Apoptotic vesicles are required to repair DNA damage and suppress premature cellular senescence

Abstract

Abstract It is well known that DNA damage can cause apoptosis. However, whether apoptosis and its metabolites contribute to DNA repair is largely unknown. In this study, we found that apoptosis‐deficient Fasmut and Bim−/− mice show significantly elevated DNA damage and premature cellular senescence, along with a significantly reduced number of 16,000 g apoptotic vesicles (apoVs). Intravenous infusion of mesenchymal stromal cell (MSC)‐derived 16,000 g apoVs rescued the DNA damage and premature senescence in Fasmut and Bim−/− mice. Moreover, a sublethal dose of radiation exposure caused more severe DNA damage, reduced survival rate, and loss of body weight in Fasmut mice than in wild‐type mice, which can be recovered by the infusion of MSC‐apoVs. Mechanistically, we showed that apoptosis can assemble multiple nuclear DNA repair enzymes, such as the full‐length PARP1, into 16,000 g apoVs. These DNA repair components are directly transferred by 16,000 g apoVs to recipient cells, leading to the rescue of DNA damage and elimination of senescent cells. Finally, we showed that embryonic stem cell‐derived 16,000 g apoVs have superior DNA repair capacity due to containing a high level of nuclear DNA repair enzymes to rescue lethal dose‐irradiated mice. This study uncovers a previously unknown role of 16,000 g apoVs in safeguarding tissues from DNA damage and demonstrates a strategy for using stem cell‐derived apoVs to ameliorate irradiation‐induced DNA damage.

Keywords

• apoptosis
• apoptotic vesicles
• DNA damage repair
• DDR‐apoV complexes
• embryonic stem cells
• mesenchymal stromal cells