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1.
Cell Stem Cell ; 30(8): 1028-1042.e7, 2023 08 03.
Article in English | MEDLINE | ID: mdl-37541209

ABSTRACT

Impaired differentiation of alveolar stem cells has been identified in a variety of acute and chronic lung diseases. In this study, we investigate the mechanisms that modulate alveolar regeneration and understand how aging impacts this process. We have discovered that the process of alveolar type II (AT2) cells differentiating into AT1 cells is an energetically costly process. During alveolar regeneration, activated AMPK-PFKFB2 signaling upregulates glycolysis, which is essential to support the intracellular energy expenditure that is required for cytoskeletal remodeling during AT2 cell differentiation. AT2 cells in aged lungs exhibit reduced AMPK-PFKFB2 signaling and ATP production, resulting in impaired alveolar regeneration. Activating AMPK-PFKFB2 signaling in aged AT2 cells can rescue defective alveolar regeneration in aged mice. Thus, beyond demonstrating that cellular energy metabolism orchestrates with stem cell differentiation during alveolar regeneration, our study suggests that modulating AMPK-PFKFB2 signaling promotes alveolar repair in aged lungs.


Subject(s)
AMP-Activated Protein Kinases , Alveolar Epithelial Cells , Mice , Animals , AMP-Activated Protein Kinases/metabolism , Alveolar Epithelial Cells/metabolism , Lung , Stem Cells , Cell Differentiation , Glycolysis
2.
Sci China Life Sci ; 62(8): 1028-1037, 2019 Aug.
Article in English | MEDLINE | ID: mdl-31321669

ABSTRACT

The aging of alveolar stem cells has been linked to many chronic lung diseases, including pulmonary fibrosis. However, the effects of aging on alveolar stem cells during homeostasis and post-injury alveolar repair have not been well characterized. Here we conducted a single-cell RNA sequencing (scRNA-seq) analysis of alveolar stem cells of 3-month-old and 12-month-old mice to characterize the aging effect on alveolar stem cells. Our results have shown that the transcriptomes of alveolar stem cells of 3-month-old and 12-month-old mice are not significantly different under the steady condition. However, after a bleomycin-induced lung injury, the alveolar stem cells of 12-month-old mice show enhanced inflammatory responses and decreased lipid metabolism. Our study suggests a close relationship among aging, lipid metabolism, inflammatory responses and chronic lung diseases.


Subject(s)
Pulmonary Fibrosis/metabolism , Stem Cells/metabolism , Age Factors , Animals , Lipid Metabolism , Male , Mice, Transgenic , Models, Animal , Pneumonia/metabolism , Pulmonary Alveoli/cytology , RNA, Small Cytoplasmic/metabolism , Sequence Analysis, RNA , Single-Cell Analysis , Transcriptome
3.
Sci Rep ; 8(1): 14344, 2018 09 25.
Article in English | MEDLINE | ID: mdl-30254199

ABSTRACT

Genetic studies have shown that FGF10/FGFR2 signaling is required for airway branching morphogenesis and FGF10 functions as a chemoattractant factor for distal epithelial cells during lung development. However, the detail downstream cellular and molecular mechanisms have not been fully characterized. Using live imaging of ex vivo cultured lungs, we found that tip airway epithelial progenitor cells migrate faster than cleft cells during airway bud formation and this migration process is controlled by FGFR2-mediated ERK1/2 signaling. Additionally, we found that airway progenitor cells that migrate faster tend to become distal airway progenitor cells. We identified that Anxa4 is a downstream target of ERK1/2 signaling. Anxa4-/- airway epithelial cells exhibit a "lag-behind" behavior and tend to stay at the stalk airways. Moreover, we found that Anxa4-overexpressing cells tend to migrate to the bud tips. Finally, we demonstrated that Anxa4 functions redundantly with Anxa1 and Anxa6 in regulating endoderm budding process. Our study demonstrates that ERK1/2/Anxa4 signaling plays a role in promoting the migration of airway epithelial progenitor cells to distal airway tips and ensuring their distal cell fate.


Subject(s)
Annexin A4/metabolism , Cell Movement , Epithelial Cells/cytology , Lung/cytology , Stem Cells/cytology , Animals , Annexin A4/deficiency , Annexin A4/genetics , Gene Expression Regulation , Gene Knockdown Techniques , MAP Kinase Signaling System , Mice , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism
4.
Dev Cell ; 44(3): 297-312.e5, 2018 02 05.
Article in English | MEDLINE | ID: mdl-29408236

ABSTRACT

The differentiation of alveolar epithelial type I (AT1) and type II (AT2) cells is essential for the lung gas exchange function. Disruption of this process results in neonatal death or in severe lung diseases that last into adulthood. We developed live imaging techniques to characterize the mechanisms that control alveolar epithelial cell differentiation. We discovered that mechanical forces generated from the inhalation of amniotic fluid by fetal breathing movements are essential for AT1 cell differentiation. We found that a large subset of alveolar progenitor cells is able to protrude from the airway epithelium toward the mesenchyme in an FGF10/FGFR2 signaling-dependent manner. The cell protrusion process results in enrichment of myosin in the apical region of protruded cells; this myosin prevents these cells from being flattened by mechanical forces, thereby ensuring their AT2 cell fate. Our study demonstrates that mechanical forces and local growth factors synergistically control alveolar epithelial cell differentiation.


