Review MATBIO-1455; No. of pages: 28; 4C: Extracellular matrix in lung development, homeostasis and disease Yong Zhou a, Jeffrey C. Horowitz b, Alexandra Naba c, Namasivayam Ambalavanan d, Kamran Atabai e, Jenna Balestrini f, Peter B. Bitterman g, Richard A. Corley h, Bi-Sen Ding i, Adam J. Engler j, Kirk C. Hansen k, James S. Hagood l, Farrah Kheradmand m, Qing S. Lin n, Enid Neptune o, Laura Niklason f, Luis A. Ortiz p, William C. Parks q,DanielJ.Tschumperlinr,EricS.Whiteb, Harold A. Chapman s and Victor J. Thannickal a a - Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, United States b - Division of Pulmonary and Critical Care Medicine, University of Michigan, United States c - Department of Physiology & Biophysics, University of Illinois at Chicago, United States d - Department of Pediatrics, University of Alabama at Birmingham, United States e - Lung Biology Center, University of California, San Francisco, United States f - Department of Anesthesiology, Yale University, United States g - Department of Medicine, University of Minnesota, United States h - Systems Toxicology & Exposure Science, Pacific Northwest National Laboratory, United States i - Weill Cornell Medical College, United States j - Sanford Consortium for Regenerative Medicine, University of California, San Diego, United States k - Biochemistry & Molecular Genetics, University of Colorado Denver, United States l - Pediatric Respiratory Medicine, University of California San Diego, United States m - Division of Pulmonary and Critical Care, Baylor College of Medicine, United States n - Division of Lung Diseases, National Heart, Lung, and Blood Institute, United States o - Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, United States p - Division of Environmental and Occupational Health, University of Pittsburgh, United States q - Department of Medicine, Cedars-Sinai Medical Center, United States r - Department of Physiology & Biomedical Engineering, Mayo Clinic College of Medicine, United States s - Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, United States Correspondence to Victor J. Thannickal: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, 1720 2nd Avenue South, Birmingham, AL 35294, United States. [email protected] https://doi.org/10.1016/j.matbio.2018.03.005 Abstract The lung's unique extracellular matrix (ECM), while providing structural support for cells, is critical in the regulation of developmental organogenesis, homeostasis and injury-repair responses. The ECM, via biochemical or biomechanical cues, regulates diverse cell functions, fate and phenotype. The composition and function of lung ECM become markedly deranged in pathological tissue remodeling. ECM-based therapeutics and bioengineering approaches represent promising novel strategies for regeneration/repair of the lung and treatment of chronic lung diseases. In this review, we assess the current state of lung ECM biology, including fundamental advances in ECM composition, dynamics, topography, and biomechanics; the role of the ECM in normal and aberrant lung development, adult lung diseases and autoimmunity; and ECM in the regulation of the stem cell niche. We identify opportunities to advance the field of lung ECM biology and provide a set recommendations for research priorities to advance knowledge that would inform novel approaches to the pathogenesis, diagnosis, and treatment of chronic lung diseases. © 2017 Published by Elsevier B.V. 0022-2836/© 2017 Published by Elsevier B.V. Matrix Biol. (2017) xx, xxxxxx Please cite this article as: Y. Zhou, et al., Extracellular matrix in lung development, homeostasis and disease, Matrix Biol (2017), https://doi.org/10.1016/j.matbio.2018.03.005 2 Review: ECM in lung development, homeostasis and disease Introduction and maintenance of the stem cell niche. The potential for ECM-based therapeutics for chronic lung diseases Over the last three decades, our understanding of is considered. Our goal is to identify specific areas that the many, diverse roles of the extracellular matrix represent gaps in our understanding of ECM biology, (ECM) in mammalian biology have greatly advanced. and to provide a set of recommendations for research It is now well established that, in addition to providing a priorities to advance the field of lung ECM biology. scaffold for cells, the ECM provides essential bio- chemical and biomechanical cues directing tissue morphogenesis during development, homeostasis The ECM in lung development and injury-repair responses. The lung is characterized by a unique ECM composition and function that The lung begins as a respiratory diverticulum (lung becomes markedly deranged in childhood disorders bud) from the foregut at