Developmental and pathologic roles of Follistatin-like 1 in the lung

    Tania, N.P. | University of Groningen , Department of Molecular Pharmacology | 23 september 2015 | (

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease that is characterized by airway remodeling, persistent inflammation, and emphysema (1). Patients with COPD suffer from airflow obstruction that is not fully reversible. Extracellular matrix remodeling of the airways and lung tissue is a hallmark of morphological changes in patients with COPD. Excessive production of the extracellular matrix in the airway, yet degradation of extracellular matrix in the lung parenchyma contribute to the development of COPD. Inhaled bronchodilators (muscarinic antagonists, β2-adrenoreceptor agonists) and anti-inflammatory drugs (glucocorticosteroids) do not modify the course of the disease (2). Therefore, the search for an effective treatment for patients with COPD is needed.

Accumulating evidence from gene expression and genome wide association studies indicates the involvement of developmental pathways such as Transforming Growth Factor-β (TGF-β), Wingless integrase-1 (Wnt), and Bone Morphogenetic Protein (BMP) to the development and progression of COPD later in life (3, 4). In addition to embryonic lung development, BMP signaling plays crucial roles in the control of adult lung homeostasis and repair (4). BMP regulates tissue remodeling by controlling cell proliferation, differentiation, and cell death (5). Production of extracellular matrix is a normal biological repair process in response to injury. This mechanism of repair is tightly coordinated in order to restore the normal tissue structure and function. It has been shown that dysregulation of BMP pathways results in aberrant wound repair processes (6). Given the importance of BMP in development and repair, endogenous BMP inhibitors including follistatin like-1 (Fstl1) and Gremlin are thus important in development and potentially in repair. Full body deletion of the BMP antagonist follistatin-like 1 in mice leads to defects in multiple organs, including the lung. This suggests a fundamental role of Fstl1 in lung organogenesis (7, 8). The role of Fstl1 in COPD is mostly unknown at present, and is the main topic of my research project.

At the American Thoracic Society International Conference 2015, there were several studies investigating the role of Fstl1 in the lung development and lung diseases. The study of Campfield and colleagues demonstrated that global, tamoxifen-inducible Fstl1 knockout mice results in spontaneous pulmonary emphysema. Fstl1 is conditionally deleted from whole body by administrating tamoxifen. By crossing the commercially available tamoxifen-inducible CAG-Cre driver (B6.Cg-Tg(CAG-cre/ESR1*)5Amc/J) and Fstl1 floxed (Fstl1fl/fl) mouse lines, 8-week-old offsprings were treated with tamoxifen resulting in conditional Fstl1fl/fl CAG-Cre/+ knockout mice. These findings indicate that Fstl1 plays a crucial role in lung homeostasis. Further characterization of the inflammatory cytokine profile of the tamoxifen-inducible Fstl1 knockout mice showed that IL-17A, IL-17F, CCL2, CCL7, as well as IL-17-dependent cytokines, including CSF3 and CXCL1 are significantly upregulated. These mice also exhibit increased matrix metalloprotease (MMP) 9 and MMP12 gene expression in their lung tissue which is paralleled by an increase in protease activity (9). These findings are in accordance with a poster presented at ATS 2014, which demonstrated that Fstl1 might contribute to maturation of alveolar epithelial cells (10).

