LIF promotes neurogenesis and maintains neural precursors in cell populations derived from spiral ganglion stem cells.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Oshima
Kazuo
K
Stanford University School of Medicine, Department of Otolaryngology, Head & Neck Surgery, Stanford CA, USA. oshimak@stanford.edu
Teo
Dawn Tju Wei
DT
Senn
Pascal
P
Starlinger
Veronika
V
Heller
Stefan
S
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D002454:Cell Differentiation; D002469:Cell Separation; D005452:Fluoresceins; D005456:Fluorescent Dyes; D007150:Immunohistochemistry; D053605:Leukemia Inhibitory Factor / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009024:Morphogenesis; D020933:Neurotrophin 3 / Q000235:genetics; D013136:Spiral Ganglion / Q000166:cytology* / Q000254:growth & development; D013234:Stem Cells / Q000166:cytology*; D013388:Succinimides
C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D019208:Brain-Derived Neurotrophic Factor; D005452:Fluoresceins; D005456:Fluorescent Dyes; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D020933:Neurotrophin 3; D013388:Succinimides