Engineering organoids that faithfully replicate the intricate architecture and region-specific features of bodily organs and extraembryonic tissues remains a significant scientific challenge. Previously, we demonstrated that craniofacial skin organoids (cSkOs)—containing epidermis, dermis, and hair—could be generated by co-developing epidermal progenitors with cranial mesenchyme. Building on this approach, we precisely adjusted cellular composition and signaling environments to generate ventral skin organoids (vSkOs) with lateral plate mesoderm (LPM) progenitors, successfully recapitulating features of abdominal or groin skin. Modulating early BMP and FGF signaling redirected these vSkOs toward an extraembryonic fate, producing human amnion-like tissues, termed Amnioids. Like native human amnion, Amnioids rapidly expanded into large, avascular, hairless cysts, in sharp contrast to the primitive vasculature and abundant hair follicles of vSkOs. Single-cell RNA sequencing identified divergent molecular signatures and developmental trajectories, highlighting key roles for NOTCH, WNT, and YAP/Hippo signaling pathways. Functional studies further underscored mesenchymal-epithelial interactions and mechanical forces as critical regulators of epithelial expansion. Together, these models provide potent tools to investigate human development at the embryonic-extraembryonic interface, offering critical insights into congenital skin and amniotic disorders and opening new avenues for precision regenerative therapies. ### Competing Interest Statement K.R.K. and J.L. are inventors of a patent relating to the skin organoid technology discussed in this article (WO2017070506A1). A.P.L. and K.R.K. with Childrens Hospital Corporation have applied for a patents relating to Amnioid (PCT/US2024/033843 Priority Date 6.13.2023) and ventral skin technology. K.R.K. is a consultant to STEMCELL Technologies that has licensed the skin organoid technology. National Institute of Arthritis and Musculoskeletal and Skin Diseases, https://ror.org/006zn3t30, R01AR075018 National Institute on Deafness and Other Communication Disorders, https://ror.org/04mhx6838, R01DC017461 National Institutes of Health, R01HD113792 National Institutes of Health, R01HD085121 National Institutes of Health, R24HD000836

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