RhoA/ROCK Signaling Modulates Lineage Commitment of Mesenchymal Stem Cells in Asthma through Lef1

Publication date: Available online 5 September 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Xia Ke, Danh C. Do, Changjun Li, Yilin Zhao, Marian Kollarik, Qingling Fu, Mei Wan, Peisong Gao

ABSTRACT

Rationale

Mesenchymal stem cells (MSCs) are increased in the airways after allergen challenge. RhoA/ROCK signaling is critical in determining the lineage fate of MSCs in tissue repair/remodeling.

Objectives

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 asthmatic lung tissues and its role in cockroach allergen-induced airway inflammation and remodeling were investigated. The RhoA/ROCK signaling-mediated MSC lineage commitment was assessed in an asthma mouse model using MSC lineage tracing mice (nestin-Cre; ROSA26-EYFP). The role of RhoA/ROCK in MSC lineage commitment was also examined by MSCs expressing constitutively active RhoA (RhoA-L63) or dominant negative RhoA (RhoA-N19). Downstream RhoA-regulated genes were identified using the stem cell signaling array.

Results

Lung tissues from asthmatic mice showed increased expression of active RhoA when compared with those from controls. Inhibition of RhoA/ROCK signaling with fasudil, a RhoA/ROCK inhibitor, reversed established cockroach allergen-induced airway inflammation and remodeling as assessed by more 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 the differentiation of MSCs to fibroblasts/myofibroblasts, whereas expression of RhoA-19 switched the differentiation toward epithelial cells. Gene Array identified the Wnt signaling effector Lef1 as the most up-regulated gene in RhoA-L63-transfected MSCs. Knockdown of Lef1 induced MSC differentiation away from fibroblasts/myofibroblasts but towards epithelial cells.

Conclusions

These findings uncover a previously unrecognized role of RhoA/ROCK signaling in MSC-involved airway repair/remodeling in asthma.

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