASCs) in the mouse lung can differentiate into bronchioles and alveoli. However, it remains unclear whether the same stem cells exist in the human lung. Here, we found that human lung epithelial (HuL) cells, derived from normal, peripheral lung tissue, in monolayer, mostly express both the N-terminally truncated isoform of p63 (∆Np63), a marker for airway basal cells, and thyroid transcription factor-1 (TTF-1), a marker for alveolar epithelial cells, even though these two molecules are usually expressed in a mutually exclusive way. Three-dimensionally cultured HuL cells differentiated to form bronchiole-like and alveolus-like organoids. We also uncovered a few bronchiolar epithelial cells expressing both ∆Np63 and TTF-1 in the human lung, suggesting that these cells are the cells of origin for HuL cells. Taken together, ΔNp63+ TTF-1+ peripheral airway epithelial cells are possibly the human counterpart of mouse DASCs and may offer potential for future regenerative medicine.


Assuntos
Pulmão/citologia , Células-Tronco/citologia , Fator Nuclear 1 de Tireoide/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Animais , Bronquíolos/citologia , Bronquíolos/crescimento & desenvolvimento , Diferenciação Celular , Linhagem Celular , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Pulmão/crescimento & desenvolvimento , Camundongos , Alvéolos Pulmonares/citologia , Alvéolos Pulmonares/crescimento & desenvolvimento , Medicina Regenerativa , Células-Tronco/metabolismo
2.
J Cell Mol Med ; 19(12): 2818-26, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26416301

RESUMO

Lung alveolar regeneration occurs in adult human lungs as a result of proliferation, differentiation and alveolar morphogenesis of stem cells. It is increasingly being believed that bronchial epithelial cells (BECs) have a potential as stem cells, because they are potent to differentiate into multiple central and peripheral lung cell types in three-dimensional (3D) cultures, and they develop multiple foci with well-differentiated histogenesis after transformed into neoplastic cells. In this study, we investigated morphogenic abilities of HBE135 human BECs immortalized by E6/E7 oncogene in 3D cultures. When HBE135 cells were cultured alone or co-cultured with endothelial cells, the cells formed spherical colonies without branching. However, in co-culture with lung fibroblast MRC-9 cells, HBE135 cells formed colonies with bronchioalveolar-like complex branching, suggesting that MRC-9-derived soluble factor(s) are responsible for the branching formation. MRC-9 cells, not endothelial cells, were found to highly express hepatocyte growth factor (HGF), a soluble molecule involved in liver and kidney regeneration. An anti-HGF neutralizing antibody severely suppressed the complex branching formation, but addition of HGF could not sufficiently compensate the morphogenic effects of MRC-9 cells, suggesting that MCR-9-derived HGF was necessary but insufficient for the bronchioalveolar structure formation. Immunohistochemistry revealed that Met, a cognate receptor for HGF, was highly expressed and phosphorylated in neoplastic BECs from lung adenocarcinomas with well-differentiated, not poorly differentiated, histogenesis. These results are consistent with the notion that BECs have an aspect of stem cells. This aspect appears to become manifest through HGF-Met signalling pathway activation.


Assuntos
Bronquíolos/crescimento & desenvolvimento , Células Epiteliais/efeitos dos fármacos , Fator de Crescimento de Hepatócito/farmacologia , Morfogênese/efeitos dos fármacos , Alvéolos Pulmonares/crescimento & desenvolvimento , Western Blotting , Brônquios/citologia , Bronquíolos/citologia , Bronquíolos/metabolismo , Técnicas de Cultura de Células/métodos , Linhagem Celular , Linhagem Celular Transformada , Técnicas de Cocultura , Citocinas/genética , Citocinas/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/fisiologia , Células Epiteliais/fisiologia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/fisiologia , Regulação Neoplásica da Expressão Gênica , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Microscopia Confocal , Morfogênese/fisiologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Alvéolos Pulmonares/citologia , Alvéolos Pulmonares/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Esferoides Celulares/citologia , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo
3.
Ultrastruct Pathol ; 39(4): 245-54, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25867690

RESUMO

The ultrastructure of the developing bronchiolar cell was studied in six age groups: prenatal (60 d post-conception); postnatal (1-, 7-, 14- and 21-day-old); and adult. Following intratracheal fixation, the lung tissue was processed for scanning and transmission electron microscopy. The lining of terminal bronchioles consists of cuboidal to columnar nonciliated bronchiolar cells (NBCs) and ciliated with or without microvilli. NBCs were recognized by indented centrally located nucleus. The apical surface extended beyond the surface of neighboring cells and was covered by minute microvilli, except in prenatal kittens. The NBCs of the adult were characterized by abundant mitochondria and glycogen inclusions. In prenatal kittens, the cytoplasm was filled with patches of alpha and beta form of glycogen. Postnatally, glycogen was reduced in quantity, became scattered throughout the cytoplasm and was predominantly of the beta form. Islands of cytoplasm, separated from the apical cytoplasm were observed in the lumen of adult bronchioles. This suggests an apocrine mode of secretion. The NBCs attain maturity by three weeks of age.


