Mesenchymal stem cell derived extracellular vesicles reverses neural aging via OSKM modulation

Intravenously infused human placenta-derived mesenchymal stem cells enhance overall function and exhibit therapeutic potential even with minimal engraftment or tissue replacement, with substances released from human placenta-derived mesenchymal stem cells playing a significant role in these positive outcomes. Stem cell-derived extracellular vesicles transfer beneficial factors that aid recovery in various tissues through genetic regulation. However, the effects of systemically injected mesenchymal stem cells and their released derivatives on normal aging have not been reported.

Aged female mice received intravenous infusions of human placenta-derived mesenchymal stem cells. Starting at 18-19 months of age, mice were given injections of either human placenta-derived mesenchymal stem cells or PBS, followed by two more injections at six-week intervals. For the in vitro study, human fetal neural progenitor cells were sourced from spontaneously aborted fetal brain tissue. Extracellular vesicles were isolated from the human placenta-derived mesenchymal stem cell culture media using the qEV original size exclusion column.

RNA sequencing showed human placenta-derived mesenchymal stem cells' effectiveness in modulating aging-related neural pathways, particularly by downregulating age-specific genes in the hippocampus, indicative of neural reactivation. A pivotal aspect of our study was the discovery of micro RNAs in human placenta-derived extracellular vesicles reactivating senescent cells, likely through inhibition of Toll-like receptor 4 signaling and a concomitant increase in OSKM (OCT4, SOX2, KLF4, C-MYC) transcription factors, notably SOX2. The regeneration process involves targeted miRNAs modulating Toll-like receptor 4 and messenger RNAs boosting OSKM levels.

Our study represents a pioneering achievement in regenerative medicine, demonstrating the potential of micro RNAs in EVs to stimulate OSKM, a significant stride forward in addressing neural aging.