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2.
Pediatr Res ; 89(3): 502-509, 2021 02.
Article in English | MEDLINE | ID: mdl-32365352

ABSTRACT

BACKGROUND: Bronchopulmonary dysplasia remains one of the most common complications of prematurity, despite significant improvements in perinatal care. Functional modeling of human lung development and disease, like BPD, is limited by our ability to access the lung and to maintain relevant progenitor cell populations in culture. METHODS: We supplemented Rho/SMAD signaling inhibition with mTOR inhibition to generate epithelial basal cell-like cell lines from tracheal aspirates of neonates. RESULTS: Single-cell RNA-sequencing confirmed the presence of epithelial cells in tracheal aspirates obtained from intubated neonates. Using Rho/SMAD/mTOR triple signaling inhibition, neonatal tracheal aspirate-derived (nTAD) basal cell-like cells can be expanded long term and retain the ability to differentiate into pseudostratified airway epithelium. CONCLUSIONS: Our data demonstrate that neonatal tracheal aspirate-derived epithelial cells can provide a novel ex vivo human cellular model to study neonatal lung development and disease. IMPACT: Airway epithelial basal cell-like cell lines were derived from human neonatal tracheal aspirates. mTOR inhibition significantly extends in vitro proliferation of neonatal tracheal aspirate-derived basal cell-like cells (nTAD BCCs). nTAD BCCs can be differentiated into functional airway epithelium. nTAD BCCs provide a novel model to investigate perinatal lung development and diseases.


Subject(s)
Epithelial Cells/drug effects , Smad Proteins/antagonists & inhibitors , TOR Serine-Threonine Kinases/antagonists & inhibitors , Trachea/cytology , rho-Associated Kinases/antagonists & inhibitors , Base Sequence , Body Fluids/cytology , Bronchopulmonary Dysplasia , Cell Differentiation/drug effects , Cell Division/drug effects , Cells, Cultured , Epithelial Cells/chemistry , Epithelial Cells/cytology , Humans , Infant, Newborn , Primary Cell Culture , Single-Cell Analysis , Sirolimus/pharmacology , Smad Proteins/physiology , Stem Cells/cytology , Stem Cells/drug effects , Suction , TOR Serine-Threonine Kinases/physiology , rho-Associated Kinases/physiology
3.
Int J Dev Neurosci ; 29(3): 325-34, 2011 May.
Article in English | MEDLINE | ID: mdl-20691252

ABSTRACT

Increased density and altered spatial distribution of subcortical white matter neurons (WMNs) represents one of the more well replicated cellular alterations found in schizophrenia and related disease. In many of the affected cases, the underlying genetic risk architecture for these WMN abnormalities remains unknown. Increased density of neurons immunoreactive for Microtubule-Associated Protein 2 (MAP2) and Neuronal Nuclear Antigen (NeuN) have been reported by independent studies, though there are negative reports as well; additionally, group differences in some of the studies appear to be driven by a small subset of cases. Alterations in markers for inhibitory (GABAergic) neurons have also been described. For example, downregulation of neuropeptide Y (NPY) and nitric oxide synthase (NOS1) in inhibitory WMN positioned at the gray/white matter border, as well as altered spatial distribution, have been reported. While increased density of WMN has been suggested to reflect disturbance of neurodevelopmental processes, including neuronal migration, neurogenesis, and cell death, alternative hypotheses--such as an adaptive response to microglial activation in mature CNS, as has been described in multiple sclerosis--should also be considered. We argue that larger scale studies involving hundreds of postmortem specimens will be necessary in order to clearly establish the subset of subjects affected. Additionally, these larger cohorts could make it feasible to connect the cellular pathology to environmental and genetic factors implicated in schizophrenia, bipolar disorder, and autism. These could include the 22q11 deletion (Velocardiofacial/DiGeorge) syndrome, which in some cases is associated with neuronal ectopias in white matter.


Subject(s)
Bipolar Disorder/pathology , Brain/pathology , Nerve Fibers, Myelinated/pathology , Neurons/pathology , Schizophrenia/pathology , Schizophrenia/physiopathology , Animals , Biomarkers/analysis , Bipolar Disorder/physiopathology , Brain/growth & development , Brain/physiopathology , Endophenotypes , Humans
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