Amniotic Epithelial Stem Cells‐Derived Exosomes Attenuate the Lesion of Alveolar Epithelial Cells Induced by SARS‐CoV‐2 Spike Protein via SENP3‐ Triggered FGF9 deSUMOylation

The spike (S) protein plays a pivotal role in the invasion of host cells by SARS‐CoV‐2 (COVID‐19). However, the underlying mechanism of spike protein interaction with host cells remains elusive. Here, it was found that human amniotic epithelial stem cells (HuAECs)‐derived exosomes were able to mitigate the cell cycle arrest and lesions of human type II alveolar epithelial primary cells (hAEPC‐II) in vitro induced by SARS‐CoV‐2 S protein. Mechanistically, HuAECs transfered SENP mRNA to hAEPC‐II by releasing exosomes, induced FGF9 protein deSUMOylation and stimulated its expression in hAEPC‐II. Silencing endogenous SENP3 mRNA in HuAECs using siRNA weakens the protective effect of HuAECs‐derived exosomes on hAEPC‐II. Meanwhile, HuAEC‐derived exosomes significantly improved lung tissue damage, inflammatory and fibrosis symptoms of humanized hACE2 KI/KI transgenic mice treated to S protein in vivo. In conclusion, this study reveals a novel mechanism by which HuAECs transfered SENP mRNA to hAEPC‐II by releasing exosomes and attenuate the lesion of hAEPC‐II induced by SARS‐CoV‐2 spike protein.