Functional effects of TGF-β1 on mesenchymal stem cell mobilization in cockroach allergen-induced asthma.
Functional effects of TGF-β1 on mesenchymal stem cell mobilization in cockroach allergen-induced asthma.
复制标题
DOI：
10.4049/jimmunol.1303461
复制
发表时间：
2014-05-15
期刊：
影响因子：
--
通讯作者：
Cao X
中科院分区：
文献类型：
--
作者：
Gao P;Zhou Y;Xian L;Li C;Xu T;Plunkett B;Huang SK;Wan M;Cao X
间充质干细胞（Mesenchymal stem cells，MSCs）被认为参与免疫调节和气道修复/重塑。转化生长因子β1（Transforming growth factor β 1，TGFβ1）在组织修复、重塑和细胞分化的干/祖细胞募集中起着关键作用。本研究旨在探讨TGFβ1在过敏性哮喘MSC迁移中的作用。我们检测了蟑螂变应原（CRE）诱导的小鼠模型气道中巢蛋白（MSC的标志物）表达和TGFβ1信号转导激活。与对照组相比，CRE组小鼠气道巢蛋白阳性细胞增多，血清TGFβ1活性升高，肺组织p-Smad 2/3表达增强。CRE-MSCs中TGFβ1信号的激活也增加。然后，我们评估了MSC迁移诱导条件培养基（ECM）从CRE挑战的人上皮细胞在空气/液体界面（ALI）培养中的Transwell测定。ECM可刺激MSC迁移，但TGFβ1中和抗体或TβR1抑制剂可显著抑制MSC迁移。有趣的是，在全身注射GFP+-MSC后也观察到MSC从血液和骨髓向气道的迁移增加，并且在CRE攻击后从Nes-GFP小鼠的骨髓中也观察到MSC向气道的迁移增加。TGFβ1中和抗体可抑制CRE诱导的MSC募集，但可促进气道炎症。最后，我们研究了MSC在调节CRE诱导的T细胞应答中的作用，发现MSC显著抑制CRE诱导的CD 4 + T细胞分泌炎性细胞因子（IL-4、IL 13、IL 17和IFN-γ）。这些结果表明，TGFβ1可能是哮喘小鼠模型中将MSC募集到气道的关键促迁移因子。
Mesenchymal stem cells (MSCs) have been suggested to participate in immune regulation and airway repair/remodeling. Transforming growth factor β1 (TGFβ1) is critical in the recruitment of stem/progenitor cells for tissue repair, remodeling and cell differentiation. In this study, we sought to investigate the role of TGFβ1 in MSC migration in allergic asthma. We examined nestin expression (a marker for MSCs) and TGFβ1 signaling activation in airways in cockroach allergen (CRE) induced mouse models. Compared with control mice, there were increased nestin+ cells in airways, and higher levels of active TGFβ1 in serum and p-Smad2/3 expression in lungs of CRE-treated mice. Increased activation of TGFβ1 signaling was also found in CRE-treated MSCs. We then assessed MSC migration induced by conditioned medium (ECM) from CRE-challenged human epithelium in air/liquid interface (ALI) culture in Transwell assays. MSC migration was stimulated by ECM, but was significantly inhibited by either TGFβ1 neutralizing antibody or TβR1 inhibitor. Intriguingly, increased migration of MSCs from blood and bone marrow to the airway was also observed after systemic injection of GFP+-MSCs, and from bone marrow of Nes-GFP mice following CRE challenge. Furthermore, TGFβ1 neutralizing antibody inhibited the CRE-induced MSC recruitment, but promoted airway inflammation. Finally, we investigated the role of MSCs in modulating CRE induced T cell response, and found that MSCs significantly inhibited CRE-induced inflammatory cytokine secretion (IL-4, IL13, IL17 and IFN-γ) by CD4+ T cells. These results suggest that TGFβ1 may be a key pro-migratory factor in recruiting MSCs to the airways in mouse models of asthma.
登录
查看更多内容
DOI：
10.1073/pnas.1310750111
发表时间：
2014-01-14
影响因子：
11.1
作者：
Fujimura, Kei E.;Demoor, Tine;Lynch, Susan V.
通讯作者：
Lynch, Susan V.
影响因子：
14.2
作者：
Gruchalla, RS;Pongracic, J;Mitchell, H
通讯作者：
Mitchell, H
影响因子：
6.1
作者：
Kumar, RK;Herbert, C;Foster, PS
通讯作者：
Foster, PS
影响因子：
8.8
作者：
Beyer, Tobias A.;Weiss, Alexander;Wrana, Jeffrey L.
通讯作者：
Wrana, Jeffrey L.
影响因子：
82.9
作者：
Ceradini, DJ;Kulkarni, AR;Gurtner, GC
通讯作者：
Gurtner, GC