Glial cell line-derived neurotrophic factor promotes increased phenotypic marker expression in femoral sensory and motor-derived Schwann cell cultures.
Glial cell line-derived neurotrophic factor promotes increased phenotypic marker expression in femoral sensory and motor-derived Schwann cell cultures.
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DOI：
10.1016/j.expneurol.2014.04.005
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发表时间：
2014-07
影响因子：
5.3
通讯作者：
Sakiyama-Elbert, Shelly E.
中科院分区：
文献类型：
--
作者：
Jesuraj, Nithya J.;Marquardt, Laura M.;Kwasa, Jasmine A.;Sakiyama-Elbert, Shelly E.
雪旺细胞（SC）分泌生长因子和细胞外基质分子，促进神经元存活并在再生过程中帮助引导轴突。干细胞移植是促进周围神经再生的一种很有前途的策略。然而，我们和其他人已经表明，在长期体外扩增后，SC恢复到去分化状态，类似于损伤后观察到的表型。在体内，胶质细胞源性神经营养因子（GDNF）可以引导干细胞分化为髓鞘再生轴突。因此，我们推测外源性GDNF可能通过刺激GDNF家族受体（GFR）α-1在体外引导SC向其天然表型分化。当在SC中激活时，GFRα-1促进Fyn的磷酸化，Fyn是一种Src家族酪氨酸激酶，负责介导分化和增殖的下游信号传导。在这项研究中，从大鼠股神经的感觉和运动分支收获的SC在体外扩增，然后用50或100 ng/mL的GDNF培养。外源性GDNF促进感觉和运动源性SC分化回其天然表型，如7天后增殖减少和S100 B β和表型特异性标记物表达增加所示。此外，用Src家族激酶抑制剂PP 2和SU 6656抑制Fyn，以及siRNA介导的Fyn敲低减少了GDNF刺激的感觉和运动源性SC的分化。这些结果表明，激活Fyn是必需的GDNF刺激的分化的股神经源性干细胞在体外进入其天然表型。因此，GDNF可以被纳入到基于SC的治疗中，以促进SC向其天然表型的分化，从而改善功能性神经再生。
Schwann cells (SCs) secrete growth factors and extracellular matrix molecules that promote neuronal survival and help guide axons during regeneration. Transplantation of SCs is a promising strategy for enhancing peripheral nerve regeneration. However, we and others have shown that after long-term in vitro expansion, SCs revert to a de-differentiated state similar to the phenotype observed after injury. In vivo, glial cell-line derived neurotrophic factor (GDNF) may guide the differentiation of SCs to remyelinate regenerating axons. Therefore, we hypothesized that exogenous GDNF may guide the differentiation of SCs into their native phenotypes in vitro through stimulation of GDNF family receptor (GFR)α-1. When activated in SCs, GFRα-1 promotes phosphorylation of Fyn, a Src family tyrosine kinase responsible for mediating downstream signaling for differentiation and proliferation. In this study, SCs harvested from the sensory and motor branches of rat femoral nerve were expanded in vitro and then cultured with 50 or 100 ng/mL of GDNF. The exogenous GDNF promoted differentiation of sensory and motor-derived SCs back to their native phenotypes, as demonstrated by decreased proliferation after 7 days and increased expression of S100Bβ and phenotype-specific markers. Furthermore, inhibiting Fyn with Src family kinase inhibitors, PP2 and SU6656, and siRNA-mediated knockdown of Fyn reduced GDNF-stimulated differentiation of sensory and motor-derived SCs. These results demonstrate that activating Fyn is necessary for GDNF-stimulated differentiation of femoral nerve-derived SCs into their native phenotypes in vitro. Therefore GDNF could be incorporated into SC-based therapies to promote differentiation of SCs into their native phenotype to improve functional nerve regeneration.
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DOI：
10.1523/jneurosci.2973-12.2013
发表时间：
2013-03-27
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Deng LX;Deng P;Ruan Y;Xu ZC;Liu NK;Wen X;Smith GM;Xu XM
通讯作者：
Xu XM
影响因子：
2.1
作者：
Brenner, MJ;Lowe, JB;Mohanakumar, T
通讯作者：
Mohanakumar, T
影响因子：
2.1
作者：
Aszmann, Oskar C.;Korak, Klaus J.;Frey, Manfred
通讯作者：
Frey, Manfred
影响因子：
2.4
作者：
Costigan M;Befort K;Karchewski L;Griffin RS;D'Urso D;Allchorne A;Sitarski J;Mannion JW;Pratt RE;Woolf CJ
通讯作者：
Woolf CJ
影响因子：
3.5
作者：
Grimm, L;Holinski-Feder, E;Ueffing, M
通讯作者：
Ueffing, M