Subject(s)
Alveolar Epithelial Cells/cytology , Cell Differentiation , Cell Movement/physiology , Embryo, Mammalian/cytology , Fibroblast Growth Factor 10/physiology , Mechanical Phenomena , Receptor, Fibroblast Growth Factor, Type 2/physiology , Alveolar Epithelial Cells/metabolism , Animals , Cells, Cultured , Embryo, Mammalian/metabolism , Female , Mesoderm/cytology , Mesoderm/metabolism , Mice , Mice, Knockout , Signal Transduction
5.
Dev Cell ; 44(3): 313-325.e5, 2018 02 05.
Article in English | MEDLINE | ID: mdl-29337000

ABSTRACT

Oriented cell division plays a key role in controlling organogenesis. The mechanisms for regulating division orientation at the whole-organ level are only starting to become understood. By combining 3D time-lapse imaging, mouse genetics, and mathematical modeling, we find that global orientation of cell division is the result of a combination of two types of spindles with distinct spindle dynamic behaviors in the developing airway epithelium. Fixed spindles follow the classic long-axis rule and establish their division orientation before metaphase. In contrast, rotating spindles do not strictly follow the long-axis rule and determine their division orientation during metaphase. By using both a cell-based mechanical model and stretching-lung-explant experiments, we showed that mechanical force can function as a regulatory signal in maintaining the stable ratio between fixed spindles and rotating spindles. Our findings demonstrate that mechanical forces, cell geometry, and oriented cell division function together in a highly coordinated manner to ensure normal airway tube morphogenesis.


Subject(s)
Cell Division , Epithelial Cells/cytology , Mechanical Phenomena , Morphogenesis/physiology , Respiratory System/cytology , Animals , Cells, Cultured , Epithelial Cells/metabolism , Female , Mice , Respiratory System/embryology , Respiratory System/metabolism
6.
Cell Rep ; 16(7): 1810-9, 2016 08 16.
Article in English | MEDLINE | ID: mdl-27498861

ABSTRACT

The pulmonary alveolar epithelium undergoes extensive regeneration in response to lung injuries, including lung resection. In recent years, our understanding of cell lineage relationships in the pulmonary alveolar epithelium has improved significantly. However, the molecular and cellular mechanisms that regulate pneumonectomy (PNX)-induced alveolar regeneration remain largely unknown. In this study, we demonstrate that mechanical-tension-induced YAP activation in alveolar stem cells plays a major role in promoting post-PNX alveolar regeneration. Our results indicate that JNK and p38 MAPK signaling is critical for mediating actin-cytoskeleton-remodeling-induced nuclear YAP expression in alveolar stem cells. Moreover, we show that Cdc42-controlled actin remodeling is required for the activation of JNK, p38, and YAP in post-PNX lungs. Our findings together establish that the Cdc42/F-actin/MAPK/YAP signaling cascade is essential for promoting alveolar regeneration in response to mechanical tension in the lung.


Subject(s)
Actins/genetics , Adaptor Proteins, Signal Transducing/genetics , Phosphoproteins/genetics , Pneumonectomy , Pulmonary Alveoli/metabolism , Regeneration/genetics , cdc42 GTP-Binding Protein/genetics , p38 Mitogen-Activated Protein Kinases/genetics , Actin Cytoskeleton/genetics , Actin Cytoskeleton/metabolism , Actins/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Animals , Anthracenes/pharmacology , Biomechanical Phenomena , Cell Cycle Proteins , Cell Proliferation , Epithelial Cells/cytology , Epithelial Cells/metabolism , Gene Expression Regulation , Imidazoles/pharmacology , MAP Kinase Kinase 4/antagonists & inhibitors , MAP Kinase Kinase 4/genetics , MAP Kinase Kinase 4/metabolism , Male , Mechanotransduction, Cellular , Mice , Phosphoproteins/metabolism , Primary Cell Culture , Pulmonary Alveoli/cytology , Pulmonary Alveoli/surgery , Pyridines/pharmacology , Respiratory Mucosa/cytology , Respiratory Mucosa/metabolism , Respiratory Mucosa/surgery , Stem Cells/cytology , Stem Cells/metabolism , YAP-Signaling Proteins , cdc42 GTP-Binding Protein/metabolism , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/metabolism
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