Xia Ke1, Danh C Do2, Changjun Li3, Yilin Zhao4, Marian Kollarik2, Qingling Fu5, Mei Wan3, Peisong Gao6. 1. Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md; Department of Otorhinolaryngology, First Affiliated Hospital of Chongqing Medical University, Chongqing, China. 2. Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md. 3. Department of Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Md. 4. Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md; Department of Respiratory Medicine, Fourth Military Medical University, Xi'an, China. 5. Otorhinolaryngology Hospital, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. 6. Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md. Electronic address: pgao1@jhmi.edu.
Abstract
BACKGROUND: Numbers of mesenchymal stem cells (MSCs) are increased in the airways after allergen challenge. Ras homolog family member A (RhoA)/Rho-associated protein kinase 1 (ROCK) signaling is critical in determining the lineage fate of MSCs in tissue repair/remodeling. OBJECTIVES: We sought to investigate the role of RhoA/ROCK signaling in lineage commitment of MSCs during allergen-induced airway remodeling and delineate the underlying mechanisms. METHODS: Active RhoA expression in lung tissues of asthmatic patients and its role in cockroach allergen-induced airway inflammation and remodeling were investigated. RhoA/ROCK signaling-mediated MSC lineage commitment was assessed in an asthma mouse model by using MSC lineage tracing mice (nestin-Cre; ROSA26-EYFP). The role of RhoA/ROCK in MSC lineage commitment was also examined by using MSCs expressing constitutively active RhoA (RhoA-L63) or dominant negative RhoA (RhoA-N19). Downstream RhoA-regulated genes were identified by using the Stem Cell Signaling Array. RESULTS: Lung tissues from asthmatic mice showed increased expression of active RhoA when compared with those from control mice. Inhibition of RhoA/ROCK signaling with fasudil, a RhoA/ROCK inhibitor, reversed established cockroach allergen-induced airway inflammation and remodeling, as assessed based on greater collagen deposition/fibrosis. Furthermore, fasudil inhibited MSC differentiation into fibroblasts/myofibroblasts but promoted MSC differentiation into epithelial cells in asthmatic nestin-Cre; ROSA26-EYFP mice. Consistently, expression of RhoA-L63 facilitated differentiation of MSCs into fibroblasts/myofibroblasts, whereas expression of RhoA-19 switched the differentiation toward epithelial cells. The gene array identified the Wnt signaling effector lymphoid enhancer-binding factor 1 (Lef1) as the most upregulated gene in RhoA-L63-transfected MSCs. Knockdown of Lef1 induced MSC differentiation away from fibroblasts/myofibroblasts but toward epithelial cells. CONCLUSIONS: These findings uncover a previously unrecognized role of RhoA/ROCK signaling in MSC-involved airway repair/remodeling in the setting of asthma.
BACKGROUND: Numbers of mesenchymal stem cells (MSCs) are increased in the airways after allergen challenge. Ras homolog family member A (RhoA)/Rho-associated protein kinase 1 (ROCK) signaling is critical in determining the lineage fate of MSCs in tissue repair/remodeling. OBJECTIVES: We sought to investigate the role of RhoA/ROCK signaling in lineage commitment of MSCs during allergen-induced airway remodeling and delineate the underlying mechanisms. METHODS: Active RhoA expression in lung tissues of asthmatic patients and its role in cockroach allergen-induced airway inflammation and remodeling were investigated. RhoA/ROCK signaling-mediated MSC lineage commitment was assessed in an asthmamouse model by using MSC lineage tracing mice (nestin-Cre; ROSA26-EYFP). The role of RhoA/ROCK in MSC lineage commitment was also examined by using MSCs expressing constitutively active RhoA (RhoA-L63) or dominant negative RhoA (RhoA-N19). Downstream RhoA-regulated genes were identified by using the Stem Cell Signaling Array. RESULTS: Lung tissues from asthmatic mice showed increased expression of active RhoA when compared with those from control mice. Inhibition of RhoA/ROCK signaling with fasudil, a RhoA/ROCK inhibitor, reversed established cockroach allergen-induced airway inflammation and remodeling, as assessed based on greater collagen deposition/fibrosis. Furthermore, fasudil inhibited MSC differentiation into fibroblasts/myofibroblasts but promoted MSC differentiation into epithelial cells in asthmatic nestin-Cre; ROSA26-EYFP mice. Consistently, expression of RhoA-L63 facilitated differentiation of MSCs into fibroblasts/myofibroblasts, whereas expression of RhoA-19 switched the differentiation toward epithelial cells. The gene array identified the Wnt signaling effector lymphoid enhancer-binding factor 1 (Lef1) as the most upregulated gene in RhoA-L63-transfected MSCs. Knockdown of Lef1 induced MSC differentiation away from fibroblasts/myofibroblasts but toward epithelial cells. CONCLUSIONS: These findings uncover a previously unrecognized role of RhoA/ROCK signaling in MSC-involved airway repair/remodeling in the setting of asthma.
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