Interleukin-6 maintains bone marrow-derived mesenchymal stem cell stemness by an ERK1/2-dependent mechanism.
Interleukin-6 maintains bone marrow-derived mesenchymal stem cell stemness by an ERK1/2-dependent mechanism.
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DOI：
10.1002/jcb.22289
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发表时间：
2009-10-15
影响因子：
4
通讯作者：
Tuan, Rocky S.
中科院分区：
文献类型：
--
作者：
Pricola, Katie L.;Kuhn, Nastaran Z.;Haleem-Smith, Hana;Song, Yingjie;Tuan, Rocky S.
成人间充质干细胞（MSC）由于其易于分离、扩增和多向分化潜能，有望成为越来越多的治疗用途。为了最大限度地发挥MSC的临床潜力，必须了解MSC功能控制的潜在机制。我们已经采取了解构的方法来了解体外的各个组成部分，即候选人的作用“干性”基因。我们最近的微阵列基因表达谱数据表明，白细胞介素-6（IL-6）可能有助于维持MSC在其未分化状态。在这项研究中，我们发现，IL-6基因的表达是显着较高的未分化间充质干细胞相比，其软骨，成骨和成脂衍生物。此外，我们发现MSC分泌大量的IL-6蛋白，其在成骨分化过程中显著减少。我们使用一系列功能测定进一步评估了IL-6在维持MSC“干性”中的作用。数据显示，IL-6对于增强MSC增殖是必要的且足够的，保护MSC免于凋亡，抑制MSC的脂肪形成和软骨形成分化，并且增加MSC的体外伤口愈合速率。我们进一步鉴定了ERK 1/2活化是IL-6调节MSC增殖和抑制分化的关键途径。总之，这些发现首次表明IL-6维持骨髓源性MSC的增殖和未分化状态，这是优化MSC体外和体内操作的重要参数。
Adult human mesenchymal stem cells (MSCs) hold promise for an increasing list of therapeutic uses due to their ease of isolation, expansion, and multilineage differentiation potential. To maximize the clinical potential of MSCs, the underlying mechanisms by which MSC functionality is controlled must be understood. We have taken a deconstructive approach to understand the individual components in vitro, namely the role of candidate “stemness” genes. Our recent microarray gene expression profiling data suggest that interleukin-6 (IL-6) may contribute to the maintenance of MSCs in their undifferentiated state. In this study, we showed that IL-6 gene expression is significantly higher in undifferentiated MSCs as compared to their chondrogenic, osteogenic, and adipogenic derivatives. Moreover, we found that MSCs secrete copious amounts of IL-6 protein, which decreases dramatically during osteogenic differentiation. We further evaluated the role of IL-6 for maintenance of MSC “stemness”, using a series of functional assays. The data showed that IL-6 is both necessary and sufficient for enhanced MSC proliferation, protects MSCs from apoptosis, inhibits adipogenic and chondrogenic differentiation of MSCs, and increases the rate of in vitro wound healing of MSCs. We further identified ERK1/2 activation as the key pathway through which IL-6 regulates both MSC proliferation and inhibition of differentiation. Taken together, these findings show for the first time that IL-6 maintains the proliferative and undifferentiated state of bone marrow-derived MSCs, an important parameter for the optimization of both in vitro and in vivo manipulation of MSCs.
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DOI：
10.1073/pnas.92.11.4857
发表时间：
1995-05-23
影响因子：
11.1
作者：
PEREIRA, RF;HALFORD, KW;PROCKOP, DJ
通讯作者：
PROCKOP, DJ
影响因子：
4
作者：
GIMBLE, JM;WANKER, F;HILL, MR
通讯作者：
HILL, MR
DOI：
10.1073/pnas.84.24.9035
发表时间：
1987-12-01
影响因子：
11.1
作者：
IKEBUCHI, K;WONG, GG;OGAWA, M
通讯作者：
OGAWA, M
影响因子：
5.4
作者：
Mainiero, F;Colombara, M;Ramarli, D
通讯作者：
Ramarli, D
影响因子：
5.2
作者：
Humphrey, RK;Beattie, GM;Hayek, A
通讯作者：
Hayek, A