Vegf signaling between Müller glia and vascular endothelial cells is regulated by immune cells and stimulates retina regeneration.
Vegf signaling between Müller glia and vascular endothelial cells is regulated by immune cells and stimulates retina regeneration.
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DOI：
10.1073/pnas.2211690119
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发表时间：
2022-12-13
影响因子：
11.1
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中科院分区：
文献类型：
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视网膜神经元变性是多种致盲性眼病的基础。因此，恢复失去的神经元是视觉科学家的主要目标。一种方法是使用内源性干细胞再生受损的视网膜神经元。与哺乳动物不同，斑马鱼可以再生受损的视网膜。这种再生反应的关键是米勒胶质细胞（MG），这是一种在鱼类和哺乳动物中发现的视网膜细胞类型。了解MG如何在斑马鱼中获得干细胞特性，可能会建议刺激人类MG类似的再生反应的策略。在这里，我们报告说，VEGF信号传导是至关重要的赋予斑马鱼MG干细胞特性，这种信号传导途径连接免疫细胞和血管内皮（VE）细胞与MG重编程和增殖。在斑马鱼视网膜中，Müller胶质细胞（MG）可以再生因损伤或疾病而失去的视网膜神经元。尽管斑马鱼MG与哺乳动物具有相同的结构和功能，但只有在斑马鱼中MG才具有视网膜干细胞的功能。先前的研究表明，垂死的神经元、小胶质细胞/巨噬细胞和T细胞有助于MG的再生反应[白色等人，Proc. Natl. Acad. Sci. U.S.A. 114，E3719（2017）; Hui等人，Dev. Cell 43，659（2017）]。虽然MG终足邻接血管内皮（VE）细胞形成血-视网膜屏障，VE细胞在视网膜再生中的作用尚未探讨。在这里，我们报告MG衍生的Vegfaa和Pgfa参与VE细胞上的Flt 1和Kdrl受体，以调节MG基因表达、Notch信号传导、增殖和神经元再生。值得注意的是，vegfaa和pgfa表达受小胶质细胞/巨噬细胞调节，而MG中的Notch信号传导受VE细胞中的Vegf-dll 4信号传导系统调节。因此，我们的研究将小胶质细胞/巨噬细胞、MG和VE细胞连接在控制MG重编程和增殖的多组分信号通路中。
Degeneration of retinal neurons underlies a variety of blinding eye diseases. Thus, restoring lost neurons is a major goal of vision scientists. One approach is to use endogenous stem cells to regenerate damaged retinal neurons. Unlike mammals, zebrafish can regenerate a damaged retina. Key to this regenerative response are Müller glia (MG), a retinal cell type found in both fish and mammals. Understanding how MG attain stem cell properties in zebrafish may suggest strategies for stimulating a similar regenerative response by human MG. Here, we report that Vegf signaling is critical for imparting zebrafish MG with stem cell properties and that this signaling pathway links immune cells and vascular endothelial (VE) cells with MG reprogramming and proliferation. In the zebrafish retina, Müller glia (MG) can regenerate retinal neurons lost to injury or disease. Even though zebrafish MG share structure and function with those of mammals, only in zebrafish do MG function as retinal stem cells. Previous studies suggest dying neurons, microglia/macrophage, and T cells contribute to MG’s regenerative response [White et al., Proc. Natl. Acad. Sci. U.S.A. 114, E3719 (2017); Hui et al., Dev. Cell 43, 659 (2017)]. Although MG end-feet abut vascular endothelial (VE) cells to form the blood–retina barrier, a role for VE cells in retina regeneration has not been explored. Here, we report that MG-derived Vegfaa and Pgfa engage Flt1 and Kdrl receptors on VE cells to regulate MG gene expression, Notch signaling, proliferation, and neuronal regeneration. Remarkably, vegfaa and pgfa expression is regulated by microglia/macrophages, while Notch signaling in MG is regulated by a Vegf-dll4 signaling system in VE cells. Thus, our studies link microglia/macrophage, MG, and VE cells in a multicomponent signaling pathway that controls MG reprogramming and proliferation.
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影响因子：
--
作者：
Alvarez Y;Cederlund ML;Cottell DC;Bill BR;Ekker SC;Torres-Vazquez J;Weinstein BM;Hyde DR;Vihtelic TS;Kennedy BN
通讯作者：
Kennedy BN
影响因子：
5.3
作者：
Fausett, Blake V.;Gumerson, Jessica D.;Goldman, Daniel
通讯作者：
Goldman, Daniel
影响因子：
4.6
作者：
Krueger, Janna;Liu, Dong;le Noble, Ferdinand
通讯作者：
le Noble, Ferdinand
影响因子：
3.4
作者：
Kassen, Sean C.;Thummel, Ryan;Hyde, David R.
通讯作者：
Hyde, David R.
影响因子：
3.9
作者：
Garhöfer G;Chua J;Tan B;Wong D;Schmidl D;Schmetterer L
通讯作者：
Schmetterer L