Restoration of retinal regenerative potential of Müller glia by disrupting intercellular Prox1 transfer

Eun Jung Lee, Museong Kim, Sooyeon Park, Ji Hyeon Shim, Hyun-Ju Cho, Jung Ah Park, Kihyun Park, Dongeun Lee, Jeong Hwan Kim, Haeun Jeong, Fumio Matsuzaki, Seon-Young Kim, Jaehoon Kim, Hanseul Yang, Jeong-Soo Lee and Jin Woo Kim ()
Additional contact information
Eun Jung Lee: Korea Advanced Institute of Science and Technology (KAIST)
Museong Kim: Korea Advanced Institute of Science and Technology (KAIST)
Sooyeon Park: Korea Advanced Institute of Science and Technology (KAIST)
Ji Hyeon Shim: Celliaz Ltd.
Hyun-Ju Cho: Korea Research Institute of Bioscience and Biotechnology
Jung Ah Park: Celliaz Ltd.
Kihyun Park: Korea Advanced Institute of Science and Technology (KAIST)
Dongeun Lee: Korea Advanced Institute of Science and Technology (KAIST)
Jeong Hwan Kim: Korea Research Institute of Bioscience and Biotechnology
Haeun Jeong: Korea Advanced Institute of Science and Technology (KAIST)
Fumio Matsuzaki: RIKEN Centre for Biosystems Dynamics Research
Seon-Young Kim: Korea Research Institute of Bioscience and Biotechnology
Jaehoon Kim: Korea Advanced Institute of Science and Technology (KAIST)
Hanseul Yang: Korea Advanced Institute of Science and Technology (KAIST)
Jeong-Soo Lee: Korea Research Institute of Bioscience and Biotechnology
Jin Woo Kim: Korea Advanced Institute of Science and Technology (KAIST)

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Individuals with retinal degenerative diseases struggle to restore vision due to the inability to regenerate retinal cells. Unlike cold-blooded vertebrates, mammals lack Müller glia (MG)-mediated retinal regeneration, indicating the limited regenerative capacity of mammalian MG. Here, we identify prospero-related homeobox 1 (Prox1) as a key factor restricting this process. Prox1 accumulates in MG of degenerating human and mouse retinas but not in regenerating zebrafish. In mice, Prox1 in MG originates from neighboring retinal neurons via intercellular transfer. Blocking this transfer enables MG reprogramming into retinal progenitor cells in injured mouse retinas. Moreover, adeno-associated viral delivery of an anti-Prox1 antibody, which sequesters extracellular Prox1, promotes retinal neuron regeneration and delays vision loss in a retinitis pigmentosa model. These findings establish Prox1 as a barrier to MG-mediated regeneration and highlight anti-Prox1 therapy as a promising strategy for restoring retinal regeneration in mammals.

Date: 2025
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DOI: 10.1038/s41467-025-58290-8

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