Characterization of Senescence and SASP in Zebrafish Retina Regeneration

Abstract

Regeneration of the retina is critical for the restoration of vision after loss of retinal neurons, however most mammals lack the ability to regenerate the retina after damage. Zebrafish have innate regenerative potential, making them ideal candidates for studying and understanding retina regeneration. Senescence is a biological process that can exist as both a damage response and a response to cellular aging. After acute NMDA damage, senescent immune cells are detectable within 2-3 days post injury, but are then cleared as retina regeneration concludes. The transient appearance and clearance of senescent cells is crucial because premature clearance of senescent cells inhibits regeneration. To determine the function of senescent cells during regeneration, we analyzed their secretomes and identified a conserved 31 factor gene signature that includes many regulators of inflammation and pro-regenerative factors. Among these, depletion of the chromatin modifier npm1a was found to inhibit regeneration. Lastly, depletion of the alternative splicing factor ptbp1a was found to induce senescence and enhance retina regeneration. Together, this thesis demonstrates a crucial role for senescence in the modulation of inflammation and stemness.