Self-assembly of progenitor cells under the aegis of platelet factors facilitates human skin organoid formation and vascularized wound healing

Stem/progenitor cells can self-organize into organoids modelling tissue function and regeneration. Here we demonstrate that human platelet-derived factors can orchestrate 3D self-assembly of clonally expanded adult skin fibroblasts, keratinocytes and endothelial progenitors forming skin organoids within three days. Organoids showed distinct signaling patterns in response to inflammatory stimuli that clearly differed from separated cell types. Human induced pluripotent stem cell (hiPSC)-derived skin cell progenitors also self-assembled into stratified human skin within two weeks, healing deep wounds of immune-deficient mice. Co-transplantation of endothelial progenitors significantly accelerated vascularization. Mechanistically, platelet-derived extracellular vesicles mediated the platelet-derived trophic effects. Long-term fitness of epidermal cells was accelerated further by keratinocyte growth factor mRNA transfection. No tumorigenesis was observed upon xenografting. This permits novel rapid 3D skin-related pharmaceutical testing opportunities and facilitates development of iPSC-based skin regeneration strategies.