MSC-derived extracellular vesicles as nanotherapeutics for promoting aged liver regeneration

Aging is one of the critical factors to impair liver regeneration leading to a high incidence of severe complications after hepatic surgery in the elderly population without any effective treatment for clinical administration. As cell -free nanotherapeutics, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been demonstrated the therapeutic potentials on liver diseases. However, the effects of MSC-EVs on the proliferation of aged he-patocytes are largely unclear. In this study, we found MSCs could reduce the expression of senescence-associated markers in the liver and stimulate its regeneration in aged mice after receiving a two-thirds partial hepatectomy (PHx) through their secreted MSC-EVs. Using RNA-Seq and AAV9 vector, we mechanistically found that these effects of UC-MSC-EVs partially attributed to inducing Atg4B-related mitophagy. This effect repairs the mito-chondrial status and functions of aged hepatocytes to promote their proliferation. And protein mass spectrum analysis uncovered that DEAD-Box Helicase 5 (DDX5) enriches in UC-MSC-EVs, which interacts with E2F1 to facilitate its nuclear translocation for activating the expression of Atg4B. Collectively, our data show that MSC-EVs act nanotherapeutic potentials in anti-senescence and promoting regeneration of aged liver by transferring DDX5 to regulate E2F1-Atg4B signaling pathway that induce mitophagy, which highlights the clinical applica-tion valuation of MSC-EVs for preventing severe complications in aged population receiving liver surgery.

Automated summary

Aging impairs liver regeneration after hepatic surgery in the elderly population, and no effective treatment is available for clinical administration. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have shown therapeutic potential in liver diseases. This study found that MSCs can reduce senescence-associated markers and promote liver regeneration in aged mice through the secretion of MSC-EVs. Mechanistically, these effects were partially attributed to inducing mitophagy via the Atg4B pathway. The presence of DEAD-Box Helicase 5 (DDX5) in MSC-EVs was found to interact with E2F1 and activate the expression of Atg4B. These findings highlight the clinical application potential of MSC-EVs in preventing severe complications in aged individuals undergoing liver surgery.