Extracellular Vesicles from Embryonic Stem Cells Reduce Cellular Senescence
Much of the communication between cells passes back and forth in the form of extracellular vesicles, membrane-wrappd packages of molecules that are presently far from completely cataloged or understood. This lack of full understanding hasn't stopped the growth of an industry seeking to replace stem cell therapies with vesicles harvested from those stem cells. It seems clear from the evidence to date that most stem cell therapies produce benefits via signaling, and not because transplanted cells survive to engraft in any meaningful numbers. In principle, use of vesicles allows for less expensive, more logistically practical forms of treatment, as vesicles can be indefinitely stored, and their production involves far fewer of the challenges of quality and consistency found in stem cell manufacture. In practice, this is a still a work in progress in the world of regulated medicine, even given that extracellular vesicle treatments are readily available in the world of medical tourism.
In today's open access paper, researchers discuss the mechanisms by which delivery of extracellular vesicles harvested from embryonic stem cells reduces measures of aging in animal studies and reduces incidence of cellular senescence in cell cultures. It may or may not be a good idea to prevent or reverse cellular senescence, as some cells become senescent for good reason, being damaged in ways that might provoke cancerous behavior if not stopped. Further, some senescent cells exhibit sizable amounts of DNA damage that is induced on the transition into a senescent state. On the other hand, in aged tissues many cells may become senescent only in response to the signaling of other senescent cells, or due to stress that is survivable given a little more resilience or support. Some of the better-studied approaches to slowing aging clearly prevent cellular senescence to some degree, such as mTOR inhibition. One suspects that when it comes to risk, the details of the biochemistry matter greatly for any novel approach to rescuing cells from the senescent state.
A few decades ago, rejuvenation or amelioration of aging seemed impossible. However, in the last decades, the concept of parabiosis and partial reprogramming with pluripotency-related factors has changed our view on the subject, indicating that factors derived from young cells prevent senescence. Researchers found that young circulating extracellular vesicles (EVs) can regenerate aged muscle. Previously, we found that EVs derived from embryonic stem cells (ESCs) could rejuvenate the aged MSCs (mesenchymal stem cells) and rescue their regenerative capacity. Recently, several rejuvenation factors enriched in ESC-EVs or ESC-CM (conditioned medium) have been identified, such as TGF-β, Smad2, PDGF-BB (platelet-derived growth factor-BB), miR-291a-3p, miR-294, and miR-200a. However, the roles and mechanisms of ESC-EVs in vivo are unknown.
Here, we investigate the anti-senescence effects of ESC-EVs in vivo using aged mice. Our data show that ESC-EVs treatment rescues the transcriptome profile of aged mice and ameliorates the senescence status of several aged organs, providing evidence that ESC-EVs may be candidates for the therapy of various age-related diseases. Others have found that EVs from young adipose-derived stem cells improved motor coordination, grip strength, fatigue resistance, and significantly reduced frailty in aged mice. However, the effects of ESC-EVs treatment on cognitive function and motor activity in aged mice remain unclear and require further investigation.
Furthermore, we identify miR-15b-5p and miR-290a-5p, which are enriched in ESC-EVs and exert rejuvenating effects by silencing of the Ccn2-mediated AKT signaling pathway. miR-15b-5p and miR-290a-5p are crucial for ESC-EVs rejuvenation. Their target gene of Ccn2 is upregulated in aged cells and can be rescued by ESC-EVs treatment. Several studies have shown that Ccn2 induces cellular senescence and activates the PI3K/AKT signaling pathway, suggesting that Ccn2 may be a potential target for anti-aging. We found that miR-15b-5p and miR-290a-5p silenced Ccn2, thereby inhibiting the Ccn2-dependent AKT signaling pathway and ameliorating the senescence.
In conclusion, here, we demonstrate a novel mechanism for ESC-EVs to protect cells from senescence. However, whether ESC-EVs rejuvenate aged mice via miR-15b-5p and miR-290a-5p remains unknown. Next, we plan to use miR-15b-5p and miR-290a-5p antagonists while treating aged mice with ESC-EVs to further investigate the mechanism by which ESC-EVs resist aging in vivo.