Metabolic adaptation drives self-organization during skin organoid morphogenesis

Self-organization in organoid morphogenesis involves the coordinated arrangement of interacting cells into higher-order structures, yet the underlying principles remain elusive. Here, we investigate how epidermal and dermal cells respond distinctively to elevated levels of hypoxia during skin organoid morphogenesis that largely resembles the skin development during embryogenesis. We unveil that autonomously generated hypoxic environment-induced metabolic adaptation drives the transition from coalesced spheroids to a planarized structure in skin organoids through the following three levels. Hif1a-mediated anaerobic metabolism positions epidermal cells in the liquid phase of the cultures under lower oxygen levels, facilitating tissue phase separation of the epidermal layer from the dermal layer. Hypoxia-driven activation of lysosomal hydrolases eliminates suprabasal keratin debris during planar epidermis formation. Fibroblasts adjacent to the basal epidermis have differential metabolic adaptation to hypoxia, which exhibit enhanced retinoid metabolism and become putative papillary dermis. Together, these hypoxia-induced metabolic adaptations contribute to reconstructing skin architecture similar to physiological development. Our findings highlight the ability of hypoxia-induced metabolic alteration to trigger varied cellular responses, leading to self-organizing coalesced spheroids-to-planar topological transformations and the restoration of tissue homeostasis.