No methods for isolating induced alveolar epithelial progenitor cells (AEPCs) from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) have been reported. Based on a study ...of the stepwise induction of alveolar epithelial cells (AECs), we identified carboxypeptidase M (CPM) as a surface marker of NKX2-1+ “ventralized” anterior foregut endoderm cells (VAFECs) in vitro and in fetal human and murine lungs. Using SFTPC-GFP reporter hPSCs and a 3D coculture system with fetal human lung fibroblasts, we showed that CPM+ cells isolated from VAFECs differentiate into AECs, demonstrating that CPM is a marker of AEPCs. Moreover, 3D coculture differentiation of CPM+ cells formed spheroids with lamellar-body-like structures and an increased expression of surfactant proteins compared with 2D differentiation. Methods to induce and isolate AEPCs using CPM and consequently generate alveolar epithelial spheroids would aid human pulmonary disease modeling and regenerative medicine.
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•Carboxypeptidase M (CPM) is a marker of alveolar epithelial progenitor cells•CPM is useful for isolating “ventralized” anterior foregut endoderm cells (VAFECs)•3D coculture of CPM+ VAFECs enables alveolar differentiation•SFTPC-GFP knockin reporter hPSCs help to detect and isolate SFTPC+ cells
No methods for isolating induced alveolar epithelial progenitor cells (AEPCs) from human pluripotent stem cells (hPSCs) have been reported. Gotoh, Ito, and colleagues developed SFTPC-GFP knockin reporter hPSCs and demonstrated that carboxypeptidase M is useful for isolating AEPCs and generating alveolar epithelial cells in a 3D coculture system.
Multi-ciliated airway cells (MCACs) play a role in mucociliary clearance of the lung. However, the efficient induction of functional MCACs from human pluripotent stem cells has not yet been reported. ...Using carboxypeptidase M (CPM) as a surface marker of NKX2-1+-ventralized anterior foregut endoderm cells (VAFECs), we report a three-dimensional differentiation protocol for generating proximal airway epithelial progenitor cell spheroids from CPM+ VAFECs. These spheroids could be induced to generate MCACs and other airway lineage cells without alveolar epithelial cells. Furthermore, the directed induction of MCACs and of pulmonary neuroendocrine lineage cells was promoted by adding DAPT, a Notch pathway inhibitor. The induced MCACs demonstrated motile cilia with a “9 + 2” microtubule arrangement and dynein arms capable of beating and generating flow for mucociliary transport. This method is expected to be useful for future studies on human airway disease modeling and regenerative medicine.
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•CPM is a useful marker for generating human proximal airway epithelium•Three-dimensional culture is useful for inducing human airway epithelium in vitro•DAPT promotes the induction of multi-ciliated and pulmonary neuroendocrine cells•Induced multi-ciliated airway cells have functionally motile cilia
Multi-ciliated airway cells (MCACs) play a crucial role in mucociliary clearance. Gotoh, Konishi, and colleagues demonstrated that three-dimensional (3D) differentiation of CPM+ ventralized anterior foregut endoderm cells is useful for generating proximal airway epithelium, involving functional MCACs as well as pulmonary neuroendocrine cells (PNECs). The induction of MCACs and PNECs was promoted by adding DAPT, a Notch pathway inhibitor.
It has been challenging to generate in vitro models of alveolar lung diseases, as the stable culture of alveolar type 2 (AT2) cells has been difficult. Methods of generating and expanding AT2 cells ...derived from induced pluripotent stem cells (iPSCs) have been established and are expected to be applicable to disease modeling. Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by dysfunction of lysosome-related organelles, such as lamellar bodies (LBs), in AT2 cells. From an HPS type 2 (HPS2) patient, we established disease-specific iPSCs (HPS2-iPSCs) and their gene-corrected counterparts. By live cell imaging, the LB dynamics were visualized and altered distribution, enlargement, and impaired secretion of LBs were demonstrated in HPS2-iPSC-derived AT2 cells. These findings provide insight into the AT2 dysfunction in HPS patients and support the potential use of human iPSC-derived AT2 cells for future research on alveolar lung diseases.
