Title:Leukemia Inhibitory Factor Protects against Degeneration of Cone
Photoreceptors Caused by RPE65 Deficiency
Volume: 31
Issue: 25
Author(s): Shuqian Dong, Fangyuan Zhen, Tongdan Zou, Yongwei Zhou, Jiahui Wu, Ting Wang and Houbin Zhang*
Affiliation:
- The Key Laboratory for Human Disease Gene
Study of Sichuan Province, Center for Medical Genetics, Sichuan Provincial People’s Hospital, University
of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China
- Research Unit for Blindness
Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences
& Sichuan Provincial People’s Hospital, Chengdu, Sichuan 610072, China
Keywords:
LCA, RPE65, rd12 , leukemia inhibitory factor, STAT3, autophagy.
Abstract:
Background: Retinal pigment epithelium (RPE) 65 is a key enzyme in the visual
cycle involved in the regeneration of 11-cis-retinal. Mutations in the human RPE65
gene cause Leber’s congenital amaurosis (LCA), a severe form of an inherited retinal disorder.
Animal models carrying Rpe65 mutations develop early-onset retinal degeneration.
In particular, the cones degenerate faster than the rods. To date, gene therapy has
been used successfully to treat RPE65-associated retinal disorders. However, gene therapy
does not completely prevent progressive retinal degeneration in patients, possibly
due to the vulnerability of cones in these patients. In the present study, we tested
whether leukemia inhibitory factor (LIF), a trophic factor, protects cones in rd12 mice
harboring a nonsense mutation in Rpe65.
Methods: LIF was administered to rd12 mice by intravitreal microinjection. Apoptosis
of retinal cells was analyzed by TUNEL assay. The degeneration of cone cells was evaluated
by immunostaining of retinal sections and retinal flat-mounts. Signaling proteins
regulated by LIF in the retinal and cultured cells were determined by immunoblotting.
Results: Intravitreal administration of LIF activated the STAT3 signaling pathway, thereby
inhibiting photoreceptor apoptosis and preserving cones in rd12 mice. Niclosamide
(NCL), an inhibitor of STAT3 signaling, effectively blocked STAT3 signaling and autophagy
in cultured 661W cells treated with LIF. Co-administration of LIF with NCL to
rd12 mice abolished the protective effect of LIF, suggesting that STAT3 signaling and
autophagy mediate the protection.
Conclusion: LIF is a potent factor that protects cones in rd12 mice. This finding implies
that LIF can be used in combination with gene therapy to achieve better therapeutic outcomes
for patients with RPE65-associated LCA.