Assuntos
Bronquíolos/crescimento & desenvolvimento , Bronquíolos/ultraestrutura , Gatos/crescimento & desenvolvimento , Células Epiteliais/ultraestrutura , Mucosa Respiratória/crescimento & desenvolvimento , Mucosa Respiratória/ultraestrutura , Animais , Gatos/anatomia & histologia , Feminino , Masculino , Microscopia Eletrônica
4.
Am J Respir Cell Mol Biol ; 49(5): 808-13, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23763491

RESUMO

Viral illness with wheezing during infancy is associated with the inception of childhood asthma. Small airway dysfunction is a component of childhood asthma, but little is known about how viral illness at an early age may affect the structure and function of small airways. We used a well-characterized rat model of postbronchiolitis chronic airway dysfunction to address how postinfectious small airway lesions affect airway physiological function and if the structure/function correlates persist into maturity. Brown Norway rats were sham- or virus inoculated at 3 to 4 weeks of age and allowed to recover from the acute illness. At 3 to 14 months of age, physiology (respiratory system resistance, Newtonian resistance, tissue damping, and static lung volumes) was assessed in anesthetized, intubated rats. Serial lung sections revealed lesions in the terminal bronchioles that reduced luminal area and interrupted further branching, affecting 26% (range, 13-39%) of the small airways at 3 months of age and 22% (range, 6-40%) at 12 to 14 months of age. At 3 months of age (n = 29 virus; n = 7 sham), small airway lesions correlated with tissue damping (rs = 0.69) but not with Newtonian resistance (rs = 0.23), and Newtonian resistance was not elevated compared with control rats, indicating that distal airways were primarily responsible for the airflow obstruction. Older rats (n = 7 virus; n = 6 sham) had persistent small airway dysfunction and significantly increased Newtonian resistance in the postbronchiolitis group. We conclude that viral airway injury at an early age may induce small airway lesions that are associated quantitatively with small airway physiological dysfunction early on and that these defects persist into maturity.


Assuntos
Obstrução das Vias Respiratórias/etiologia , Asma/etiologia , Bronquíolos/patologia , Bronquiolite Viral/complicações , Fatores Etários , Envelhecimento , Obstrução das Vias Respiratórias/patologia , Obstrução das Vias Respiratórias/fisiopatologia , Resistência das Vias Respiratórias , Animais , Asma/patologia , Asma/fisiopatologia , Bronquíolos/crescimento & desenvolvimento , Bronquíolos/fisiopatologia , Bronquiolite Viral/patologia , Bronquiolite Viral/fisiopatologia , Modelos Animais de Doenças , Medidas de Volume Pulmonar , Masculino , Ratos , Ratos Endogâmicos BN , Recuperação de Função Fisiológica , Fatores de Risco , Fatores de Tempo
5.
Toxicol Pathol ; 37(2): 256-63, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19332666

RESUMO

UNLABELLED: The direct effect of environmental tobacco smoke (ETS) exposure in utero on the development of the lung parenchyma is not known. We used design-based stereologic methods to evaluate in utero and postnatal ETS exposure on alveolar and respiratory bronchiole (RB) development in the rhesus macaque. METHODS: Timed-pregnant rhesus macaques and their offspring were exposed to filtered air or various amounts of ETS during the prenatal and postnatal period. The left cranial lobe from necropsied infants was evaluated by design-based stereological methods and general pathological review. RESULTS: Infants in the in utero and six-month ETS groups had an 18% and 17% relative decrease, respectively, in alveolar number and a 57% and 33% increase, respectively, in alveolar size compared to filtered air (FA) monkeys. Lung volume positively correlated with alveolar number in the FA and six-month ETS group and negatively correlated in the in utero ETS group. The distribution of alveolar size was much more variable in the in utero group. Overall, RB volume was significantly increased in the six-month ETS group (p < .04). CONCLUSIONS: Taken together, these results indicate that in utero and postnatal ETS exposure is associated with altered parenchymal lung development.


Assuntos
Bronquíolos/crescimento & desenvolvimento , Exposição Ambiental/efeitos adversos , Exposição Materna/efeitos adversos , Prenhez , Alvéolos Pulmonares/crescimento & desenvolvimento , Poluição por Fumaça de Tabaco/efeitos adversos , Animais , Animais Recém-Nascidos , Embrião de Mamíferos , Feminino , Macaca mulatta , Gravidez , Fatores de Tempo
6.
Artigo em Inglês | MEDLINE | ID: mdl-19028985

RESUMO

The adult lung consists of a trachea leading into a system of branched airways ending in millions of alveolar sacs. It contains many different epithelial cell types arranged in precise patterns along the proximodistal axis. Each region of the lung has the capacity to repair through the proliferation of different epithelial cell types. However, the precise identity of the cells mediating repair is not fully resolved. To address this problem, we are using genetic lineage-labeling techniques in the mouse. The tools we have made will also be useful for understanding how progenitor cell behavior is regulated under normal and pathological conditions.


Assuntos
Células-Tronco Adultas/citologia , Pulmão/citologia , Pulmão/crescimento & desenvolvimento , Células-Tronco Adultas/fisiologia , Animais , Bronquíolos/citologia , Bronquíolos/crescimento & desenvolvimento , Bronquíolos/fisiologia , Diferenciação Celular , Proliferação de Células , Células Epiteliais/citologia , Células Epiteliais/fisiologia , Pulmão/fisiologia , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Alvéolos Pulmonares/citologia , Alvéolos Pulmonares/crescimento & desenvolvimento , Alvéolos Pulmonares/fisiologia , Traqueia/citologia , Traqueia/crescimento & desenvolvimento , Traqueia/fisiologia
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