Trophic Factors and Neuronal Interactions Regulate the Cell Cycle and Pax6 Expression in Müller Stem Cells

INSUA MF; SIMON V.; GARELLI A; DE LOS SANTOS EB; ROTSTEIN N.P.*; POLITI L.E.

JOURNAL OF NEUROSCIENCE RESEARCH

Wiley Interscience-Blackwell

Año: 2008 vol. 86 p. 1459 - 1471

0360-4012

  The finding that Muller cells have stem cell properties in the retina has led to the hypothesis that they might be a source for replacing neurons lost in neurodegenerative diseases. However, utilization of Muller cells for regenerative purposes in the mammalian eye still requires identifying those factors that regulate their multipotentiality and proliferation. In addition, since Pax6 expression is indispensable for eye development, its regulation would be required during regeneration. We here investigated the regulation of cell cycle progression and Pax6 expression in pure Muller glial cell cultures and neuroglia co-cultures from rat retina. At early times in vitro glial cells showed a high expression of Pax6 and nestin, a stem cell marker, and of cell cycle progression markers; these markers decreased during development, in parallel with the increase of glial differentiation. Addition of glial derived neurotrophic factor (GDNF), basic fibroblast growth factor (bFGF) and insulin restored proliferation and also Pax6 and nestin expression. Noteworthy, in neuroglia co-cultures Muller cells retained Pax6 expression for longer periods and, in turn, neuroblasts preserved their proliferative potential for several days in vitro. This suggests that neuro-glial interactions mutually regulate their mitogenic capacity. In addition, in glial secondary cultures incubated with insulin, many neuroblast-like cells expressed the neuronal marker Neu-N. Our results imply that the proliferative capacity and the features of eye stem cells of Muller glial cells might be regulated by molecular and cellular factors, which might then provide potential tools for manipulating retina regeneration.