Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
Hum Mol Genet. 2010 Nov 1;19(21):4229-38. doi: 10.1093/hmg/ddq341. Epub 2010 Aug 13.
Age-related macular degeneration (AMD) is characterized by the loss or dysfunction of retinal pigment epithelium (RPE) and is the most common cause of vision loss among the elderly. Stem-cell-based strategies, using human embryonic stem cells (hESCs) or human-induced pluripotent stem cells (hiPSCs), may provide an abundant donor source for generating RPE cells in cell replacement therapies. Despite a significant amount of research on deriving functional RPE cells from various stem cell sources, it is still unclear whether stem-cell-derived RPE cells fully mimic primary RPE cells. In this report, we demonstrate that functional RPE cells can be derived from multiple lines of hESCs and hiPSCs with varying efficiencies. Stem-cell-derived RPE cells exhibit cobblestone-like morphology, transcripts, proteins and phagocytic function similar to human fetal RPE (fRPE) cells. In addition, we performed global gene expression profiling of stem-cell-derived RPE cells, native and cultured fRPE cells, undifferentiated hESCs and fibroblasts to determine the differentiation state of stem-cell-derived RPE cells. Our data indicate that hESC-derived RPE cells closely resemble human fRPE cells, whereas hiPSC-derived RPE cells are in a unique differentiation state. Furthermore, we identified a set of 87 signature genes that are unique to human fRPE and a majority of these signature genes are shared by stem-cell-derived RPE cells. These results establish a panel of molecular markers for evaluating the fidelity of human pluripotent stem cell to RPE conversion. This study contributes to our understanding of the utility of hESC/hiPSC-derived RPE in AMD therapy.
年龄相关性黄斑变性（AMD）的特征是视网膜色素上皮（RPE）的丧失或功能障碍，是老年人视力丧失的最常见原因。基于干细胞的策略，使用人胚胎干细胞（hESC）或人诱导多能干细胞（hiPSC），可能为生成 RPE 细胞的细胞替代疗法提供丰富的供体来源。尽管已经对从各种干细胞来源中获得功能性 RPE 细胞进行了大量研究，但仍不清楚干细胞来源的 RPE 细胞是否完全模拟原代 RPE 细胞。在本报告中，我们证明了功能性 RPE 细胞可以从多种 hESC 和 hiPSC 线以不同的效率衍生而来。干细胞衍生的 RPE 细胞表现出鹅卵石样形态、转录本、蛋白质和吞噬功能，类似于人胎儿 RPE（fRPE）细胞。此外，我们对干细胞衍生的 RPE 细胞、天然和培养的 fRPE 细胞、未分化的 hESC 和成纤维细胞进行了全基因组表达谱分析，以确定干细胞衍生的 RPE 细胞的分化状态。我们的数据表明，hESC 衍生的 RPE 细胞与人 fRPE 细胞非常相似，而 hiPSC 衍生的 RPE 细胞处于独特的分化状态。此外，我们鉴定了一组 87 个独特的人 fRPE 特异性基因，其中大多数这些特征基因也存在于干细胞衍生的 RPE 细胞中。这些结果建立了一个评估人多能干细胞向 RPE 转化的保真度的分子标记物。这项研究有助于我们理解 hESC/hiPSC 衍生的 RPE 在 AMD 治疗中的应用。
