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Theranostics 2023; 13(5):1698-1715. doi:10.7150/thno.79538 This issue Cite

Research Paper

Repopulated retinal microglia promote Müller glia reprogramming and preserve visual function in retinal degenerative mice

Xuan Cheng^1,2,3#, Hui Gao^2,3#, Zui Tao^2,3#, Zhiyuan Yin^2,3, Zhe Cha^2,3, Xiaona Huang^2,3, Yikui Zhang⁴, Yuxiao Zeng^2,3, Juncai He^2,3, Lingling Ge^2,3, Luodan A^2,3, Haiwei Xu^2,3✉, Guang-Hua Peng^1,5✉

1. Department of Ophthalmology, First medical center of Chinese PLA General Hospital, Beijing, 100853, China.
2. Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.
3. Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China.
4. The Eye Hospital, School of Ophthalmology & Optometry, Wenzhou Medical University, Wenzhou 325027, China.
5. Lab of Visual Cell Differentiation and Regulation, Basic Medical College, Zhengzhou University, Zhengzhou, China.
^# These authors contributed equally to this work.

✉ Corresponding authors: Haiwei Xu (xuhaiweiedu.cn) and Guang-Hua Peng (ghpedu.cn).

Abstract

Rationale: Müller glia (MG) play a key role in maintaining homeostasis of the retinal microenvironment. In zebrafish, MG reprogram into retinal progenitors and repair the injured retina, while this MG regenerative capability is suppressed in mammals. It has been revealed that microglia in zebrafish contribute to MG reprogramming, whereas those in mammals are over-activated during retinal injury or degeneration, causing chronic inflammation, acceleration of photoreceptor apoptosis, and gliosis of MG. Therefore, how to modulate the phenotype of microglia to enhance MG reprogramming rather than gliosis is critical.

Methods: PLX3397, a colony-stimulating factor 1 receptor inhibitor, was applied to deplete microglia in the retinas of retinal degeneration 10 (rd10) mice, and withdrawal of PLX3397 was used to induce the repopulated microglia (Rep-MiG). The protective roles of the Rep-MiG on the degenerative retina were assessed using a light/dark transition test, and scotopic electroretinogram recordings. Immunofluorescence, western blot, transcriptomic sequencing, and bioinformatics analysis were performed to investigate the effects and mechanisms of microglia on MG reprogramming.

Results: Following PLX3397 withdrawal, Rep-MiG replenished the entire retina with a ramified morphology and significantly improved the retinal outer nuclear layer structure, the electroretinography response, and the visual behavior of rd10 mice. Coincidentally, MG were activated, de-differentiated, and showed properties of retina progenitors in a spatial correlation with Rep-MiG. Morphological and transcriptomic analyses revealed Rep-MiG significantly enhanced protease inhibitor activity and suppressed extracellular matrix (ECM) levels during retinal degeneration.

Conclusions: It suggested that Rep-MiG with the homeostasis characteristic stimulated the progenitor cell-like properties of MG, probably through regulating ECM remodeling, which protected photoreceptors and improved visual function of rd10 mice. It might be a potential protocol to reprogram MG and delay mammal retinal degeneration.

Keywords: Microglia, Müller glia, reprogramming, repopulation, extracellular matrix

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