We sought to elucidate how and when the ocular surface ectoderm commits to its differentiation into the corneal epithelium in eye development from human induced pluripotent stem cells (hiPSCs) under the influence of WNT signaling and the actions of BMP4. These signals are key drivers ocular surface ectodermal cell fate determination. It was discovered that secreted frizzled related protein-2 (SFRP2) and Dickkopf1 (DKK1), which are expressed in neural ectoderm, are both influential in the differentiation of hiPSCs, where they act as canonical WNT antagonists. BMP4, moreover, was found to simultaneously initiate non-neural ectodermal differentiation into a corneal epithelial lineage. Combined treatment of hiPSCs with exogenous BMP4 aligned to WNT inhibition for the initial four days of differentiation increased the ocular surface ectodermal cell population and induced a corneal epithelial phenotype. Specification of a surface ectodermal lineage and its fate is thus determined by a fine balance of BMP4 exposure and WNT inhibition in the very earliest stages of human eye development.

我们试图阐明在 WNT 信号传导和 BMP4 作用的影响下，眼表外胚层如何以及何时从人诱导的多能干细胞 (hiPSC) 分化为眼发育过程中的角膜上皮。这些信号是确定眼表外胚层细胞命运的关键驱动因素。发现在神经外胚层中表达的分泌的卷曲相关蛋白 2 (SFRP2) 和 Dickkopf1 (DKK1) 都对 hiPSCs 的分化有影响，它们作为典型的 WNT 拮抗剂。此外，发现 BMP4 同时启动非神经外胚层分化为角膜上皮谱系。在分化的最初四天，将 hiPSCs 与外源性 BMP4 与 WNT 抑制相结合，增加了眼表外胚层细胞群并诱导了角膜上皮表型。因此，表面外胚层谱系及其命运的规范取决于人眼发育最早期阶段 BMP4 暴露和 WNT 抑制的良好平衡。