Abstract
BackgroundThe persistence in adult teleost fish of retinal stem cells that exhibit all of the features of true 'adult stem cells' – self-renewal, multipotency, and the capacity to respond to injury by mitotic activation with the ability to regenerate differentiated tissues – has been known for several decades. However, the specialized cellular and molecular characteristics of these adult retinal stem cells and the microenvironmental niches that support their maintenance in the differentiated retina and regulate their activity during growth and regeneration have not yet been elucidated.ResultsOur data show that the zebrafish retina has two kinds of specialized niches that sustain retinal stem cells: 1) a neuroepithelial germinal zone at the interface between neural retina and ciliary epithelium, called the ciliary marginal zone (CMZ), a continuous annulus around the retinal circumference, and 2) the microenvironment around some Müller glia in the differentiated retina. In the uninjured retina, scattered Müller glia (more frequently those in peripheral retina) are associated with clusters of proliferating retinal progenitors that are restricted to the rod photoreceptor lineage, but following injury, the Müller-associated retinal progenitors can function as multipotent retinal stem cells to regenerate other types of retinal neurons. The CMZ has several features in common with the neurogenic niches in the adult mammalian brain, including access to the apical epithelial surface and a close association with blood vessels. Müller glia in the teleost retina have a complex response to local injury that includes some features of reactive gliosis (up-regulation of glial fibrillary acidic protein, GFAP, and re-entry into the cell cycle) together with dedifferentiation and re-acquisition of phenotypic and molecular characteristics of multipotent retinal progenitors in the CMZ (diffuse distribution of N-cadherin, activation of Notch-Delta signaling, and expression of rx1, vsx2/Chx10, and pax6a) along with characteristics associated with radial glia (expression of brain lipid binding protein, BLBP). We also describe a novel specific marker for Müller glia, apoE.ConclusionThe stem cell niches that support multi-lineage retinal progenitors in the intact, growing and regenerating teleost retina have properties characteristic of neuroepithelia and neurogenic radial glia. The regenerative capacity of the adult zebrafish retina with its ability to replace lost retinal neurons provides an opportunity to discover the molecular regulators that lead to functional repair of damaged neural tissue.
Highlights
The persistence in adult teleost fish of retinal stem cells that exhibit all of the features of true 'adult stem cells' – self-renewal, multipotency, and the capacity to respond to injury by mitotic activation with the ability to regenerate differentiated tissues – has been known for several decades
Molecular profile of retinal stem cells and progenitor cells in the zebrafish CMZ The initial differentiation of retinal neurons and formation of retinal laminae in zebrafish is completed by the end of embryonic development at 3 days post-fertilization, after which proliferating retinal progenitors are concentrated in a germinal zone at the peripheral margins of the retina in a wedge of cells formed by the converging retinal laminae, called the ciliary marginal zone, CMZ (Fig. 1A)
We found that zebrafish apoE is expressed selectively and at high levels in gfap: green fluorescent protein (GFP)+ differentiated Müller glia, and the signal is largely confined to the cell bodies in the inner nuclear layer (INL) (Fig. 5E)
Summary
The persistence in adult teleost fish of retinal stem cells that exhibit all of the features of true 'adult stem cells' – self-renewal, multipotency, and the capacity to respond to injury by mitotic activation with the ability to regenerate differentiated tissues – has been known for several decades. Some common features of neural stem cells and their niches include: prominent cadherin-mediated adhesive junctions, a rich extracellular matrix and contact with a specialized basal lamina via integrin-mediated junctions, close association with blood vessels, cell-surface carbohydrate markers (e.g., stage-specific embryonic antigen-1, SSEA-1, called Lewis X, LeX or leukocyte cluster of differentiation 15, CD15), expression of BLBP (brain lipid binding protein, encoded by the gene brain-type fatty-acid binding protein 7, FABP7), expression of selected classes of intermediate filament proteins (e.g., nestin), responsiveness to extrinsic signals such as IGF (insulin-like growth factor), TGFβ/BMP (transforming growth factorβ/bone morphogenetic protein) family, Wnts, Shh (sonic hedgehog), Notch, and LIF (leukemia inhibitory factor) Not coincidentally, these extrinsic regulators represent all of the major families of signaling pathways that are essential for early embryonic development [14]
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