ACE2 Overexpressing Mesenchymal Stem Cells Alleviates COVID-19 Lung Injury by Inhibiting Pyroptosis

Abstract

Mesenchymal stem cells (MSCs) have shown some efficacy in the treatment of COVID-19, negatively express ACE2. We proposed that exogenous supplementation of ACE2 via MSCs (ACE2-MSCs) might have better therapeutic effects. Here, we constructed SARS-CoV-2 spike glycoprotein stably transfected AT -II and Beas-2B cells, and used SARS-CoV-2 spike pseudovirus to infect hACE2 transgenic mice. The results showed that spike glycoprotein transfection triggers the release of apoptotic bodies and formation of membrane pores in pyroptosis. Inflammatory factors and pyroptosis factors were highly upregulated by spike glycoprotein transfection. SARS-CoV-2 spike pseudovirus worsened lung injury and increased the main factors of cytokine storm and pyroptosis. Compared to using MSCs alone, the administration of ACE2-MSCs could much more significantly reduce these factors and alleviated lung injury in vivo and in vitro , which might be due to the increased activities of secretory ACE2. Our proposal is a promising therapeutic solution for preclinical or clinical research. Funding: This work was supported by grants from the Key Research and Development Program (Social Development) of Jiangsu Province (BE2020667), the National Natural Science Foundation of China (32070998), the Foundation of Jiangsu Province 333 Project High-level Talents (BRA2020076), Nantong Science and Technology Bureau (MS12020056), Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX21_3097) and Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: Animal studies were performed according to guidelines established by the Institutional Animal Care and Use Committee of Nantong University (permission number: S20200013-025).