Delivery of Extracellular Vesicles as a Potential Basis for Therapies

Here I'll point out a readable open access review paper on the potential use of extracellular vesicles as a basis for therapy: harvested from, say, some form of stem cell, and then delivered to a patient. One of the ways in which stem cell therapies might branch and evolve in the near future is to discard the cells themselves in favor of the signals produced by those cells. The evidence to date strongly suggests that many of the current forms of cell therapy produce their beneficial effects, such as a reduction in inflammation, via signaling. The cells themselves do not survive for long enough in large enough numbers to be making a difference through other activities.

This is not to say that all cell therapies should be replaced by signals - in most of the cases relevant to human rejuvenation, it is vital to deliver cells that stick around, integrate with tissues, and perform all of the necessary tasks required of them. To augment a failing organ such as the heart that is not naturally regenerative to a great degree, for example, or replace age-related losses in a small but necessary cell population, such as the dopamine generating neurons lost in Parkinson's disease. The present state of biotechnology isn't all that good at achieving this goal of cell survival, unfortunately, but that will improve. So there may be two fields in the future where there is one today, the first focused on delivering cells, the second on delivering cell signals absent the cells. Both can be useful, though only the replacement of lost cells directly addresses a root cause of aging. If we are prepared to accept stem cell therapies as a worthwhile endeavor even if they only work through signaling and fail to address root causes of aging, then we should be as accepting of the delivery of signals alone.

What are extracellular vesicles? These are numerous different forms of membrane-wrapped package that are constructed and released by cells, containing all sorts of proteins and other molecules. Other cells take them up and their behavior adjusts based on the way in which the contents interact with internal cellular machinery. A rough taxonomy of vesicles exist, based on their size - exosomes versus microvesicles, for example. This will no doubt give way to a better taxonomy based on function, given further research. Currently, only a comparatively crude understanding exists of the specific functions that vesicles accomplish, and how that differs between types. So while it is possible to say that stem cells produce beneficial effects via vesicles, and senescent cells produce harmful effects via vesicles, it isn't yet possible to break down that flow of vesicles into its component parts and talk in detail about each part in isolation.

Extracellular vesicles and aging

It is estimated that in the next 20 years, the number of individuals in the United States over the age of 65 will double, numbering more than 70 million individuals. Unfortunately, as we age there is an unavoidable and progressive loss of the ability to maintain tissue homeostasis under stress and an attrition of functional reserve. Over 90% of individuals older than 65 years of age have at least one chronic disease, while more than 70% have at least two. These chronic diseases account for 75% of our healthcare costs, amounting to approximately $3 trillion in costs last year alone. Thus, there is a significant need to understand mechanisms driving aging and to develop novel therapeutics.

There is compelling evidence to support the hypothesis that the underlying cause of aging is the cell autonomous, time-dependent accumulation of stochastic damage to cells, organelles, and macromolecules. However, it is also clear from heterochronic parabiosis and serum transfer studies that cell non-autonomous mechanisms play important roles in suppressing or driving degenerative changes that arise as the consequence of spontaneous, stochastic damage. For example, using heterochronic parabiosis, it was demonstrated that factors in young blood rejuvenate certain cell types and tissues in old mice.

Conversely, factors in old blood can drive aging of certain cell types and tissues in young mice. These blood-borne pro-geronic factors include the chemokine CCL-11 and β-2 microglobulin. In addition to these identified geronic factors, it is likely there are other circulating factors that also play key, cell non-autonomous roles in aging. Indeed, it is likely a combination of loss of anti-geronic factors and an increase in pro-geronic factors that drives aging. Given that almost all cell types release extracellular vesicles (EVs), including stem/progenitor cells and senescent cells, it is likely that subsets of blood-borne EVs play key roles as both anti- and pro-geronic factors.

EVs are comprised of both microvesicles, released from the plasma membrane by shedding, and nanovesicles or exosomes, generated by reverse budding of multivesicular bodies (MVBs). Although their contents likely differ, both small and large EVs are enriched for a subset of diverse proteins, lipids, messenger RNAs (mRNAs), and non-coding RNAs (ncRNAs), such as miRNAs, which are derived from the parental cells. EVs have a variety of reported functions and some of their better-documented activities are associated with some form of immune regulation. EVs derived from stem cells also have significant ability to repair damaged tissue.

Consistent with the regenerative capacities of stem cell EVs, a recent study demonstrated that implantation of healthy hypothalamic stem/progenitor cells into the hypothalamus leads to the slowing of ageing. Moreover, it was demonstrated that the functional hypothalamic stem/progenitor cells release exosomes into the cerebral spinal fluid that likely contribute to slowing aging through transfer of miRNAs. Conversely, it has been demonstrated that senescent cells release more EVs and with a different composition, likely contributing to the senescence-associated secretory phenotype (SASP). These results suggest that functional stem/progenitor cell-derived EVs are able to extend healthspan and lifespan whereas senescent cell-derived EVs could function as pro-geronic factors. Taken together, there is substantial circumstantial evidence that EVs play key roles in aging and that regenerative EVs could be used to extend healthy aging. Finally, given the likely role of EVs in aging, components of EVs could be developed as biomarkers of unhealthy aging.


"The researchers believe their study represents the first step down a new path for tissue regeneration with the potential to help repair bone, teeth, and cartilage. They point out that current methods have important limitations; i.e., autologous grafts cannot meet demand, they cause patient morbidity, allogeneic bone lacks bioactive factors, and growth factor-based approaches (e.g., BMP-2) may have serious side-effects and high costs. .

This team's technique delivers all the advantages of cell-based therapies but without using viable cells, by harnessing the regenerative capacity of EVs that are naturally generated during bone formation, according to Sophie Cox, Ph. D., from the School of Chemical Engineering, adding that the scientists have demonstrated in vitro that if EVs are applied in combination with a simple phosphate the therapy outperforms the current gold standard, BMP-2."

Posted by: Jim at January 25th, 2018 6:31 PM

"...These chronic diseases account for 75% of our healthcare costs, amounting to approximately $3 trillion in costs last year alone." And we can't round up a few percent of this sum to target the aging that enables these diseases?

$3T/year to the sick care industrial complex and big pharma. We need to fight back in our personal lives and make others aware.

Posted by: Tom Schaefer at January 26th, 2018 10:30 AM

Some of the root cause of aging may lie in declining levels of activity of organs needed to provide vesicles/signal molecules via the blood or spinal fluid cord. For example the pituitary gland and the hypothalamus are known to provide anti-aging exosomes/molecular signals to other tissues of the body, but their stem cell pools, brain circulation, etc., decline with aging, with the result being old blood is lacking the youth-providing vesicles/molecular signals in old animals. To complicate matters further, metabolic waste products increase with age in the blood, such as CCL11, B2M, and numerous other aging particles. Perhaps older animals have declining liver, kidneys, spleen, etc., that more effectively removed these vesicles/aging particles in young animals. It seems we must study both of these root causes of aging before we can substantially increase lifespan.

Posted by: Biotechy at January 27th, 2018 9:14 AM
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