Developing vascularized immune-competent skin organoids for advanced dermatological research

Summary: Abstract Body: A large amount of research has been devoted to developing skin equivalent for studying developmental pathways, modelling diseases, or regenerative medicine purposes. Despite progress, the field remains far from creating fully structured skin, including appendages like hair follicles and sweat glands, and lacks vascularization. Here, we present a pioneering approach for engineering stratified skin layers with their appendages using human induced pluripotent stem cells (hiPSCs)-derived skin organoids (SKOs) from multiple distinct hiPSCs lines. Comprehensive cellular and molecular analyses confirm that mature SKOs contain skin stem/progenitor populations, including dermal papilla cells, and can develop sebaceous glands, sweat glands, fat, and touch-receptive Merkel cells, highlighting their complexity and fidelity to native human skin. However, skin’s vascularization, vital for homeostasis, remains an unmet challenge. Thus, to further enhance physiological relevance of SKO, we investigate the vascularization of human SKO using hiPSCs-derived vascular organoids. This approach results in developing fully vascularized SKOs, sustaining hair follicle formation and demonstrating the integration of CD45+ immune cells, like in vivo skin microenvironment. Generation of both immune cells and vascular components within the complete-appendage SKO mimics the structure of in vivo skin setting a new benchmark for translational skin research. The human immune-competent vascularized skin organoids demonstrate substantial translational potential and could be used as valuable platforms for advancing dermatological research, understanding skin development, modelling diseases, and advanced regenerative solutions and personalized medicine. Jane Sun¹, Mitchell Mostina¹, Imaan Ahmed¹, Seen Ling Sim¹, Kiarash Khosrotehrani¹, Abbas Shafiee^{1, 2} 1. Frazer Institute, The University of Queensland, Brisbane, QLD, Australia. 2. Metro North Hospital and Health Service, Queensland Health, Brisbane, QLD, Australia. Stem Cell Biology, Tissue Regeneration and Wound Healing