Exosomes are a popular topic in the regenerative medicine field these days. Exosomes are a class of extracellular vesicle, membrane-bound packages of molecules that cells use as a means of communication. Much of the cell signaling that mediates the benefits of first generation stem cell therapies is in the form of exosomes rather than secreted proteins. Transplanted cells do not survive in large numbers, but their signals do meaningfully affect the behavior of native cells, producing results such as a reduction in chronic inflammation. Exosomes can be easily harvested from cell cultures and are a great deal easier to manage, logistically, than is the case for cells. Thus much of the clinical community presently offering stem cell therapies is shifting focus to exosomes.

Today’s open access paper is a look at the delivery of exosomes from mesenchymal stem cells as a basis to treat skin aging. As an approach to therapy, this may function largely by improving clearance of senescent cells. As senescent cells actively maintain chronic inflammation via their secretions, removing them should reduce the chronic inflammation of age and its disruptive effects on skin maintenance. Whether this is the primary mode of action for stem cell therapies or exosome therapies has yet to be rigorously determined. Recent studies suggest that clearance of senescent cells is still ongoing even in older people, but not at a high enough rate to keep their numbers under control. Therapies that adjust clearance rates or creation rates for cellular senescence – as opposed to just directly destroying the excess senescent cells, which is the present focus of the senolytics community – may prove to be useful.

Mesenchymal Stem/Stromal Cell-Derived Exosomes for Immunomodulatory Therapeutics and Skin Regeneration

Aging, defined as irreversible deterioration of physiological processes of organisms over time, is characterized by nine hallmarks: cellular senescence, mitochondrial dysfunction, deregulated nutrient sensing, epigenetic alterations, telomere attrition, genomic instability, altered intercellular communication, and stem cell exhaustion. Among these, cellular senescence has recently been focused on as one of the key factors in the complex aging process as it is interlinked with other hallmarks. Senescent cells are accumulated in tissues of vertebrates with age. Interestingly, removal of senescent cells in animals results in the delayed onset of age-associated diseases.

Senescence is characterized by a stable cell-cycle arrest in the G1 phase and an inflammatory response called senescence-associated secretory phenotype (SASP), which modifies the microenvironment around senescent cells. Components of the SASP include growth factors, pro-inflammatory cytokines, chemokines, and extracellular matrix remodeling enzymes. SASP contributes to inflammaging, a term that describes low-grade, controlled, asymptomatic, chronic, and systemic inflammation associated with aging processes. Evidence points out that inflammaging may ultimately lead to age-related diseases. Thus, interventions that suppress SASP and inflammaging processes may hold potential to alleviate various chronic diseases.

It has been elusive that circulating mediators are responsible for rejuvenating multiple tissues of old organisms by parabiosis of young organisms. Very recently, it was demonstrated that extracellular vesicles (EVs) from young mice plasma extend the lifespan of old mice by delaying aging through exosomal nicotinamide phosphoribosyl transferase (eNAMPT). Another study also reported that exosomes from young mice could transfer miR-126b-5p to tissue of old mice, and reverse the expression of aging-associated molecules. Another report revealed that EVs derived from serum of young mice attenuated inflammaging in old mice by partially rejuvenating aged T-cell immunotolerance. Implantation of hypothalamic stem cells or progenitor cells, which were genetically engineered to survive from aging-related hypothalamic inflammation, was reported to induce retardation of aging and extension of lifespan in mid-aged mice.

More importantly, growing evidence suggests that cellular senescence can be alleviated or reversed by EVs or exosomes derived from stem cells. For example, human exosomes reduced the high glucose-induced premature senescence of endothelial progenitor cells (EPCs) and enhanced wound healing in diabetic rats. Taken together, mesenchymal stem cell derived exosomes confer anti-senescence effects through their unique miRNA, lnRNA, and enzyme contents. By inducing proliferation and reducing SASP in senescent cells, they hold great potential to reduce senescent cells in tissues. Since removal of senescent cells from tissues was reported to create a pro-regenerative environment and tissue homeostasis, application of mesenchymal stem cell derived exosomes to remove the senescent cells may be a preferable approach to induce the regeneration or rejuvenation of tissues.