Trans-differentiation of alveolar epithelial type II cells to type I cells involves autocrine signaling by transforming growth factor β1 through the Smad pathway
Trans-differentiation of alveolar epithelial type II cells to type I cells involves autocrine signaling by transforming growth factor β1 through the Smad pathway
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DOI：
10.1074/jbc.m609060200
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发表时间：
2007-02-09
影响因子：
4.8
通讯作者：
Liu, Lin
中科院分区：
文献类型：
--
作者：
Bhaskaran, Manoj;Kolliputi, Narasaiah;Liu, Lin
肺泡II型上皮细胞(AEC II)在肺泡内正常AEC I群受损时，增殖并转分化为I型肺泡上皮细胞(AEC I)。我们推测，在正常细胞中，转化生长因子β1通过其下游的Smad蛋白参与了AEC II向AEC I的转分化。在正常肺中，转化生长因子β1和Smad4在AEC II中高表达。通过体外细胞培养模型，我们证明了AEC II向AEC I样细胞的转分化始于增殖期，随后是分化期。细胞周期抑制因子p15(Ink4b)和p21(Cip1)的表达在增殖期较低，而在分化期较高。此外，细胞周期蛋白依赖性激酶2、4和6的表达趋势相反。在分化阶段，转化生长因子β1分泌到培养上清液中的量增加，表明是一种自分泌调节。在增殖期后加入转化生长因子β1中和抗体，并通过RNA干扰沉默Smad4，可抑制反式分化过程。综上所述，我们的结果表明，AEC II向AEC I的反式分化是通过Smad依赖的转化生长因子β1途径，通过改变细胞周期中控制G期到S期的蛋白的表达来调节的。
Type II alveolar epithelial cells (AEC II) proliferate and trans-differentiate into type I alveolar epithelial cells (AEC I) when the normal AEC I population is damaged in the lung alveoli. We hypothesized that signaling by transforming growth factor beta 1 (TGF beta 1), through its downstream Smad proteins, is involved in keeping AEC II quiescent in normal cells and its altered signaling may be involved in the trans-differentiation of AEC II to AEC I. In the normal lung, TGF beta 1 and Smad4 were highly expressed in AEC II. Using an in vitro cell culture model, we demonstrated that the trans-differentiation of AEC II into AEC I-like cells began with a proliferative phase, followed by a differentiation phase. The expression of TGF beta 1, Smad2, and Samd3 and their phosphorylated protein forms, and cell cycle inhibitors, p15(Ink4b) and p21(Cip1), was lower during the proliferative phase but higher during the differentiation phase. Furthermore, cyclin-dependent kinases 2, 4, and 6 showed an opposite trend of expression. TGF beta 1 secretion into the media increased during the differentiation phase, indicating an autocrine regulation. The addition of TGF beta 1 neutralizing antibody after the proliferative phase and silencing of Smad4 by RNA interference inhibited the trans-differentiation process. In summary, our results suggest that the trans-differentiation of AEC II to AEC I is modulated by signaling through the Smad-dependent TGF beta 1 pathway by altering the expression of proteins that control the G, to S phase entry in the cell cycle.