The challenge of photoreceptor renewal

Abstract

Light is critical to support life and most living animals have developed photoreceptors to detect it. This relevance is underscored by the presence of stem cells in most multi-cellular animals to replace these neurons in case of injury or disease. However, this capacity is very limited in higher vertebrates, so that neurodegenerative diseases of the retina, like retinitis pigmentosa in humans, or in the retinal degeneration (“rd”) mice, end up in blindness. We have recently shown that rat Muller glial cells (MGC) express the stem cell markers nestin and Pax6, and promote trans-differentiation of photoreceptor progenitors into multipotent stem cells, which in turn, acquire morphological and functional properties of photoreceptors. However, it is not known why MGC are unable to replace photoreceptor loss in the “rd” mice. We investigated this problem by comparing mixed neuron-glia cultures from wild type (wt) and “rd” mice. Nuclear morphology was substantially modified in “rd” MGC: in wt cultures nearly all of their nuclei showed a regular shape and less than 10% of them evidenced indentations. By contrast, in the “rd” cultures the percentage of MGC nuclei having deep indentations doubled. Moreover, nestin expression was reduced from about 80% in cultured wt MGC, to almost 40% in the “rd” cultures. Noteworthy, while in wt cultures each MGC supported about 2 photoreceptor progenitors, this number was 3 times higher in “rd” cultures, thus suggesting that this “overload” in “rd” mice might affect the availability of trophic support for photoreceptors, thus favoring their degeneration. In summary, our results suggest that, in addition to the already known defects in "rd" photoreceptors, the alterations in the structure of MGC and in their crosstalk with photoreceptors might contribute to the loss of photoreceptors and impair their possible renewal.