Cell plasticity in lung injury and repair: report from an NHLBI workshop, April 19-20, 2010.

In April 2010, a NIH workshop was convened to discuss the current state of understanding of lung cell plasticity, including the responses of epithelial cells to injury, with the objectives of summarizing what is known, what the field needs to know, and how to get there. The proximal stimulus for this workshop is the body of recent evidence suggesting that plasticity is a prominent but incompletely characterized property of lung epithelial cells, and that a focus on understanding this aspect of epithelial cell biology in particular, may be an important window into disease pathobiology and pathogenesis. In addition to their many vital functions in maintaining tissue homeostasis, epithelial cells have emerged as both a central target of disease initiation and an active contributor to disease progression, making a workshop to investigate the role of cell plasticity in lung injury and repair timely. The workshop was organized around four major themes: lung epithelial cell plasticity, signaling control of plasticity, fibroblast plasticity and crosstalk, and translation to human disease. Although this breakdown was recognized to be somewhat artificial, it was felt that this approach would promote cross-fertilization among groups that ordinarily do not communicate and lend itself to the generation of new approaches. The summary reports of individual group discussions below are followed by consensus priorities and recommendations of the workshop participants.

[1]  A. Desmoulière,et al.  The Myofibroblast: one function, multiple origins , 2010 .

[2]  V. Thannickal,et al.  Challenges in translating preclinical studies to effective drug therapies in idiopathic pulmonary fibrosis. , 2010, American journal of respiratory and critical care medicine.

[3]  Frank Speleman,et al.  miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis , 2010, Nature Cell Biology.

[4]  Curtis C. Harris,et al.  Microenvironmental modulation of asymmetric cell division in human lung cancer cells , 2010, Proceedings of the National Academy of Sciences.

[5]  J. McQualter,et al.  Evidence of an epithelial stem/progenitor cell hierarchy in the adult mouse lung , 2010, Proceedings of the National Academy of Sciences.

[6]  J. Hogg,et al.  The Disruption of the Epithelial Mesenchymal Trophic Unit in COPD , 2009, COPD.

[7]  Eric T. Domyan,et al.  β-Catenin promotes respiratory progenitor identity in mouse foregut , 2009, Proceedings of the National Academy of Sciences.

[8]  L. Mariani,et al.  Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment , 2009, Proceedings of the National Academy of Sciences.

[9]  M. Lu,et al.  Wnt2/2b and beta-catenin signaling are necessary and sufficient to specify lung progenitors in the foregut. , 2009, Developmental cell.

[10]  Scott H. Randell,et al.  Basal cells as stem cells of the mouse trachea and human airway epithelium , 2009, Proceedings of the National Academy of Sciences.

[11]  R. Weinberg,et al.  Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits , 2009, Nature Reviews Cancer.

[12]  P. Wolters,et al.  Epithelial cell alpha3beta1 integrin links beta-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis. , 2008, The Journal of clinical investigation.

[13]  Wenjun Guo,et al.  The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells , 2008, Cell.

[14]  K. Kimura,et al.  Hypoxia-inducible factor signaling in the development of tissue fibrosis , 2008, Cell cycle.

[15]  M. Biffoni,et al.  Identification and expansion of the tumorigenic lung cancer stem cell population , 2008, Cell Death and Differentiation.

[16]  Ross Tubo,et al.  Mesenchymal stem cells within tumour stroma promote breast cancer metastasis , 2007, Nature.

[17]  P. Brown,et al.  Transcriptional Program Induced by Wnt Protein in Human Fibroblasts Suggests Mechanisms for Cell Cooperativity in Defining Tissue Microenvironments , 2007, PloS one.

[18]  B. Willis,et al.  TGF-β-induced EMT: mechanisms and implications for fibrotic lung disease , 2007 .

[19]  Stephen Lam,et al.  Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. , 2007, Cancer research.

[20]  F. Martinez,et al.  Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts. , 2007, The Journal of clinical investigation.

[21]  D. Sheppard,et al.  Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix , 2006, Proceedings of the National Academy of Sciences.

[22]  J. Lü,et al.  Regulation of early lung morphogenesis: questions, facts and controversies , 2006, Development.

[23]  F. Chu,et al.  Alteration of fibroblast architecture and loss of Basal lamina apertures in human emphysematous lung. , 2006, American journal of respiratory and critical care medicine.

[24]  Kwon-Sik Park,et al.  Transdifferentiation of ciliated cells during repair of the respiratory epithelium. , 2006, American journal of respiratory cell and molecular biology.

[25]  A. Nicholson,et al.  Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis. , 2005, The American journal of pathology.

[26]  J. Horowitz,et al.  Hydrogen peroxide is a diffusible paracrine signal for the induction of epithelial cell death by activated myofibroblasts , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[27]  T. Moore,et al.  CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury. , 2005, The American journal of pathology.

[28]  M. Burdick,et al.  Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. , 2004, The Journal of clinical investigation.

[29]  P. Paré,et al.  The nature of small-airway obstruction in chronic obstructive pulmonary disease. , 2004, The New England journal of medicine.

[30]  M. Ponec,et al.  Diffusible factors released by fibroblasts support epidermal morphogenesis and deposition of basement membrane components , 2004, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[31]  Douglas Curran-Everett,et al.  Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis. , 2004, Chest.

[32]  D. Warburton,et al.  Isolation of a putative progenitor subpopulation of alveolar epithelial type 2 cells. , 2004, American journal of physiology. Lung cellular and molecular physiology.

[33]  Irving L Weissman,et al.  Plasticity of Adult Stem Cells , 2004, Cell.

