Sphingosine-1-phosphate signaling regulates the ability of Müller glia to become neurogenic, proliferating progenitor-like cells

The purpose of these studies is to investigate how Sphingosine-1-phosphate
(S1P) signaling regulates glial phenotype, dedifferentiation of Müller
glia (MG), reprogramming into proliferating MG-derived progenitor cells
(MGPCs), and neuronal differentiation of the progeny of MGPCs in the chick
retina. We found that S1P-related genes are highly expressed by retinal
neurons and glia, and levels of expression were dynamically regulated
following retinal damage. Drug treatments that activate S1P receptor 1
(S1PR1) or increase levels of S1P suppressed the formation of MGPCs.
Conversely, treatments that inhibit S1PR1 or decrease levels of S1P
stimulated the formation of MGPCs. Inhibition of S1P receptors or S1P
synthesis significantly enhanced the neuronal differentiation of the
progeny of MGPCs. We report that S1P-related gene expression in MG is
modulated by microglia and inhibition of S1P receptors or S1P synthesis
partially rescues the loss of MGPC formation in damaged retinas missing
microglia. Finally, we show that TGFβ/Smad3 signaling in the resting
retina maintains S1PR1 expression in MG. We conclude that the S1P
signaling is dynamically regulated in MG and MGPCs in the chick retina,
and activation of S1P signaling depends, in part, on signals produced by
reactive microglia.

本研究旨在探究1-磷酸鞘氨醇（Sphingosine-1-phosphate, S1P）信号通路如何调控鸡视网膜中的米勒胶质细胞（Müller glia, MG）表型、米勒胶质细胞去分化、重编程为增殖性米勒胶质细胞源性祖细胞（MGPCs），以及祖细胞子代的神经元分化。研究发现，视网膜神经元与胶质细胞可高表达S1P相关基因，且其表达水平在视网膜损伤后呈动态调控模式。激活S1P受体1（S1PR1）或提升S1P水平的药物处理可抑制MGPCs的形成；反之，抑制S1PR1或降低S1P水平的处理则会促进MGPCs的生成。抑制S1P受体或S1P合成，可显著增强MGPCs子代的神经元分化能力。本研究证实，米勒胶质细胞中的S1P相关基因表达受小胶质细胞调控；而抑制S1P受体或S1P合成，可部分挽救缺失小胶质细胞的受损视网膜中MGPCs形成的缺陷。最后，本研究发现静息状态视网膜中的转化生长因子β/Smad3（TGFβ/Smad3）信号通路可维持米勒胶质细胞中S1PR1的表达。综上，鸡视网膜内米勒胶质细胞与MGPCs中的S1P信号通路呈动态调控状态，且S1P信号通路的激活一定程度上依赖于反应性小胶质细胞产生的信号。