Enolase 1 (ENO1) and protein disulfide-isomerase associated 3 (PDIA3) regulate Wnt/β-catenin-driven trans-differentiation of murine alveolar epithelial cells
The alveolar epithelium represents a major site of tissue destruction during lung injury. It consists of alveolar epithelial type I (ATI) and type II (ATII) cells. ATII cells are capable of self-renewal and exert progenitor function for ATI cells upon alveolar epithelial injury. Cell differentiation...
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2015-08-01
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| Series: | Disease Models & Mechanisms |
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| Online Access: | http://dmm.biologists.org/content/8/8/877 |
| _version_ | 1818215448444928000 |
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| author | Kathrin Mutze Sarah Vierkotten Jadranka Milosevic Oliver Eickelberg Melanie Königshoff |
| author_facet | Kathrin Mutze Sarah Vierkotten Jadranka Milosevic Oliver Eickelberg Melanie Königshoff |
| author_sort | Kathrin Mutze |
| collection | DOAJ |
| description | The alveolar epithelium represents a major site of tissue destruction during lung injury. It consists of alveolar epithelial type I (ATI) and type II (ATII) cells. ATII cells are capable of self-renewal and exert progenitor function for ATI cells upon alveolar epithelial injury. Cell differentiation pathways enabling this plasticity and allowing for proper repair, however, are poorly understood. Here, we applied proteomics, expression analysis and functional studies in primary murine ATII cells to identify proteins and molecular mechanisms involved in alveolar epithelial plasticity. Mass spectrometry of cultured ATII cells revealed a reduction of carbonyl reductase 2 (CBR2) and an increase in enolase 1 (ENO1) and protein disulfide-isomerase associated 3 (PDIA3) protein expression during ATII-to-ATI cell trans-differentiation. This was accompanied by increased Wnt/β-catenin signaling, as analyzed by qRT-PCR and immunoblotting. Notably, ENO1 and PDIA3, along with T1α (podoplanin; an ATI cell marker), exhibited decreased protein expression upon pharmacological and molecular Wnt/β-catenin inhibition in cultured ATII cells, whereas CBR2 levels were stabilized. Moreover, we analyzed primary ATII cells from mice with bleomycin-induced lung injury, a model exhibiting activated Wnt/β-catenin signaling in vivo. We observed reduced CBR2 significantly correlating with surfactant protein C (SFTPC), whereas ENO1 and PDIA3 along with T1α were increased in injured ATII cells. Finally, siRNA-mediated knockdown of ENO1, as well as PDIA3, in primary ATII cells led to reduced T1α expression, indicating diminished cell trans-differentiation. Our data thus identified proteins involved in ATII-to-ATI cell trans-differentiation and suggest a Wnt/β-catenin-driven functional role of ENO1 and PDIA3 in alveolar epithelial cell plasticity in lung injury and repair. |
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| institution | Directory Open Access Journal |
| issn | 1754-8411 1754-8403 |
| language | English |
| last_indexed | 2024-12-12T06:36:14Z |
| publishDate | 2015-08-01 |
| publisher | The Company of Biologists |
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| series | Disease Models & Mechanisms |
| spelling | doaj.art-3b61ca0e185b40cbb3bf83954da290722022-12-22T00:34:28ZengThe Company of BiologistsDisease Models & Mechanisms1754-84111754-84032015-08-018887789010.1242/dmm.019117019117Enolase 1 (ENO1) and protein disulfide-isomerase associated 3 (PDIA3) regulate Wnt/β-catenin-driven trans-differentiation of murine alveolar epithelial cellsKathrin Mutze0Sarah Vierkotten1Jadranka Milosevic2Oliver Eickelberg3Melanie Königshoff4 Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München, University Hospital, Ludwig-Maximilians University, 81377 Munich, Member of the German Center for Lung Research (DZL), Germany Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München, University Hospital, Ludwig-Maximilians University, 81377 Munich, Member of the German Center for Lung Research (DZL), Germany University of Pittsburgh Medical Center, Pittsburgh, PA 15213-258, USA Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München, University Hospital, Ludwig-Maximilians University, 81377 Munich, Member of the German Center for Lung Research (DZL), Germany Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München, University Hospital, Ludwig-Maximilians University, 81377 Munich, Member of the German Center for Lung Research (DZL), Germany The alveolar epithelium represents a major site of tissue destruction during lung injury. It consists of alveolar epithelial type I (ATI) and type II (ATII) cells. ATII cells are capable of self-renewal and exert progenitor function for ATI cells upon alveolar epithelial injury. Cell differentiation pathways enabling this plasticity and allowing for proper repair, however, are poorly understood. Here, we applied proteomics, expression analysis and functional studies in primary murine ATII cells to identify proteins and molecular mechanisms involved in alveolar epithelial plasticity. Mass spectrometry of cultured ATII cells revealed a reduction of carbonyl reductase 2 (CBR2) and an increase in enolase 1 (ENO1) and protein disulfide-isomerase associated 3 (PDIA3) protein expression during ATII-to-ATI cell trans-differentiation. This was accompanied by increased Wnt/β-catenin signaling, as analyzed by qRT-PCR and immunoblotting. Notably, ENO1 and PDIA3, along with T1α (podoplanin; an ATI cell marker), exhibited decreased protein expression upon pharmacological and molecular Wnt/β-catenin inhibition in cultured ATII cells, whereas CBR2 levels were stabilized. Moreover, we analyzed primary ATII cells from mice with bleomycin-induced lung injury, a model exhibiting activated Wnt/β-catenin signaling in vivo. We observed reduced CBR2 significantly correlating with surfactant protein C (SFTPC), whereas ENO1 and PDIA3 along with T1α were increased in injured ATII cells. Finally, siRNA-mediated knockdown of ENO1, as well as PDIA3, in primary ATII cells led to reduced T1α expression, indicating diminished cell trans-differentiation. Our data thus identified proteins involved in ATII-to-ATI cell trans-differentiation and suggest a Wnt/β-catenin-driven functional role of ENO1 and PDIA3 in alveolar epithelial cell plasticity in lung injury and repair.http://dmm.biologists.org/content/8/8/877Alveolar epithelial cellsDifferentiationLung injury and repairBeta-cateninWnt pathwayFibrosis |
| spellingShingle | Kathrin Mutze Sarah Vierkotten Jadranka Milosevic Oliver Eickelberg Melanie Königshoff Enolase 1 (ENO1) and protein disulfide-isomerase associated 3 (PDIA3) regulate Wnt/β-catenin-driven trans-differentiation of murine alveolar epithelial cells Disease Models & Mechanisms Alveolar epithelial cells Differentiation Lung injury and repair Beta-catenin Wnt pathway Fibrosis |
| title | Enolase 1 (ENO1) and protein disulfide-isomerase associated 3 (PDIA3) regulate Wnt/β-catenin-driven trans-differentiation of murine alveolar epithelial cells |
| title_full | Enolase 1 (ENO1) and protein disulfide-isomerase associated 3 (PDIA3) regulate Wnt/β-catenin-driven trans-differentiation of murine alveolar epithelial cells |
| title_fullStr | Enolase 1 (ENO1) and protein disulfide-isomerase associated 3 (PDIA3) regulate Wnt/β-catenin-driven trans-differentiation of murine alveolar epithelial cells |
| title_full_unstemmed | Enolase 1 (ENO1) and protein disulfide-isomerase associated 3 (PDIA3) regulate Wnt/β-catenin-driven trans-differentiation of murine alveolar epithelial cells |
| title_short | Enolase 1 (ENO1) and protein disulfide-isomerase associated 3 (PDIA3) regulate Wnt/β-catenin-driven trans-differentiation of murine alveolar epithelial cells |
| title_sort | enolase 1 eno1 and protein disulfide isomerase associated 3 pdia3 regulate wnt β catenin driven trans differentiation of murine alveolar epithelial cells |
| topic | Alveolar epithelial cells Differentiation Lung injury and repair Beta-catenin Wnt pathway Fibrosis |
| url | http://dmm.biologists.org/content/8/8/877 |
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