Title:Leukemia Inhibitory Factor Protects against Degeneration of Cone
Photoreceptors Caused by RPE65 Deficiency
Volume: 31
Issue: 25
关键词:
LCA, RPE65, rd12，白血病抑制因子，STAT3，自噬。
摘要:
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.
