Editors' ChoiceRetinal Disease

Reprogramming to help the old see like the young

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Science Translational Medicine  16 Dec 2020:
Vol. 12, Issue 574, eabf7738
DOI: 10.1126/scitranslmed.abf7738

Abstract

Transcription factors associated with pluripotency restore molecular and functional characteristics resembling youth in aged mouse retinal ganglion cells.

The molecular programs that specify cellular fate and function are slowly eroded during natural aging. Essential cells that are attenuated with age are retinal ganglion cells (RGCs), which form the optic nerve and confer eyesight. In aging, RGCs lose regenerative potential, and there are no therapies that restore RGCs after optic nerve damage.

To address this issue, Lu and colleagues utilized ectopic expression of Oct4, Sox2, and Klf4 genes (OSK), which encode transcription factors associated with pluripotency, to reprogram aged murine fibroblasts. They observed that transient expression of OSK induced transcriptomes similar to young fibroblasts without a loss of cell identity. The authors next evaluated the safety of persistent OSK expression in RGCs in vivo using murine models and found no tumor formation or change in overall health. To determine if OSK expression in RGCs could revert loss of regenerative potential in aging, Lu et al. employed an optic-nerve crush-injury mouse model and induced OSK expression followed by injury and quantification of axonal regeneration. The authors observed that only the combination of all 3 factors promoted regeneration and increased RGC survival, while individual or combinations of two factors partially promoted regeneration.

To understand the underlying molecular mechanisms, Lu et al. quantified DNA methylation at sites that correlated strongly with aging and observed that injured RGCs increase DNA methylation in a manner akin to aging. OSK induction prevented this effect through two enzymes that remove DNA methylation, Tet1 and Tet2. To further evaluate if OSK induction could re-establish RGC function and vision loss, the authors administered the reprogramming system to murine models of glaucoma and aging and observed increased axonal density, visual acumen, and opto-motor responses. RGCs from aged mice treated with OSK also displayed changes in DNA methylation at loci associated with synaptic and neuronal processes.

Additional studies are needed to determine if other conditions are also permissible for reprogramming such as Alzheimer’s disease, osteoporosis, and sarcopenia. The stability of the rejuvenative effect after OSK expression is turned off, also needs to be established. These results suggest that epigenetic reprogramming may be a promising strategy for reverting aged-induced pathologies.

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