Forced p27 Suppression Synergizes with Cyclin D1 Overexpression to Stimulate Mammalian Müller Glia Proliferation and Reprogramming


Student thesis: Doctoral Thesis

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Award date31 Aug 2023


In humans, retinal degenerative diseases or age-related diseases, such as glaucoma, retinitis pigmentosa (RP), and age-related macular degeneration (AMD), lead to the death of retinal neurons and irreversible vision loss. An ideal treatment approach would involve mobilizing endogenous retinal stem or progenitor cells to regenerate lost neurons. Müller glia (MG), the primary glial cell type in the retina, possesses regenerative potential that could be harnessed for retinal repair in response to injury or retinal degenerative disease. In this thesis, I aimed to promote MG proliferation and reprogramming by manipulating two cell cycle regulators in mouse retinas.

First, I found that both high level of cyclin-dependent kinase (CDKs) inhibitor p27 and low level of cyclin D1 are the road blockers preventing MG from re-entering the cell cycle, as knocking down p27 or overexpressing cyclin D1 stimulated the proliferation of small amounts of MG in uninjured mouse retina. Importantly, the combination of p27 knockdown and cyclin D1 overexpression (referred to as cell cycle activator, CCA) showed a strong synergistic effect, inducing more than half of MG to re-enter the cell cycle. Subsequently, I used single cell transcriptome profiling combined with histological analysis to demonstrate that CCA could induce MG proliferation and reprogram MG into neurogenic, rod-like, and bipolar cells. I then further tested the safety of CCA treatment, and after one year of CCA treatment, no tumors developed, and retinal structure and visual function were normal compared to the control eyes. Together, my findings suggest a novel and viable strategy to awaken the proliferative and neurogenic potential of MG in the retina of adult mammals by directly targeting cell cycle regulators.