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Tooth enamel secreted by ameloblasts (AMs) is the hardest material in the human body, acting as a shield to protect the teeth. However, the enamel is gradually damaged or partially lost in over 90% of adults and cannot be regenerated due to a lack of ameloblasts in erupted teeth. Here, we use single-cell combinatorial indexing RNA sequencing (sci-RNA-seq) to establish a spatiotemporal single-cell census for the developing human tooth and identify regulatory mechanisms controlling the differentiation process of human ameloblasts. We identify key signaling pathways involved between the support cells and ameloblasts during fetal development and recapitulate those findings in human ameloblast in vitro differentiation from induced pluripotent stem cells (iPSCs). We furthermore develop a disease model of amelogenesis imperfecta in a three-dimensional (3D) organoid system and show AM maturation to mineralized structure in vivo. These studies pave the way for future regenerative dentistry., Competing Interests: Declaration of interests A.A., S.H.-D., Y.T.Z., D.D.E., Y.W., A.P.P., H.Z., J.M., D.B., and H.R.-B. are co-inventors on a patent application entitled “Human IPSC Derived Ameloblasts and Uses Thereof” (PCT/US2022/053517 filed 12/20/2022 and published 7/6/2023)., (Copyright © 2023 Elsevier Inc. All rights reserved.)