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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.

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.

SUBMITTER: Ke X

PROVIDER: S-EPMC6401351 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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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.

Ke Xia X Do Danh C DC Li Changjun C Zhao Yilin Y Kollarik Marian M Fu Qingling Q Wan Mei M Gao Peisong P

The Journal of allergy and clinical immunology 20180905 4

<h4>Background</h4>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.<h4>Objectives</h4>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.<h4>Methods</h4>Active RhoA expre ...[more]

PMID: 30194990

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Project description:BackgroundTo provide tacrolimus is first-line treatment after liver and kidney transplantation. However, hypertension and nephrotoxicity are common tacrolimus side effects that limit its use. Although tacrolimus-related hypertension is well known, the underlying mechanisms are not. Here, we test whether tacrolimus-induced hypertension involves the RhoA (Ras homolog family member A)/ROCK (Rho-associated protein kinase) pathway in male C57Bl/6 mice.MethodsIntra-arterial blood pressure was measured under anesthesia. The reactivity of renal afferent arterioles and mesenteric arteries were assessed in vitro using microperfusion and wire myography, respectively.ResultsTacrolimus induced a transient rise in systolic arterial pressure that was blocked by the RhoA/ROCK inhibitor Fasudil (12.0±0.9 versus 3.2±0.7; P<0.001). Moreover, tacrolimus reduced the glomerular filtration rate, which was also prevented by Fasudil (187±20 versus 281±8.5; P<0.001). Interestingly, tacrolimus enhanced the sensitivity of afferent arterioles and mesenteric arteries to Ang II (angiotensin II), likely due to increased intracellular Ca2+ mobilization and sensitization. Fasudil prevented increased Ang II-sensitivity and blocked Ca2+ mobilization and sensitization. Preincubation of mouse aortic vascular smooth muscle cells with tacrolimus activated the RhoA/ROCK/MYPT-1 (myosin phosphatase targeting subunit 1) pathway. Further, tacrolimus increased cytoplasmic reactive oxygen species generation in afferent arterioles (107±5.9 versus 163±6.4; P<0.001) and in cultured mouse aortic vascular smooth muscle cells (100±7.5 versus 160±23.2; P<0.01). Finally, the reactive oxygen species scavenger Tempol inhibited tacrolimus-induced Ang II hypersensitivity in afferent arterioles and mesenteric arteries.ConclusionsThe RhoA/ROCK pathway may play an important role in tacrolimus-induced hypertension by enhancing Ang II-specific vasoconstriction, and reactive oxygen species may participate in this process by activating the RhoA/ROCK pathway.

Dataset Information

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.

Publications

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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