approximately 5 weeks such as bronchopulmonary dysplasia (BPD), and post-conception in the human embryo and develops adult diseases such as chronic obstructive pulmonary by stages until full development is complete. Alveo- disease (COPD) and idiopathic pulmonary fibrosis logenesis is thought to proceed well into post-natal life (IPF) (Fig. 1). in humans, reaching the maximal number of 200–300 In this review, we assess the current state of the field million during early adolescence [1]. The stages of of lung ECM biology, and identify opportunities to lung development consist of a pseudoglandular advance knowledge that would inform novel ap- stage (human: 5–17 weeks of gestation; mouse: proaches to understand, diagnose, and treat lung E9.5-E16.6), canalicular stage (human: 16–25 diseases of childhood and adults. Areas of focus in this weeks; mouse: E16.6-E17.4), terminal saccular review include fundamental advances in ECM com- stage (human: 24–32 or 36 weeks; mouse: position, dynamics, topography, and biomechanics; E17.4-P5), and the alveolar stage (human: 32 or the role of the ECM in normal lung development and 36 weeks to childhood or early teen years; mouse: aberrant development; ECM dynamics and altered P5-P28 or P42) [2,3]. During these stages, the initial deposition in adult lung diseases, namely COPD and processes of branching morphogenesis, vasculogen- IPF; the role of ECM in inflammation/autoimmunity; esis and angiogenesis transition to alveolar septation Fig. 1. Role of the ECM in lung homeostasis and disease. Normal lung ECM is critical for embryonic lung development and the maintenance of lung homeostasis in adulthood. Aberrant alterations of the properties of lung ECM, including composition, biomechanics, dynamics and topography, are characteristic of a number of adult and child lung diseases, including IPF, COPD and BPD. IPF = idiopathic pulmonary fibrosis; COPD = chronic obstructive pulmonary disease; BPD = bronchopulmonary dysplasia. Please cite this article as: Y. Zhou, et al., Extracellular matrix in lung development, homeostasis and disease, Matrix Biol (2017), https://doi.org/10.1016/j.matbio.2018.03.005 Review: ECM in lung development, homeostasis and disease 3 and maturation accompanied by marked changes branching is occurring can induce branching of in lung ECM composition. The two main concepts epithelial tissue where it does not, otherwise, occur regarding ECM in lung development are: (1) the lung [17]. During early human lung development, the ECM, not only provides vital physical support or a collagens I, III, and VI and PGs (decorin, biglycan, “scaffold” for resident cells of the lung and contributes and lumican) are primarily seen at the to its mechanical properties but, is also essential for epithelial-mesenchymal interface, forming a sleeve biophysical and biochemical signaling of lung cells, around the developing airways [18]. The PG compo- and (2) reciprocally, lung cells regulate the production nent of the ECM may regulate airway branching, in and deposition of ECM over the course of develop- part related to the ability of sulfated PGs to bind ment [4]. The processes by which ECM regulates lung FGF10, which is necessary for branching [19]. cells and lung cells, in turn, produce or break down Comprehensive gene expression profiling of murine ECM are critical to normal lung development; alter- lung development identified patterns of ECM gene ations in these processes may lead to impaired lung expression, and determined possible relationships development such as that seen in BPD. Additionally, among groups of these genes that coordinate defined abnormal recapitulation of developmental processes developmental processes [20]. may contribute to disorders such as IPF, pulmonary arterial hypertension, or lung cancer with correspond- Alveolar septation and ECM ing alterations in the ECM [5,6]. The composition and topography of lung ECM The saccular stage is characterized by further changes over the course of lung development, and is widening of the air spaces and a thinner air-blood very heterogeneous depending on location (e.g. close interface, accompanied by a reduction in the mesen- to bronchi, in alveolar septum, in pleura etc.) and chymal ECM, and organized deposition of elastin developmental stage (e.g. saccular stage vs. early which is maximal along the sites of the future alveolar septation vs. mature adult lung). The lung secondary crests (alveolar septa) [4]. Tropoelastin, ECM in fetal, neonatal and adult tissues are distinct, the precursor of elastin, is produced during alveolar and temporally regulates the shape, migration, differ- septation and is cross-linked by lysyl oxidase, and this entiation of resident cells