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 1.
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 1.
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DOI：
10.1016/j.jaci.2018.08.023
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发表时间：
2019-04
期刊：
影响因子：
--
通讯作者：
Gao P
中科院分区：
文献类型：
--
作者：
Ke X;Do DC;Li C;Zhao Y;Kollarik M;Fu Q;Wan M;Gao P
间充质干细胞（MSCs）在过敏原攻击后气道中增加。RhoA/ROCK信号是决定MSCs在组织修复/重塑中的谱系命运的关键。研究RhoA/ROCK信号在过敏原诱导的气道重塑过程中MSCs谱系承诺中的作用，并描述其潜在机制。研究了哮喘肺组织RhoA活性表达及其在蟑螂变应原诱导的气道炎症和重塑中的作用。在哮喘小鼠模型中，使用MSC谱系追踪小鼠（nesting - cre; ROSA26-EYFP）评估RhoA/ROCK信号介导的MSC谱系承诺。RhoA/ROCK在MSC谱系承诺中的作用也通过MSCs表达组成型活性RhoA （RhoA- l63）或显性阴性RhoA （RhoA- n19）来检测。下游rhoa调控基因通过干细胞信号阵列进行鉴定。与对照组相比，哮喘小鼠肺组织中活性RhoA的表达增加。法舒地尔（一种RhoA/ROCK抑制剂）对RhoA/ROCK信号的抑制，通过更多的胶原沉积/纤维化来评估，逆转了既定的蟑螂过敏原诱导的气道炎症和重塑。此外，法舒地尔抑制哮喘巢细胞间充质干细胞向成纤维细胞/肌成纤维细胞分化，但促进间充质干细胞向上皮细胞分化；ROSA26-EYFP老鼠。与此一致的是，RhoA-L63的表达促进了MSCs向成纤维细胞/肌成纤维细胞的分化，而RhoA-19的表达使MSCs向上皮细胞分化。Gene Array发现Wnt信号效应因子Lef1是rhoa - l63转染MSCs中上调最多的基因。敲除Lef1诱导间充质干细胞从成纤维细胞/肌成纤维细胞向上皮细胞分化。这些发现揭示了RhoA/ROCK信号在哮喘中与msc相关的气道修复/重塑中先前未被认识到的作用。间充质干细胞在哮喘气道修复/重塑中起关键作用。RhoA/ROCK信号在气道修复/重塑过程中作为MSCs谱系命运的分子开关。靶向RhoA/ROCK信号可能是治疗哮喘的有效策略。
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. To investigate the role of RhoA/ROCK signaling in lineage commitment of MSCs during allergen-induced airway remodeling and delineate the underlying mechanisms. 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. 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. These findings uncover a previously unrecognized role of RhoA/ROCK signaling in MSC-involved airway repair/remodeling in asthma. MSCs are critical in airway repair/remodeling in asthma. RhoA/ROCK signaling functions as a molecular switch for the lineage fate of MSCs during airway repair/remodeling. Targeting RhoA/ROCK signaling might be an effective therapeutic strategy for asthma.
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影响因子：
4.8
作者：
Bryan, Brad A.;Dennstedt, Emily;D'Amore, Patricia A.
通讯作者：
D'Amore, Patricia A.
影响因子：
29.4
作者：
Holvoet, Tom;Devriese, Sarah;Laukens, Debby
通讯作者：
Laukens, Debby
DOI：
10.4049/jimmunol.1303461
发表时间：
2014-05-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Gao P;Zhou Y;Xian L;Li C;Xu T;Plunkett B;Huang SK;Wan M;Cao X
通讯作者：
Cao X
Wnt/β-连环蛋白信号激活促进间充质干细胞修复脂多糖诱导的小鼠肺泡上皮损伤
影响因子：
7.5
作者：
Cai SX;Liu AR;Chen S;He HL;Chen QH;Xu JY;Pan C;Yang Y;Guo FM;Huang YZ;Liu L;Qiu HB
通讯作者：
Qiu HB
影响因子：
14.2
作者：
Al-Muhsen, Saleh;Johnson, Jill R.;Hamid, Qutayba
通讯作者：
Hamid, Qutayba