Zhang Jianing, Li Wanhong, Xiong Zhen, Zhu Juanhua, Ren Xiangrong, Wang Shasha, Kuang Haiqing, Lin Xianchai, Mora Antonio, Li Xuri
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, Guangdong, China.
Joint School of Life Sciences, Guangzhou Medical University and Guangzhou Institutes of Biomedicine and Health (Chinese Academy of Sciences), Xinzao, Panyu district, Guangzhou 511436, Guangdong, China.
Comput Struct Biotechnol J. 2023 Mar 28;21:2405-2418. doi: 10.1016/j.csbj.2023.03.047. eCollection 2023.
Platelet-derived growth factor-D (PDGF-D) is abundantly expressed in ocular diseases. Yet, it remains unknown whether and how PDGF-D affects ocular cells or cell-cell interactions in the eye. In this study, using single-cell RNA sequencing (scRNA-seq) and a mouse model of PDGF-D overexpression in retinal pigment epithelial (RPE) cells, we found that PDGF-D overexpression markedly upregulated the key immunoproteasome genes, leading to increased antigen processing/presentation capacity of RPE cells. Also, more than 6.5-fold ligand-receptor pairs were found in the PDGF-D overexpressing RPE-choroid tissues, suggesting markedly increased cell-cell interactions. Moreover, in the PDGF-D-overexpressing tissues, a unique cell population with a transcriptomic profile of both stromal cells and antigen-presenting RPE cells was detected, suggesting PDGF-D-induced epithelial-mesenchymal transition of RPE cells. Importantly, administration of ONX-0914, an immunoproteasome inhibitor, suppressed choroidal neovascularization (CNV) in a mouse CNV model . Together, we show that overexpression of PDGF-D increased pro-angiogenic immunoproteasome activities, and inhibiting immunoproteasome pathway may have therapeutic value for the treatment of neovascular diseases.
血小板衍生生长因子-D（PDGF-D）在眼部疾病中大量表达。然而，PDGF-D是否以及如何影响眼内细胞或细胞间相互作用仍不清楚。在本研究中，我们使用单细胞RNA测序（scRNA-seq）以及视网膜色素上皮（RPE）细胞中PDGF-D过表达的小鼠模型，发现PDGF-D过表达显著上调关键免疫蛋白酶体基因，导致RPE细胞的抗原加工/呈递能力增强。此外，在过表达PDGF-D的RPE-脉络膜组织中发现了超过6.5倍的配体-受体对，表明细胞间相互作用显著增加。此外，在过表达PDGF-D的组织中，检测到一个具有基质细胞和抗原呈递RPE细胞转录组特征的独特细胞群体，提示PDGF-D诱导RPE细胞发生上皮-间质转化。重要的是，给予免疫蛋白酶体抑制剂ONX-0914可抑制小鼠脉络膜新生血管（CNV）模型中的脉络膜新生血管形成。总之，我们表明PDGF-D过表达增加了促血管生成免疫蛋白酶体活性，抑制免疫蛋白酶体途径可能对治疗新生血管疾病具有治疗价值。
