Coordinated Development of Immune Cell Populations in Vascularized Skin Organoids from Human Induced Pluripotent Stem Cells

Abstract Human skin is a highly vascularized organ, where blood vessels perform essential roles in maintaining skin homeostasis and participate in thermal regulation. Currently, there is an unmet challenge to generate vascularized, functional skin models. In this study, human fetal placental endothelial colony forming cells (ECFC) are incorporated into human induced pluripotent stem cell (hiPSC)‐derived skin organoids (SKO), forming capillary‐like structures and generating endothelialized SKOs. However, this approach is limited by the inability of ECFCs to establish a complete vascular network, and impeding full epidermal stratification and hair follicle morphogenesis. In independent experiments, hiPSC‐derived vascular organoids (VO), are incorporated into the SKO, forming complex vascular structures and generating fully vascularized skin organoids (VSKO) with resident immune cell populations. Immunofluorescence microscopy and flow cytometric analyses reveal the transfer and integration of endothelial, mural, hematopoietic, and mesenchymal cells from VOs into the skin components of VSKOs. This study pioneers the establishment of VSKOs as a transformative platform for studying human skin biology, and immune‐skin interactions with applications in investigating inflammatory and other immune‐mediated skin disorders.