Interleukin-34 and debris clearance by mononuclear phagocytes drive retinal pigment epithelium regeneration in zebrafish

The retinal pigment epithelium (RPE) surrounds the posterior eye and maintains the health and function of the photoreceptors. Consequently, RPE dysfunction or damage has a devastating impact on vision. Due to complex etiologies, there are currently no cures for patients with RPE degenerative diseases, which remain some of the most prevalent causes of vision loss worldwide. Further, owing to a limited capacity for mammalian tissue repair, we know little about how the RPE regenerates. Here, we utilize zebrafish as a model to uncover novel mechanisms driving intrinsic RPE regeneration. We show that interleukin-34 signaling from damaged RPE is required for precisely timed recruitment of mononuclear phagocytes (MNPs) to the injury site. Additionally, we find that cellular debris clearance by MNPs is indispensable for regeneration, as microglia-deficient zebrafish fail to regenerate RPE and photoreceptor tissues. Together, our results establish specific pro-regenerative functions of MNPs after RPE damage.