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•HPS2-iPSCs and cHPS2-iPSCs were generated from HPS2 patient fibroblasts•Anti-NaPi2b antibody was useful for isolating AT2 cells from human lung and AOs•The enlargement and abnormal distribution of LBs were observed in HPS2-AOs•Impaired surfactant secretion was demonstrated in HPS2-AOs
Pulmonary surfactant secretion by alveolar type 2 (AT2) cells is crucial for alveolar homeostasis. Gotoh and colleagues generated Hermansky-Pudlak syndrome type 2 (HPS2) patient-derived iPSCs and their gene-corrected counterparts and differentiated them into alveolar organoids (AOs). In HPS2-AOs, aberrant lamellar bodies and impaired surfactant secretion were demonstrated. Human iPSC-derived AOs might be useful for investigating alveolar lung diseases.
Epidermal growth factor receptor (EGFR) mutations are found mostly in adenocarcinoma, and rarely in squamous cell carcinoma (SQC). Little is known about SQC harboring EGFR mutations.
Between April ...2006 and October 2010, we investigated the incidence of EGFR activating mutations in SQC of the lung using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method. The efficacy of EGFR-tyrosine kinase inhibitors (TKIs) was retrospectively evaluated in patients with EGFR-mutated SQC. Further pathologic analyses were performed using immunohistochemistry.
Thirty-three of 249 patients with SQC (13.3%) had EGFR mutations, including exon 19 deletion (19 of 33 patients, 58%), L858R point mutation in exon 21 (12 of 33, 36%), and G719S point mutation in exon 18 (2 of 33, 6%). Twenty of these 33 patients received EGFR-TKI therapy, and five of these 20 responded to EGFR-TKIs with a response rate of 25.0% (95% confidence interval CI, 8.7%–49.1%). The patients’ median progression-free survival and median overall survival were 1.4 months (95% CI, 0.7–5.8 months) and 14.6 months (95% CI, 2.9–undeterminable months), respectively. Approximately one third of the EGFR-mutated SQC patients achieved progression-free survival for longer than 6 months. Some of these patients had high carcinoembryonic antigen levels or a history of never smoking, or were positive for thyroid transcription factor-1.
Although EGFR-TKIs seem to be generally less effective in EGFR-mutated SQC than in EGFR-mutated adenocarcinoma, some EGFR-mutated SQC patients can obtain clinical benefit from EGFR-TKIs. To better identify these patients, not only EGFR mutation status, but also clinical factors and pathologic findings should be taken into consideration.
Key message
When a patient with Behçet disease presents with haemoptysis, pulmonary vascular involvement should be considered.
Here, we describe a case of complete occlusion of right pulmonary artery ...seen in a patient with Behçet disease.
Gefitinib and erlotinib are first-generation small molecular inhibitors of EGFR tyrosine kinase activity. To the best of our knowledge, to date, two reports have stated that patients with NSCLC who ...develop severe hepatotoxicity secondary to gefitinib treatment can be safely switched to erlotinib. However, the reverse situation has not been reported. Here, we present the first case with non-small cell lung cancer harboring EGFR mutation who developed grade 3/4 hepatotoxicity after initiation of erlotinib, which resolved when therapy was changed to gefitinib. As far as we know, this is the first report showing the efficacy of gefitinib for a non-small cell lung cancer patient who developed severe hepatotoxicity while under erlotinib therapy.
We herein report the clinical and laboratory characteristics of two anti-OJ (anti-isoleucyl-tRNA synthetase) autoantibody-positive interstitial lung disease patients with polymyositis/dermatomyositis ...(PM/DM). We compared these characteristics with previously published findings. Previous reports and our present cases show that anti-OJ autoantibody-positive interstitial lung disease (ILD) patients with PM/DM lack the manifestations of Raynaud's phenomenon and sclerodactyly and show good prognoses and responses to glucocorticoid therapy. These results indicate that the presence of anti-OJ autoantibodies may be useful for predicting the prognosis of ILD and its clinical course in PM/DM patients.
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