[34]  H. Chapman.  Disorders of lung matrix remodeling. , 2004, The Journal of clinical investigation.

[35]  S. Phan,et al.  Bone marrow-derived progenitor cells in pulmonary fibrosis. , 2004, The Journal of clinical investigation.

[36]  F. Chu,et al.  Human alveolar wall fibroblasts directly link epithelial type 2 cells to capillary endothelium. , 2003, American journal of respiratory and critical care medicine.

[37]  W. Birchmeier,et al.  β-Catenin Is Required for Specification of Proximal/Distal Cell Fate during Lung Morphogenesis* , 2003, Journal of Biological Chemistry.

[38]  M. O’Reilly,et al.  Identification and isolation of mouse type II cells on the basis of intrinsic expression of enhanced green fluorescent protein. , 2003, American journal of physiology. Lung cellular and molecular physiology.

[39]  R. Day,et al.  Myofibroblast Differentiation by Transforming Growth Factor-β1 Is Dependent on Cell Adhesion and Integrin Signaling via Focal Adhesion Kinase* , 2003, Journal of Biological Chemistry.

[40]  C. Smith,et al.  Unique structural features that influence neutrophil emigration into the lung. , 2003, Physiological reviews.

[41]  David Botstein,et al.  Diversity, topographic differentiation, and positional memory in human fibroblasts , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[42]  J. Westcott,et al.  Rat alveolar type II cells inhibit lung fibroblast proliferation in vitro. , 2001, American journal of respiratory cell and molecular biology.

[43]  M. Entman,et al.  Stem Cell Plasticity in Muscle and Bone Marrow , 2001, Annals of the New York Academy of Sciences.

[44]  A. Pardo,et al.  Idiopathic Pulmonary Fibrosis: Prevailing and Evolving Hypotheses about Its Pathogenesis and Implications for Therapy , 2001, Annals of Internal Medicine.

[45]  C. Plopper,et al.  The attenuated fibroblast sheath of the respiratory tract epithelial-mesenchymal trophic unit. , 1999, American journal of respiratory cell and molecular biology.

[46]  L. D. Nielsen,et al.  Mesenchyme specifies epithelial differentiation in reciprocal recombinants of embryonic lung and trachea , 1998, Developmental dynamics : an official publication of the American Association of Anatomists.

[47]  F. Chu,et al.  Fibroblasts are in a position to provide directional information to migrating neutrophils during pneumonia in rabbit lungs. , 1996, Microvascular research.

[48]  B. Stripp,et al.  Plasticity of airway cell proliferation and gene expression after acute naphthalene injury. , 1995, The American journal of physiology.

[49]  F. Chu,et al.  Neutrophil migration through preexisting holes in the basal laminae of alveolar capillaries and epithelium during streptococcal pneumonia. , 1995, Microvascular research.

[50]  Z. Borok,et al.  Reversible transdifferentiation of alveolar epithelial cells. , 1995, American journal of respiratory cell and molecular biology.

[51]  I. Adamson,et al.  Bleomycin-induced injury and metaplasia of alveolar type 2 cells. Relationship of cellular responses to drug presence in the lung. , 1979, The American journal of pathology.

[52]  N. Dekker,et al.  Quantitation of damage to the alveolar epithelium by means of type 2 cell proliferation. , 1978, The American review of respiratory disease.

[53]  M. J. Evans,et al.  Role of the Clara cell in renewal of the bronchiolar epithelium. , 1978, Laboratory investigation; a journal of technical methods and pathology.

[54]  I. Adamson,et al.  Origin of ciliated alveolar epithelial cells in bleomycin-induced lung injury. , 1977, The American journal of pathology.

[55]  R. J. Stephens,et al.  Renewal of the terminal bronchiolar epithelium in the rat following exposure to NO2 or O3. , 1976, Laboratory investigation; a journal of technical methods and pathology.

[56]  R. J. Stephens,et al.  Transformation of alveolar type 2 cells to type 1 cells following exposure to NO2. , 1975, Experimental and molecular pathology.

[57]  R. J. Stephens,et al.  Acute kinetic response and renewal of the alveolar epithelium following injury by nitrogen dioxide. , 1974, Chest.

[58]  N. K. Wessells,et al.  Mammalian lung development: interactions in primordium formation and bronchial morphogenesis. , 1970, The Journal of experimental zoology.

[59]  J. Wyatt,et al.  Reaction of the lung cells to a high concentration of oxygen. , 1968, Archives of pathology.

[60]  B. Willis,et al.  TGF-beta-induced EMT: mechanisms and implications for fibrotic lung disease. , 2007, American journal of physiology. Lung cellular and molecular physiology.

[61]  Anna-Lu.  Epithelial Necrosis and Alveolar Collapse in the Pathogenesis of Usual Interstitial Pneumonia , 2006 .

[62]  Susan J Wilson,et al.  Epithelial-mesenchymal communication in the pathogenesis of chronic asthma. , 2004, Proceedings of the American Thoracic Society.

[63]  M. J. Evans,et al.  Effects of NO2 on the lungs of rats. I. Morphology. , 1977, Experimental and molecular pathology.

[64]  D H Bowden,et al.  The type 2 cell as progenitor of alveolar epithelial regeneration. A cytodynamic study in mice after exposure to oxygen. , 1974, Laboratory investigation; a journal of technical methods and pathology.

[65]  R. J. Stephens,et al.  Renewal of alveolar epithelium in the rat following exposure to NO2. , 1973, The American journal of pathology.