We presented data demonstrating that the loss of endothelial Fstl1 is postnatally lethal. Tie2-cre endothelial-specific Fstl1 knockout mice were generated by breeding Fstl1fl/fl mice with Fstl1WT/KO Tie2-cre mice to generate Fstl1fl/KO Tie2-cre mice. Histological analysis of the heart showed remodeling of the right ventricle of Fstl1fl/KO Tie2-cre mice, suggesting pulmonary hypertension. Interestingly, we observed the percentage of actin-positive small pulmonary vessels is increased in 3 weeks old pups of Fstl1fl/KO Tie2-cre mice. These findings suggested that endothelial follistatin-like 1 is crucial for normal maturation of the pulmonary vasculature (11). Furthermore, the study of Liu and colleagues indicated that Fstl1 is important in controlling airway smooth muscle differentiation during embryonic mouse lung morphogenesis. Fstl1 knockout mice showed reduced α-smooth muscle actin (α-SMA) and SM22, a marker of adult smooth muscle cells in trachea and bronchiolar airways (12). It has been recently demonstrated that blocking Fstl1 attenuates bleomycin-induced pulmonary fibrosis (13). The authors demonstrated that blocking Fstl1 with neutralizing antibody or haplodeletion of Fstl1 in mice reduced bleomycin-induced myofibroblasts accumulation and extracellular matrix deposition (13). Fstl1 regulates myofibroblasts activation by promoting TGF-β signaling in a BMP-independent manner (13). Accordingly, the study of Fang and coworkers showed that neutralizing monoclonal antibody against Fstl1 reduces silica-induced pulmonary fibrosis in mice. These data suggested that Fstl1 contributes to silica-induced fibrosis (14). In addition, Huan and colleagues presented a poster demonstrating that the BMP antagonist BMPER activates fibroblasts and induces lung fibrosis in vitro and in vivo. They proposed that methylation of BMP binding proteins may be therapeutic approaches for patients with pulmonary fibrosis (15). Furthermore, Walsh and colleagues showed that gremlin, which negatively regulates BMP signaling, is exclusively expressed in myofibroblasts-derived IPF fibroblasts based on human fibrosis RT profiler PCR array (16).

Attending ATS conference is not only fruitful to keep up to date to the current knowledge of the contribution of BMP signaling in morphogenesis but also provokes further research in understanding the cellular and molecular mechanism underlying the pathogenesis of COPD. Unraveling the role of BMP signaling in normal lung morphogenesis, lung homeostasis, and injury-repair processes are needed in order to identify a potential drug target and develop a rational targeted therapy to improve the treatment of COPD.

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9. Campfield BT, Kolls JK. Loss of Follistatin-Like Protein 1 Causes Spontaneous Emphysema in a Murine Model. In: American Thoracic Society; 2015. p. A5561-.
10. Zheng XH, Geng Y, Liu X, Ning W. The Processing Of Surfactant Proteins Is Affected By Follistatin-Like 1. In: American Thoracic Society; 2014. p. A3448-.
11. Tania NP, Gosens R, Bos S, Mattioti A, Prakash S, Timens W, et al. Endothelial Follistatin-Like-1 is Crucial for Normal Development of the Pulmonary Vasculature in Mice. In: American Thoracic Society; 2015. p. A5960-.
12. Liu X, Ning W. Essential Role of Follistatin Like-1 in Regulating Airway Smooth Muscle Differentiation During Embryonic Mouse Lung Morphogenesis. In: American Thoracic Society; 2015. p. A3532-.
13. Dong Y, Geng Y, Li L, Li X, Yan X, Fang Y, et al. Blocking follistatin-like 1 attenuates bleomycin-induced pulmonary fibrosis in mice. The Journal of Experimental Medicine. 2015 January 12.
14. Fang Y, Ning W. Neutralizing Monoclonal Antibody to Follistatin-Like 1 Ameliorates Silica-Induced Pulmonary Fibrosis in Mice. In: American Thoracic Society; 2015. p. A2594-.
15. Huan C, Liang J, Yang T, Xie T, Liu N, Jiang D, et al. The Role of BMPER in Lung Fibrosis. In: American Thoracic Society; 2015. p. A4930-.
16. Walsh S, Worrell J, Fabre A, Kane R, Keane M. Gremlin Distinguishes the Myofibroblast Derived from the IPF Fibroblast from the Myofibroblast Derived from Normal Fibroblast, Fibrocyte and Epithelial Cell in Pulmonary Fibrosis. In: American Thoracic Society; 2015. p. A4929-.

Keyword: COPD follistatin like-1 (Fstl1)

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