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 hACE2KI/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.