Regulation of human lung alveolar multipotent cells by a novel p38α MAPK/miR-17-92 axis

Oeztuerk-Winder, Feride; Guinot, Anna; Ochałek, Anna; Ventura, Juan-José

doi:10.1038/emboj.2012.234

Cited by 26 publications

(39 citation statements)

References 29 publications

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“…These cells specifically express the membrane marker Lgr6 (16). In mouse lung cancer models, bronchioalveolar stem cells are expanded during adenocarcinoma transformation (19,20).…”

Section: Resultsmentioning

confidence: 99%

“…Lgr6 þ human lung stem cells' isolation and culture has been previously described by our group (16). Lgr6 þ p38a knockdown cells (Lgr6 þ p38KD) were obtained by infecting Lgr6 þ human lung stem cells with lentiviral vector pLKO.1-TRC (Sigma, catalog no: SHC001) carrying an short hairpin RNA (shRNA) construct to knock down p38a (5 0 -CCCGGT-GTCCATCATTCATGCGAAA-TTCAAGAGA-TTTCGCA-TGAATGATGGACTG-TTTTTT-G) and a puromycin selection marker.…”

Section: P38a Sirna Knockdownmentioning

confidence: 99%

“…These cells showed a disruption in the balance between the p38a and miR-17-92 pathways. p53 mutation prevents its repression of miR-17-92 expression (16). Cross-talk between signaling pathways and its role in cancer has been extensively reported elsewhere (17,18).…”

Section: Introductionmentioning

confidence: 99%

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miR-17-92/p38α Dysregulation Enhances Wnt Signaling and Selects Lgr6+ Cancer Stem-like Cells during Lung Adenocarcinoma Progression

2016

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Defining the molecular and cellular roots of lung cancer relapse after initial treatment remains an imperative to improve survival. Here we report that the lung stem cell marker Lgr6 becomes enriched in non-small cell lung cancer (NSCLC) cells during malignant progression. Lgr6 þ NSCLC cells displayed self-renewal and differentiation properties along with a higher tumorigenic potential. Mechanistic investigations suggested that a defective repression of the miR-17-92 gene cluster was responsible for evolution of a selection for outgrowth of Lgr6 þ NSCLC cells. High levels of expression of miR-19 family members were found to target and downregulate levels of p38a kinase, providing a specific survival signal for Lgr6 þ cells as mediated by increased Wnt/ß-catenin activity. Our results identify a specific stem-like cell population in NSCLC with increased malignant potential, the elucidation of which may enable earlier prognosis and possibly the development of more effective targeted treatments. CancerRes; 76(13); 4012-22. Ó2016 AACR.

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“…These cells specifically express the membrane marker Lgr6 (16). In mouse lung cancer models, bronchioalveolar stem cells are expanded during adenocarcinoma transformation (19,20).…”

Section: Resultsmentioning

confidence: 99%

Section: P38a Sirna Knockdownmentioning

confidence: 99%

See 1 more Smart Citation

miR-17-92/p38α Dysregulation Enhances Wnt Signaling and Selects Lgr6+ Cancer Stem-like Cells during Lung Adenocarcinoma Progression

2016

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“…31,40 Provided that LMDEC Maj were committed to alveolar progenitor lineage as a sub-subpopulation of AEC II, the activity of p38a probably affects the yield efficiency of LMDEC Maj from the mixed culture. Then, we elucidated this hypothesis by means of p38a d.n.-TG mice and a p38 inhibitor, SB203580.…”

Section: Discussionmentioning

confidence: 99%

“…31 Expression of CD34, CD90, c-kit, prominin-1, and LGR6 on LMDECs was rarely observed (Supplementary Figure 2). On the other hand, a small cell population showing SP-C þ CCSP þ Sca1 þ (1.8% of LMDECs) was observed in LMDECs, indicating that LMDECs include BASCs (Figure 3e).…”

Section: Classification Of Lmdecsmentioning

confidence: 99%

Therapeutic effect of lung mixed culture-derived epithelial cells on lung fibrosis

Tanaka

Fujita

Umezawa

et al. 2014

Laboratory Investigation

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Cell-based therapy is recognized as one of potential therapeutic options for lung fibrosis. However, preparing stem/ progenitor cells is complicated and not always efficient. Here, we show easily prepared cell populations having therapeutic capacity for lung inflammatory disease that are named as 'lung mixed culture-derived epithelial cells' (LMDECs). LMDECs expressed surfactant protein (SP)-C and gave rise to type I alveolar epithelial cells (AECs) in vitro and in vivo that partly satisfied type II AEC-like characteristics. An intratracheal delivery of not HEK 293 cells but LMDECs to the lung ameliorated bleomycin (BLM)-induced lung injury. A comprehensive analysis of bronchoalveolar fluid by western blot array revealed that LMDEC engraftment could improve the microenvironment in the BLM-instilled lung in association with stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 signaling axis. SDF-1 enhanced both migration activity and differentiating efficiency of LMDECs. Further classification of LMDECs by flow cytometric study showed that a major population of LMDECs (LMDEC Maj , 84% of total LMDECs) was simultaneously SP-C þ , CD44 þ , CD45 þ , and hematopoietic cell lineage þ and that LMDECs included bronchioalveolar stem cells (BASCs) showing SP-C þ Clara cell secretory protein þ stem cell antigen (Sca)1 þ as a small population (1.8% of total LMDECs). CD44 þ -sorted LMDEC Maj and Sca1 þ -sorted LMDECs equally ameliorated fibrosis induced by BLM like LMDECs did. However, infiltrated neutrophils were observed in Sca1 þ -sorted LMDEC-treated alveoli that was not typical in LMDEC Maj -or LMDEC-treated alveoli. These findings suggest that the protective effect of LMDECs against BLM-induced lung injury depends greatly on that of LMDEC Maj . Furthermore, the cells expressing both alveolar epithelial and hematopoietic cell lineage markers (SP-C þ CD45 þ ) that have characteristics corresponding to LMDEC Maj were observed in the alveoli of lung and increased approximately threefold in response to BLM instillation. Taken together, LMDECs newly classified in the present study are easily culture expanded and have a potential role in future regenerative cell therapy for pulmonary fibrosis.

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Properties of Adult Lung Stem and Progenitor Cells

Bertoncello

2016

Journal Cellular Physiology

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The last decade has seen significant progress in understanding the organisation of regenerative cells in the adult lung. Cell-lineage tracing and in vitro clonogenic assays have enabled the identification and characterisation of endogenous lung epithelial stem and progenitor cells. Selective lung injury models, and genetically engineered mice have revealed highly conserved gene networks, factors, signalling pathways, and cellular interactions important in maintaining lung homeostasis and regulating lung regeneration and repair following injury. This review describes the current models of lung epithelial stem and progenitor cell organisation in adult mice, and the impediments encountered in translational studies aiming to identify and characterise their human homologs. J. Cell. Physiol. 231: 2582-2589, 2016. © 2016 Wiley Periodicals, Inc.

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Regulation of human lung alveolar multipotent cells by a novel p38α MAPK/miR-17-92 axis

Cited by 26 publications

References 29 publications

miR-17-92/p38α Dysregulation Enhances Wnt Signaling and Selects Lgr6+ Cancer Stem-like Cells during Lung Adenocarcinoma Progression

miR-17-92/p38α Dysregulation Enhances Wnt Signaling and Selects Lgr6+ Cancer Stem-like Cells during Lung Adenocarcinoma Progression

Therapeutic effect of lung mixed culture-derived epithelial cells on lung fibrosis

Properties of Adult Lung Stem and Progenitor Cells

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