Abstract
Purpose: :
Retinal progenitor cells (RPCs) were shown to reside in a quiescent non–proliferative state within the ciliary marginal zone (CMZ) and cliary epithelium (CE) of the adult retina. In this study we asked to determine whether a T–cell based immune modulation, previously shown to be neuroprotective, could induce the proliferation and neuronal differentiation of endogenous RPCs in the adult degenerating retina.
Methods: :
Two established models of retinal injury were used in this study: (i) optic nerve crush and (ii) glutamate eye intoxication. Adult mice were immunized with peptides derived from an uveitogenic retinal protein 7 days prior to the induction of retinal injury. The cell proliferation marker BrdU was injected (i.p.) once daily for 6 days starting at day 3 post injury. Mice were euthanized 1 day or 21 days after the last BrdU injection and their eyes were excised for immunohistochemical analysis.
Results: :
Staining for BrdU revealed substantial proliferation in the CMZ and CE of mice that were immunized with the uveitogenic antigen, while very low numbers of proliferating cells were found in these areas in control (non immunized) mice. Staining for markers of T cells and microglia/macrophages confirmed that the observed proliferating cells in the CMZ and CE of immunized mice were not resident or infiltrating immune cells. Some of the BrdU+ cells in the CMZ and CE also expressed the neuronal progenitor marker Nestin and the neurogenic transcription factor Pax–6, while none of these cells expressed the astrocytic marker GFAP.
Conclusions: :
The findings of this study imply that post injury immune modulation can reverse the inhibition of progenitor cell proliferation imposed by the local microenvironment of the adult retina, and even direct proliferating progenitors to adapt a neuronal fate. We suggest that harnessing the local immune response in a well–controlled manner is a promising approach to boost cell renewal in the adult degenerating retina.
Keywords: retina • differentiation • retinal development