The adult retinal stem cell is a rare cell in the ciliary epithelium whose progeny can differentiate into photoreceptors

Abstract

SummarySelf-renewing, multipotential retinal stem cells (RSCs) reside in the pigmented ciliary epithelium of the peripheral retina in adult mammals. RSCs can give rise to rhodopsin positive-cells, which can integrate into early postnatal retina, and represent a potentially useful option for cellular therapy. The ability to purify a stem cell population and direct the differentiation toward a particular cell lineage is a challenge facing the application of stem cells in regenerative medicine. Here we use cell sorting to prospectively enrich mouse RSCs based on size, granularity and low expression of P-cadherin and demonstrate that only rare cells with defined properties proliferate to form colonies. We show that clonally-derived mouse and human RSC progeny are multipotent and can differentiate into mature rhodopsin-positive cells with high efficiency using combinations of exogenous culture additives known to influence neural retinal development, including taurine and retinoic acid. This directed RSC differentiation follows the temporal sequence of photoreceptor differentiation in vivo, and the cells exhibit morphology, protein and gene expression consistent with primary cultures of rods in vitro. These results demonstrate that the RSC, an adult stem cell, can be enriched and directed to produce photoreceptors as a first step toward a targeted cell replacement strategy to treat retinal degenerative disease.

A Hyaluronan-Based Injectable Hydrogel Improves the Survival and Integration of Stem Cell Progeny following Transplantation

“…The observation that RSC-derived rods maintained their post-mitotic phenotype in the absence of taurine/RA suggests that they are terminally differentiated (Figure 3C). By contrast, pan-retinal cultures derived in 1% FBS, which include a significant number of multipotent proliferative progenitors (Ballios et al., 2012), showed similar overall in vitro survival in both HAMC and SFM alone (Figure S4). There was no difference in the proportions of the Rhodopsin-positive population.…”

Adult ciliary epithelial stem cells generate functional neurons and differentiate into both early and late born retinal neurons under non-cell autonomous influences

“…Further characterization revealed that these are a rare population of adult CE cells and unlike progenitors in the embryonic retina they displayed a cardinal feature of stem cells, i.e., they could self-renew [1,3]. The presence of such cells in rodent eyes was re-confirmed [6-11] and the evidence for their presence in postnatal chicken [12], rabbit [13], porcine [14,15], humans [9,16-18] and monkeys [18] emerged, suggesting evolutionary conservation of such cell population in adult vertebrate eyes. Further examination of their properties in rodents showed their relationship with retinal progenitor cells at the transcriptome level [8,19].…”

Importance of the stem cell microenvironment for ophthalmological cell-based therapy

“…They can be induced to differentiate into specific types of neuronal cells in the retina, such as the rod cells, bipolar cells and glial cells, indicating that retinal stem cells exist in adult mammalian eyes. Ballios et al [146] found that retinal stem cells (retinal stem cell, RSC) also exist in the ciliary margin zone in people of different ages. These cells have proliferative capacity in vitro and can be induced to differentiate into different retinal neurons.…”