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  • Title: Modulation of osmotic stress-induced TRPV1 expression rescues human iPSC-derived retinal ganglion cells through PKA.
    Author: Hsu CC, Chien KH, Yarmishyn AA, Buddhakosai W, Wu WJ, Lin TC, Chiou SH, Chen JT, Peng CH, Hwang DK, Chen SJ, Chang YL.
    Journal: Stem Cell Res Ther; 2019 Sep 23; 10(1):284. PubMed ID: 31547874.
    Abstract:
    BACKGROUND: Transient receptor potential vanilloid 1 (TRPV1), recognized as a hyperosmolarity sensor, is a crucial ion channel involved in the pathogenesis of neural and glial signaling. Recently, TRPV1 was determined to play a role in retinal physiology and visual transmission. In this study, we sought to clarify the role of TRPV1 and the downstream pathway in the osmotic stress-related retina ganglion cell (RGC) damage. METHODS: First, we modified the RGC differentiation protocol to obtain a homogeneous RGC population from human induced pluripotent stem cells (hiPSCs). Subsequently, we induced high osmotic pressure in the hiPSC-derived RGCs by administering NaCl solution and observed the behavior of the TRPV1 channel and its downstream cascade. RESULTS: We obtained a purified RGC population from the heterogeneous retina cell population using our modified method. Our findings revealed that TRPV1 was activated after 24 h of NaCl treatment. Upregulation of TRPV1 was noted with autophagy and apoptosis induction. Downstream protein expression analysis indicated increased phosphorylation of CREB and downregulated brain-derived neurotrophic factor (BDNF). However, hyperosmolarity-mediated defective morphological change and apoptosis of RGCs, CREB phosphorylation, and BDNF downregulation were abrogated after concomitant treatment with the PKA inhibitor H89. CONCLUSION: Collectively, our study results indicated that the TRPV1-PKA pathway contributed to cellular response under high levels of osmolarity stress; furthermore, the PKA inhibitor had a protective effect on RGCs exposed to this stress. Therefore, our findings may assist in the treatment of eye diseases involving RGC damage.
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