Functional transfer of integrin co-receptor CD98hc by small extracellular vesicles improves wound healing in vivo

Abstract

Extracellular vesicles (EVs) mediate intercellular communication. EVs are composed of a lipid bilayer and contain cytosolic proteins and RNAs. Studies highlight EVs striking functions in cell-cell crosstalk. Here, we found that small EVs can transfer functional signaling molecules through their lipid bilayer and participate in skin homeostasis. We identified a transmembrane protein CD98hc (a.k.a. SLC3A2), an integrin co-receptor (Itgb1 and Itgb3), implicated in epidermis homeostasis via its capacity in regulating extracellular matrix, as an important mediator of EV-based intercellular communication in vivo. We first demonstrated that healthy dermal fibroblasts produced and secreted EVs bearing characteristic of exosome-like small EVs (sEVs). We show that CD98hc, Itgb1 co-receptor, is present at the surface of sEVs, transferred and stabilized at the plasma membrane. The transferred complex is functional on recipient cells both in vitro and in vivo. Indeed, treatment with sEVs from WT, but not KO cells rescued migratory defects observed either in CD98hc KO dermal fibroblasts or in keratinocytes in vitro. Furthermore, injection of sEVs at the margins of wound in impaired wound healing mouse models (epidermal CD98hc KO mice exhibiting healing defect and elderly mice) improved wound closure in vivo. CD98hc complex transferred from sEVs remained stabilized at least 7 days after injection. Thus, our findings reveal that in vivo treatment with sEVs containing integrin co-receptor CD98hc could improve multiple skin afflictions.