Cartilaginous Extracellular Matrix Enriched with Human Gingival Mesenchymal Stem Cells Derived “Matrix Bound Extracellular Vesicles” Enabled Functional Reconstruction of Tracheal Defect

Abstract Stem cells derived extracellular vesicles (EVs) conceive cues essential for tissue repair. Mammalian cartilaginous extracellular matrix (cECM) may not be optimally inductive for tracheal regeneration because of the granulomatous, instead of regenerative, responses in injured adult mammalian tracheas. Given the high regenerative capacity of gingiva, it is hypothesized human gingival mesenchymal stem cells derived EVs (gEVs) can induce mammalian tracheal epithelia regeneration. Coculturing chondrocytes with GMSCs produce abundant “matrix bound gEVs (gMVs)” in forming cartilaginous ECM, which are further preserved in acellular cECM (cACM) following mild, short‐period decellularization. The results show that gMVs‐cACM could be well anchored on polyglycerol sebacate microporous patch thus enforce the surgical suturability and mechanical strength. In rabbit tracheal defect, the gMVs‐cACM patch induces rapid regeneration of vascularized ciliated columnar epithelium, which supports long‐term survival of animals. gMVs‐cACM treated groups exhibit proliferation of tracheal progenitors‐basal epithelial cells, as well as, activation of JAK2/STAT1 pathway in reparative cells. This study departs from conventional focuses on tissue derived ECM and introduces a new approach for tracheal tissue regeneration.