Ras homolog family member A/Rho-associated protein kinase 1 signaling modulates lineage commitment of mesenchymal stem cells in asthmatic patients through lymphoid enhancer-binding factor

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:143

Article

Ke, Xia^1,3  Do, Danh C.¹  Li, Changjun²  Zhao, Yilin^1,4  Kollarik, Marian¹  Fu, Qingling⁵  Wan, Mei²  Gao, Peisong¹ 

[1] Johns Hopkins Univ, Sch Med, Div Allergy & Clin Immunol, Baltimore, MD USA

[2] Johns Hopkins Univ, Sch Med, Dept Orthoped Surg, Baltimore, MD USA

[3] Chongqing Med Univ, Affiliated Hosp 1, Dept Otorhinolaryngol, Chongqing, Peoples R China

[4] Fourth Mil Med Univ, Dept Resp Med, Xian, Shaanxi, Peoples R China

[5] Sun Yat Sen Univ, Affiliated Hosp 1, Otorhinolaryngol Hosp, Guangzhou, Guangdong, Peoples R China

关键词: Asthma;    cockroach allergen;    Ras homolog family member A/Rho-associated protein kinase 1;    mesenchymal stem cell;    Lef1;   

DOI  :  10.1016/j.jaci.2018.08.023

来源: Elsevier

【 摘 要 】

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.

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