Mesenchymal stem cells cultured under hypoxia escape from senescence via down-regulation of p16 and extracellular signal regulated kinase
Mesenchymal stem cells cultured under hypoxia escape from senescence via down-regulation of p16 and extracellular signal regulated kinase
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DOI：
10.1016/j.bbrc.2009.12.096
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发表时间：
2010-01-15
影响因子：
3.1
通讯作者：
Toguchida, Junya
中科院分区：
文献类型：
--
作者：
Jin, Yonghui;Kato, Tomohisa;Toguchida, Junya
缺氧被认为会影响包括间充质干细胞（MSC）在内的组织干细胞的特性。然而，长期暴露于缺氧对人MSC的影响尚未得到明确证实。在常氧条件（20%pO（2））下培养的MSC在15-25个群体倍增后停止增殖，而在低氧条件（1%pO（2））下培养的MSC在另外8-20个群体倍增后保留增殖能力。常氧培养100天后，大部分MSCs处于衰老状态，而低氧培养中几乎没有发现衰老细胞，这与p16基因表达下调有关。在低氧条件下培养100天的MSC在分化成软骨和脂肪形成，但不成骨，谱系的能力上级在常氧条件下培养的那些。在与丝裂原活化蛋白激酶（MAPK）信号通路相关的分子中，细胞外信号调节激酶（ERK）在缺氧条件下显著下调，从而抑制p16基因表达的上调。因此，低氧培养通过下调p16和ERK将MSC保持在未分化和无衰老状态（c）2010由Elsevier Inc.出版。
Hypoxia has been considered to affect the properties of tissue stem cells including mesenchymal stem cells (MSCs). Effects of long periods of exposure to hypoxia on human MSCs, however, have not been clearly demonstrated. MSCs cultured under normoxic conditions (20% pO(2)) ceased to proliferate after 15-25 population doublings, while MSCs cultured under hypoxic conditions (1% pO(2)) retained the ability to proliferate with an additional 8-20 population doublings. Most of the MSCs cultured under normoxic conditions were in a senescent state after 100 days, while few senescent cells were found in the hypoxic culture, which was associated with a down-regulation of p16 gene expression. MSCs cultured for 100 days under hypoxic conditions were superior to those cultured under normoxic conditions in the ability to differentiate into the chondro- and adipogenic, but not osteogenic, lineage. Among the molecules related to mitogen-activated protein kinase (MAPK) signaling pathways, extracellular signal regulated kinase (ERK) was significantly down-regulated by hypoxia, which helped to inhibit the up-regulation of p16 gene expression. Therefore, the hypoxic culture retained MSCs in an undifferentiated and senescence-free state through the down-regulation of p16 and ERK (c) 2010 Published by Elsevier Inc.