The nail matrix containing stem cell populations produces nails and may contribute to fingertip regeneration. Nails are important tissues that maintain the functions of the hand and foot for handling objects and locomotion. Tumor chemotherapy impairs nail growth and, in many cases, loses them, although not permanently. In this report, we have achieved the successful differentiation of nail stem (NS)-like cells from human-induced pluripotent stem cells (iPSCs) via digit organoids by stepwise stimulation, tracing the molecular processes involved in limb development. Comprehensive mRNA sequencing analysis revealed that the digit organoid global gene expression profile fits human finger development. The NS-like cells expressed Lgr6 mRNA and protein and produced type-I keratin, KRT17, and type-II keratin, KRT81, which are abundant in nails. Furthermore, we succeeded in producing functional Lgr6-reporter human iPSCs. The reporter iPSC-derived Lgr6-positive cells also produced KRT17 and KRT81 proteins in the percutaneously transplanted region. To the best of our knowledge, this is the first report of NS-like cell differentiation from human iPSCs. Our differentiation method and reporter construct enable the discovery of drugs for nail repair and possibly fingertip-regenerative therapy.
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