Retinal regeneration by Lgr5+ amacrine cells in adult mammals

Abstract

Purpose: Like other regions of the central nervous system, the retina is subject to degenerative diseases. Current common knowledge suggests that the retina of adult mammals lacks regenerative capacity. However, the retina of non-mammalian vertebrates, like fish and amphibians, possesses remarkable capacity of regeneration. Two major cell types in these lower vertebrates have been demonstrated to contribute to continuous retinal regeneration: cells of the ciliary marginal zone (CMZ) and Müller glial cells within the neuroretina. However, the CMZ is evolutionarily lost in mammals. Müller cells in mammalian retinas do not proliferate under normal physiological conditions, and they only possess limited regenerative potential in response to injury. Based on the anatomical similarity between the mammalian ciliary body and the lower vertebrate CMZ, a population of pigmented epithelial cells from the ciliary body was identified as the mammalian retinal stem cell a few years ago. Initial observations suggested these cells possess retinal stem cell properties, yet further analysis demonstrated that they could not differentiate into retinal neurons in vitro and in vivo. Therefore, whether the mammalian retina possesses regenerative capacity under normal physiological conditions still remains undetermined and if so, the cellular source that serves as the precursors for retinal regeneration in adulthood is also unknown. The purpose of the current study is to identify retinal cells in adult mammals that possess regenerative capacity and function as the putative adult retinal stem cell.

Methods: To identify the putative adult retinal stem cell, we used a genetic lineage tracing approach.

Results: We demonstrated that Lgr5, an adult stem cell marker in high turnover tissues and organs, is expressed in a subgroup of retinal cells in adult mice. Despite exhibiting features of differentiated retinal amacrine interneurons, these Lgr5+ retinal cells can re-enter the cell cycle, proliferate and generate other retinal lineages, beginning in early adulthood and continuing as the animal ages.

Conclusions: These findings suggest the retina in adult mammals is not devoid of regeneration as previously thought. Rather, it is plastic and Lgr5+ amacrine cells contribute to its homeostatic maintenance, functioning as the putative mammalian adult retinal stem cell. The identification of such cells provides new therapeutic strategies for degenerative retinal diseases.

Keywords: 688 retina • 687 regeneration • 721 stem cells