Department of Ophthalmology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Department of Chemical and Biomolecular Engineering, Institute for NanoBioTechnology, Johns Hopkins University Baltimore, Maryland, USA.
JCI Insight. 2020 Mar 26;5(6):131828. doi: 10.1172/jci.insight.131828.
Ischemic retinopathies are major causes of blindness worldwide. Local hypoxia created by loss of vascular supply leads to tissue injury and aberrant neovascularization in the retina. There is a great need for therapies that enhance revascularization of hypoxic neuroretinal tissue. To test the therapeutic feasibility of human-induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs) for the treatment of ischemic retinopathies, we compared the angiogenic potential of hiPSC-ECs with mature human retinal endothelial cells (HRECs) in response to hypoxia. hiPSC-ECs formed more robust and complex vascular networks in collagen gels, whereas HRECs displayed minimal sprouting. The cells were further tested in the mouse oxygen-induced retinopathy (OIR) model. Retinas with hiPSC-EC injection showed colocalization with host vessels, whereas HRECs lacked such responses. hiPSC-ECs markedly reduced vaso-obliteration and pathological neovascularization. This beneficial effect of hiPSC-ECs was explained by the stromal cell-derived factor-1a (SDF1a)/CXCR4 axis; hiPSC-ECs exhibited much higher cell-surface expression of CXCR4 than HRECs and greater chemotaxis toward SDF1a-embedded 3D collagen hydrogel. Furthermore, treatment with neutralizing antibody to CXCR4 abolished recruitment of hiPSCs in the OIR model. These findings suggest superior angiogenic potential of hiPSC-ECs under hypoxia and underscore the importance of SDF1a/CXCR4 in the reparative function of hiPSC-ECs in ischemic diseases.
缺血性视网膜病变是全球范围内导致失明的主要原因。由于血管供应的丧失而导致局部缺氧，导致视网膜组织损伤和异常新生血管形成。因此，迫切需要能够增强缺氧神经视网膜组织再血管化的治疗方法。为了测试人诱导多能干细胞衍生的内皮细胞（hiPSC-ECs）治疗缺血性视网膜病变的治疗可行性，我们比较了 hiPSC-ECs 和成熟的人视网膜内皮细胞（HRECs）在缺氧反应下的血管生成潜力。hiPSC-ECs 在胶原凝胶中形成了更健壮和复杂的血管网络，而 HRECs 则显示出最小的发芽。然后将这些细胞进一步在小鼠氧诱导的视网膜病变（OIR）模型中进行测试。注射 hiPSC-EC 的视网膜与宿主血管共定位，而 HRECs 则没有这种反应。hiPSC-ECs 显著减少了血管闭塞和病理性新生血管形成。hiPSC-ECs 的这种有益作用可以通过基质细胞衍生因子-1a（SDF1a）/CXCR4 轴来解释；hiPSC-ECs 比 HRECs 表现出更高的细胞表面 CXCR4 表达水平，并且对嵌入 3D 胶原水凝胶中的 SDF1a 表现出更强的趋化性。此外，用 CXCR4 的中和抗体处理会消除 hiPSC 在 OIR 模型中的募集。这些发现表明 hiPSC-ECs 在缺氧下具有更高的血管生成潜力，并强调了 SDF1a/CXCR4 在缺血性疾病中 hiPSC-ECs 的修复功能中的重要性。
