Single-Cell Analysis Reveals Fibroblast-Derived Migrasomes as CXCL12 Carriers Promoting Skin Wound Repair

Abstract

Migrasomes are newly discovered organelles with demonstrated functions in organ morphogenesis and angiogenesis. However, the effect of migrasomes in tissue repair remains unreported. Our super-resolution confocal microscopy and focused ion beam scanning electron microscopy results confirmed that migrasomes were directly connected with retraction fibres and could release their contents into the surroundings in human and rat skins and oral mucosae. Multiplex immunofluorescence staining results revealed that these retraction fibres and migrasomes originated from fibroblasts. Live-cell imaging demonstrated that human oral mucosal fibroblast-derived migrasomes could be taken up by both fibroblasts and HaCaT cells. In addition, the injection of purified fibroblast-derived migrasomes into the edges of rat skin wounds significantly accelerated wound healing. Single-cell sequencing results suggested that the clusters of keratinocytes, fibroblasts, and endothelial cells play key roles in the wound-healing process. Moreover, the expression of Vegfa, Il-6, and Col1a1 in the fibroblast subcluster was significantly upregulated. Furthermore, these purified migrasomes increased the protein levels of VEGFA, IL-6, and COL1A1 in cultured fibroblasts in vitro. Mechanistically, migrasomes may facilitate wound healing by delivering CXCL12. Thus, our research revealed that fibroblast-derived migrasomes are potential therapeutic vesicles for skin wound-healing repair.