Age-dependent decline in mouse lung regeneration with loss of lung fibroblast clonogenicity and increased myofibroblastic differentiation.
Age-dependent decline in mouse lung regeneration with loss of lung fibroblast clonogenicity and increased myofibroblastic differentiation.
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DOI：
10.1371/journal.pone.0023232
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Hoffman AM
中科院分区：
文献类型：
--
作者：
Paxson JA;Gruntman A;Parkin CD;Mazan MR;Davis A;Ingenito EP;Hoffman AM
虽然衰老导致大多数哺乳动物肺切除术（PNX）后再生能力降低，但这种生物学现象在小鼠的一生中尚未得到表征。我们测量了年龄特异性（3，9，24个月）PNX对生理学，形态计量学，细胞增殖和凋亡，整体基因表达，肺成纤维细胞表型和克隆形成的影响，在雌性C57BL6小鼠。数据显示，只有3个月大的小鼠能够在第7天完全恢复肺体积，在第21天完全恢复总肺泡表面积。到9个月时，再生速度较慢（21天时再生不完全），到24个月时，PNX后21天没有再生。早期再生率的下降与肺泡上皮细胞II型（AECII）增殖或凋亡率的变化无关。然而，在24个月的小鼠中，在PNX后，在总细胞和AECII细胞中明显的细胞凋亡和缺乏细胞增殖。在9个月与3个月小鼠中PNX后几个时间点（1、3和7天）的基因表达分析与肌成纤维细胞特征（增加的Tnc、Lox1、Col3A1、Eln和Tnfrsf12a）一致，并且在9个月与3个月小鼠中PNX后存在更多的α平滑肌肌动蛋白（αSMA）阳性肌成纤维细胞。分离的肺成纤维细胞表现出显着的年龄依赖性克隆形成的损失。此外，从9和17月龄小鼠分离的肺成纤维细胞显示出较高的αSMA、Col3A1、Fn1和S100A表达，以及与终末分化一致的较低的存活基因Mdk表达。这些数据表明，伴随的克隆形成和进行性肌纤维母细胞分化的损失有助于肺再生率的年龄依赖性下降。
While aging leads to a reduction in the capacity for regeneration after pneumonectomy (PNX) in most mammals, this biological phenomenon has not been characterized over the lifetime of mice. We measured the age-specific (3, 9, 24 month) effects of PNX on physiology, morphometry, cell proliferation and apoptosis, global gene expression, and lung fibroblast phenotype and clonogenicity in female C57BL6 mice. The data show that only 3 month old mice were fully capable of restoring lung volumes by day 7 and total alveolar surface area by 21 days. By 9 months, the rate of regeneration was slower (with incomplete regeneration by 21 days), and by 24 months there was no regrowth 21 days post-PNX. The early decline in regeneration rate was not associated with changes in alveolar epithelial cell type II (AECII) proliferation or apoptosis rate. However, significant apoptosis and lack of cell proliferation was evident after PNX in both total cells and AECII cells in 24 mo mice. Analysis of gene expression at several time points (1, 3 and 7 days) post-PNX in 9 versus 3 month mice was consistent with a myofibroblast signature (increased Tnc, Lox1, Col3A1, Eln and Tnfrsf12a) and more alpha smooth muscle actin (αSMA) positive myofibroblasts were present after PNX in 9 month than 3 month mice. Isolated lung fibroblasts showed a significant age-dependent loss of clonogenicity. Moreover, lung fibroblasts isolated from 9 and 17 month mice exhibited higher αSMA, Col3A1, Fn1 and S100A expression, and lower expression of the survival gene Mdk consistent with terminal differentiation. These data show that concomitant loss of clonogenicity and progressive myofibroblastic differentiation contributes to the age-dependent decline in the rate of lung regeneration.
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DOI：
10.18632/aging.100060
发表时间：
2009-06-22
期刊：
Aging
影响因子：
--
作者：
Jin J;Wang GL;Timchenko L;Timchenko NA
通讯作者：
Timchenko NA
影响因子：
3.8
作者：
Daly, HE;BaecherAllan, CM;Finkelstein, JN
通讯作者：
Finkelstein, JN
影响因子：
4
作者：
Mora, Ana L.;Rojas, Mauricio
通讯作者：
Rojas, Mauricio
影响因子：
10.8
作者：
Han, Juhee;Liu, Jin Yu;Andreadis, Stelios T.
通讯作者：
Andreadis, Stelios T.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y