Cao Jing, Yang Rong, Smith Taylor E, Evans Stephanie, McCollum Gary W, Pomerantz Steven C, Petley Theodore, Harris Ian R, Penn John S
Janssen Research & Development, LLC, Spring House, PA 19477, USA.
Department of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Mol Ther Methods Clin Dev. 2019 May 22;14:37-46. doi: 10.1016/j.omtm.2019.05.007. eCollection 2019 Sep 13.
Exudative age-related macular degeneration (AMD), characterized by choroidal neovascularization (CNV), is the leading cause of irreversible blindness in developed countries. Anti-vascular endothelial growth factor (VEGF) drugs are the standard treatment for AMD, but they have limitations. Cell therapy is a promising approach for ocular diseases, and it is being developed in the clinic for the treatment of retinal degeneration, including AMD. We previously showed that subretinal injection of human umbilical tissue-derived cells (hUTCs) in a rodent model of retinal degeneration preserved photoreceptors and visual function through rescue of retinal pigment epithelial (RPE) cell phagocytosis. Here we investigated the effect of hUTCs on a rat model of laser-induced CNV and on a human RPE cell line, ARPE-19, for VEGF production. We demonstrate that subretinal injection of hUTCs significantly inhibited CNV and lowered choroidal VEGF . VEGF release from ARPE-19 decreased when co-cultured with hUTCs. Soluble VEGF receptor 1 (sVEGFR1) is identified as the only factor in hUTC conditioned medium (CM) that binds to VEGF. The level of exogenous recombinant VEGF in hUTC CM was dramatically reduced and could be recovered with sVEGFR1-neutralizing antibody. This suggests that hUTC inhibits angiogenesis through the secretion of sVEGFR1 and could serve as a novel treatment for angiogenic ocular diseases, including AMD.
渗出性年龄相关性黄斑变性（AMD）以脉络膜新生血管（CNV）为特征，是发达国家不可逆性失明的主要原因。抗血管内皮生长因子（VEGF）药物是AMD的标准治疗方法，但存在局限性。细胞疗法是治疗眼部疾病的一种有前景的方法，目前正在临床中开发用于治疗包括AMD在内的视网膜变性。我们之前在视网膜变性的啮齿动物模型中表明，视网膜下注射人脐组织来源的细胞（hUTC）可通过挽救视网膜色素上皮（RPE）细胞吞噬作用来保留光感受器和视觉功能。在此，我们研究了hUTC对激光诱导的CNV大鼠模型以及对人RPE细胞系ARPE-19产生VEGF的影响。我们证明视网膜下注射hUTC可显著抑制CNV并降低脉络膜VEGF。与hUTC共培养时，ARPE-19释放的VEGF减少。可溶性VEGF受体1（sVEGFR1）被确定为hUTC条件培养基（CM）中唯一与VEGF结合的因子。hUTC CM中外源重组VEGF的水平显著降低，并且可以用sVEGFR1中和抗体恢复。这表明hUTC通过分泌sVEGFR1抑制血管生成，并且可以作为包括AMD在内的血管生成性眼部疾病的一种新的治疗方法。
