The modulation of the oxidative stress response in chondrocytes by Wip1 and its effect on senescence and dedifferentiation during in vitro expansion
The modulation of the oxidative stress response in chondrocytes by Wip1 and its effect on senescence and dedifferentiation during in vitro expansion
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DOI：
10.1016/j.biomaterials.2012.12.009
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发表时间：
2013-03-01
期刊：
影响因子：
14
通讯作者：
Lee, Soo-Hong
中科院分区：
文献类型：
--
作者：
Cha, Byung-Hyun;Lee, Ji-Seon;Lee, Soo-Hong
获得足够数量的细胞离体用于组织再生，这是适合于软骨修复，需要改进的技术，以连续扩增软骨细胞的方式，不改变其先天特性。在体外扩增过程中的快速衰老或去分化导致软骨细胞表型的丧失，并在移植后形成纤维软骨替代组织，而不是透明质软骨。正如在目前的研究中所证明的，野生型p53-诱导磷酸酶（Wip 1），一个完善的应激调节剂，在早期传代软骨细胞中高度表达，但在体外扩增过程中迅速下降。通过微穿孔产生的稳定的Wip 1表达软骨细胞对衰老和去分化的发生不太敏感，并且对氧化应激更具抵抗力。Wip 1软骨细胞对氧化应激的抵抗力增加是由于p38丝裂原活化蛋白激酶（MAPK）活性的调节。重要的是，表达Wip 1的软骨细胞在更长的时间内保持其固有的软骨形成特性，从而改善了移植后的软骨再生。与野生型小鼠相比，Wip 1基因敲除（Wip 1（-/-））小鼠的软骨细胞在软骨再生方面存在缺陷。因此，Wip 1表达代表了一种潜在有用的机制，通过该机制，软骨细胞表型可以在体外扩增期间通过调节细胞应激反应而保留。(C)2013爱思唯尔有限公司保留所有权利。
Obtaining a sufficient number of cells ex vivo for tissue regeneration, which are appropriate for cartilage repair, requires improved techniques for the continuous expansion of chondrocytes in a manner that does not change their innate characteristics. Rapid senescence or dedifferentiation during in vitro expansion results in loss of chondrocyte phenotype and the formation of fibrous cartilage replacement tissue, rather than hyaluronic cartilage, after transplantation. As demonstrated in the current study, wildtype p53-inducible phosphatase (Wip1), a well-established stress modulator, was highly expressed in early-passage chondrocytes, but declined rapidly during in vitro expansion. Stable Wip1-expressing chondrocytes generated by microporation were less susceptible to the onset of senescence and dedifferentiation, and were more resistant to oxidative stress. The increased resistance of Wip1 chondrocytes to oxidative stress was due to modulation of p38 mitogen-activated protein kinase (MAPK) activity. Importantly, chondrocytes expressing Wip1 maintained their innate chondrogenic properties for a longer period of time, resulting in improvements in cartilage regeneration after transplantation. Chondrocytes from Wip1 knocicout (Wip1(-/-)) mice were defective in cartilage regeneration compared with those from wild-type mice. Thus, Wip1 expression represents a potentially useful mechanism by which a chondrocyte phenotype can be retained during in vitro expansion through modulation of cellular stress responses. (C) 2013 Elsevier Ltd. All rights reserved.