Oshima Kazuo, Teo Dawn Tju Wei, Senn Pascal, Starlinger Veronika, Heller Stefan
Stanford University School of Medicine, Department of Otolaryngology, Head & Neck Surgery, Stanford CA, USA.
BMC Dev Biol. 2007 Oct 12;7:112. doi: 10.1186/1471-213X-7-112.
Stem cells with the ability to form clonal floating colonies (spheres) were recently isolated from the neonatal murine spiral ganglion. To further examine the features of inner ear-derived neural stem cells and their derivatives, we investigated the effects of leukemia inhibitory factor (LIF), a neurokine that has been shown to promote self-renewal of other neural stem cells and to affect neural and glial cell differentiation.
LIF-treatment led to a dose-dependent increase of the number of neurons and glial cells in cultures of sphere-derived cells. Based on the detection of developmental and progenitor cell markers that are maintained in LIF-treated cultures and the increase of cycling nestin-positive progenitors, we propose that LIF maintains a pool of neural progenitor cells. We further provide evidence that LIF increases the number of nestin-positive progenitor cells directly in a cell cycle-independent fashion, which we interpret as an acceleration of neurogenesis in sphere-derived progenitors. This effect is further enhanced by an anti-apoptotic action of LIF. Finally, LIF and the neurotrophins BDNF and NT3 additively promote survival of stem cell-derived neurons.
Our results implicate LIF as a powerful tool to control neural differentiation and maintenance of stem cell-derived murine spiral ganglion neuron precursors. This finding could be relevant in cell replacement studies with animal models featuring spiral ganglion neuron degeneration. The additive effect of the combination of LIF and BDNF/NT3 on stem cell-derived neuronal survival is similar to their effect on primary spiral ganglion neurons, which puts forward spiral ganglion-derived neurospheres as an in vitro model system to study aspects of auditory neuron development.
最近从小鼠新生螺旋神经节中分离出了具有形成克隆性漂浮集落（球体）能力的干细胞。为了进一步研究内耳来源神经干细胞及其衍生物的特征，我们研究了白血病抑制因子（LIF）的作用，LIF是一种神经因子，已被证明可促进其他神经干细胞的自我更新，并影响神经和胶质细胞的分化。
LIF处理导致球体来源细胞培养物中神经元和胶质细胞数量呈剂量依赖性增加。基于对LIF处理培养物中维持的发育和祖细胞标志物的检测以及循环中巢蛋白阳性祖细胞的增加，我们提出LIF维持了神经祖细胞池。我们进一步提供证据表明，LIF以细胞周期非依赖性方式直接增加巢蛋白阳性祖细胞的数量，我们将其解释为球体来源祖细胞中神经发生的加速。LIF的抗凋亡作用进一步增强了这种效应。最后，LIF与神经营养因子BDNF和NT3协同促进干细胞来源神经元的存活。
我们的结果表明LIF是控制干细胞来源的小鼠螺旋神经节神经元前体神经分化和维持的有力工具。这一发现可能与以螺旋神经节神经元变性为特征的动物模型的细胞替代研究相关。LIF与BDNF/NT3组合对干细胞来源神经元存活的协同作用与其对原代螺旋神经节神经元的作用相似，这提出了螺旋神经节来源的神经球作为研究听觉神经元发育方面的体外模型系统。
