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Summary: The extracellular matrix plays a key role in stem cell maintenance, expansion, and differentiation. Laminin, a basement membrane protein, is a widely used substrate for cell culture including the growth of human induced pluripotent stem cells (hiPSCs). Here, we show that different isoforms of laminin lead to the selective differentiation of hiPSCs into different eye-like tissues. Specifically, the 211 isoform of the E8 fragment of laminin (LN211E8) promotes differentiation into neural crest cells via Wnt activation, whereas LN332E8 promotes differentiation into corneal epithelial cells. The immunohistochemical distributions of these laminin isoforms in the developing mouse eye mirrors the hiPSC type that was induced in vitro. Moreover, LN511E8 enables generation of dense hiPSC colonies due to actomyosin contraction, which in turn led to cell density-dependent YAP inactivation and subsequent retinal differentiation in colony centers. Thus, distinct laminin isoforms determine the fate of expanded hiPSCs into eye-like tissues. : Shibata et al. report that laminin isoforms differentially regulate the ocular cell differentiation from hiPSCs. The binding affinity of laminin and integrins determines the nature of expanded hiPSC colonies in terms of cell motility, cell-cell interactions, and cell density, with the involvement of Wnt and YAP signals. Keywords: human induced pluripotent stem cells, hiPSCs, laminin isoforms, YAP, Wnt, ocular cell differentiation, self-formed ectodermal autonomous multi-zone, SEAM