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TISSUE-SPECIFIC STEM CELLS

Epidermal Growth Factor Is a Neuronal Differentiation Factor for Retinal Stem Cells In Vitro

^a Unit of Gene Therapy and Stem Cell Biology, Jules Gonin Eye Hospital, Lausanne, Switzerland;
^b Department of Ophthalmology, University of Lausanne, Lausanne, Switzerland;
^c Institute of Research in Ophthalmology, Sion, Switzerland

Key Words. Radial glia • Cell competence • Retinal ganglion cells • Neurogenesis • Retinal progenitor cell

Correspondence: Yvan Arsenijevic, Ph.D., Unit of Gene Therapy and Stem Cell Biology, Jules Gonin Eye Hospital, 15, av. de France, 1004 Lausanne, Switzerland. Telephone: +41-21-626-82-60; Fax: +41-21-626-88.88; e-mail: yvan.arsenijevic{at}ophtal.vd.ch

Received April 25, 2005; accepted for publication September 11, 2005.
Stem cells are a tool for in vitro elucidation of the putative role of factors on cell fate. Herein we analyze the role of epidermal growth factor (EGF) on progeny derived from retinal stem cells (RSCs). We isolated cells from neuroretinas of neonate mice. All the proliferating cells harbored the radial glia marker RC2, expressed transcription factors usually found in radial glia (Mash1, Pax6), and met the criteria of stem cells: high capacity of expansion, maintenance of an undifferentiated state, and multipotency demonstrated by clonal analysis. We analyzed the differentiation 7 days after transfer of the cells in different culture media. In absence of serum, EGF led to the expression of the neuronal marker ß-tubulin-III and acquisition of neuronal morphology in 15% of the cells. Analysis of cell proliferation by bromodeoxyuridine incorporation revealed that EGF mainly induced the formation of neurons without stimulating cell cycle progression. Moreover, a pulse of 2-hour EGF stimulation was sufficient to induce neuronal differentiation. Some neurons were committed to the retinal ganglion cell (RGC) phenotype, as revealed by the expression of retinal ganglion markers (Ath5, Brn3b, and melanopsin) and in a few cases to other retinal phenotypes (photoreceptors [PRs] and bipolar cells). We confirmed that the late RSCs were not restricted over time and that they conserved their multipotency by generating retinal phenotypes that usually appear at early (RGC) or late (PRs) developmental stages. Our results show that EGF is not only a factor controlling glial development, as previously shown, but also a potent differentiation factor for retinal neurons, at least in vitro.

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