Human Amniotic Epithelial Cells Promote Chx10-/Pax6+ Muller Glia Subpopulation Reprogramming into Photoreceptor-like Cells

Reprogramming Muller glia to regenerate neurons is a promising strategy for treating retinal degeneration, but whether Muller glia contain subpopulations with different regenerative fates remains unclear. Here, using single-cell RNA-seq analysis and Muller glia lineage-tracing mice with retinal degeneration, we reveal that Muller glia were heterogeneous and identify a specific Muller glial subpopulation (Chx10-/Pax6+) in healthy retinas that is activated and migrate to the outer nuclear layer (ONL) during photoreceptor degeneration. Transplantation of human amniotic epithelial cells (hAECs) facilitates the activation and extensive migration of the Chx10-/Pax6+ Muller glial subpopulation to the ONL, where they are reprogrammed into photoreceptor-like cells. Mechanistically, hAECs degrade the inhibitory extracellular matrix through regulating matrix metalloproteinases, which probably induces remodeling of the microenvironment of Muller glia and contributes to cell reprogramming. Consequently, hAEC transplantation improves visual function in rd10 mice. Our findings uncover a distinctive Muller glial subpopulation with the potential for reprogramming into photoreceptors.