Exosome Therapy : Overview and benefits
Potential of extracellular vesicles
Extracellular vesicles (EVs) are membrane-enclosed nano size objects excreted by all cell types. Their composition is cell-type dependent: a wide range of biomolecules such as proteins, enzymes, lipids, or nucleic acids can be found encapsulated in those particles . Widely considered serving as information vectors between cells and, at a greater range, organs, EVs are active players participating in homeostasis and disease, acting as biological effectors in many physiological processes such as immune response, pregnancy, coagulation, and cancer. Extracellular vesicles as new therapeutic tools would allow opening a new era in cell therapy and in drug delivery. In cell therapy, by mitigating the limitations and hurdles related to the administration of viable stem cells such as the risks of uncontrolled cell replication, differentiation, or vascular occlusion.
Additionally, EVs benefit from leading advantages in terms of sterilization, storage and shelf-life compared to their cellular counterparts. In fact, many clinical trials registered at www.ClinicalTrials.gov attempt to propose an EV therapy as an alternative to a cellular therapy. For drug delivery, EVs have proven a huge potential for precise targeted delivery, paving the way for precision medicine. Because of all these properties, the EV use in therapy is supported by a growing research field. There are two main approaches in using EVs as therapeutic agents: using them as they are excreted by unmodified cells and engineering them or the producer cells.
Regenerative and immunomudalotory properties
Unmodified EVs can be used for their immune-modulatory properties and in regenerative medicine. Mesenchymal stem cells’ (MSCs) EVs are the most investigated type for those applications. Historically, MSCs were widely studied as they exhibit, when injected in animal models, very interesting immune-modulating and regenerative activities.
Essential processes in regenerative medicine are cell viability, immune responses, extracellular matrix interaction and angiogenesis. To explain tissue regeneration after the injection of MSCs in any injured organ, it was first hypothesized that MSCs would differentiate into the desired cell type to induce tissue regeneration. However, it was discovered a poor cell retention and survival in the injury site [2,3] resulting in unsatisfactory engraftment rates.
With these considerations, the second mechanism proposed is related to the cell paracrine effect mediated, amongst others, by EVs (exosomes, microvesicles and apoptotic bodies) [4,5]. Recent discoveries demonstrate that EVs generated by MSCs have protective and reparative properties to induce a regenerative effect in vivo in cardiovascular diseases, acute kidney injury, brain injury, liver injury, osteoarthritis, bone regeneration, lung injury and cutaneous wound healing [6-12]. Clinical studies on the efficacy of MSC EVs for applications in regenerative medicine are currently running (NCT05078385).
Detailed mechanism of actions
To go more in the details of the effects of EVs in regenerative processes, let’s begin with the effect on cell death and senescence. It has been demonstrated that exosomes from endothelial cells promote angiogenesis by inhibiting cellular senescence . The effect has also been shown for exosomes derived from umbilical cord mesenchymal stem cells, with a suppression of apoptosis : it was interestingly both demonstrated in vivo and in vitro. These protective effects seem to lead to an accelerated epithelialization in rat skin burn models .
Tissue regeneration requires a good local cell nutrition: angiogenesis is therefore a key milestone for the process to be successful . Some results suggest MSC-derived exosomes promote angiogenesis in vitro and in vivo in rat models [17, 18]. However, EVs should be produced under hypoxic conditions to be active.
Regarding the role of EVs in extracellular matrix interaction, it has been shown that they express adhesion molecules as well as extracellular matrix remodeling proteins. Adhesion molecules such as ICAM-1, CD44, CD166 or integrins has been identified in extracellular vesicles derived from endothelial cells, dendritic cells, and reticulocytes [19, 20, 21]. As for the process of extracellular matrix remodeling, it participates in cytokine release, cell migration and angiogenesis. EVs have been shown to express proteins participating in those processes, such as matrix metalloproteinases: it is the case for cardiomyocyte progenitor cells, for example .
For the immune-modulatory effect, it has been shown that immune responses have a key effect on regenerative processes, allowing better recruitment, proliferation, and angiogenesis . MSC EVs were demonstrated to have an immune-suppressive effect . This effect was proved to be an advantaged for clinical approaches in a clinical trial using MSC derived EVs to ameliorate the progression of chronic kidney diseases .
For more information on translational studies employing MSC-derived microvesicles and exosomes, please refer to Donald G. Phinney et. al. (2017)  and Lee et. al. (2021)  for all the fields of application of MSC-EV based therapies.
Finally, one of the major hurdles hampering the translation of extracellular vesicles into clinical therapies is the regulatory classification of those particles, as it impacts the manufacturing and quality control requirements. Also, there are questions to be answered regarding the regulatory aspects of using products from genetically modified cells. Guidelines addressing those matters are available in Silva et al. EVOLVE review .
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 : Zhang, H. et al. (2007) ‘Injection of bone marrow mesenchymal stem cells in the borderline area of infarcted myocardium: Heart status and cell distribution’, The Journal of Thoracic and Cardiovascular Surgery, 134(5), pp. 1234-1240.e1. Available at: https://doi.org/10.1016/j.jtcvs.2007.07.019.
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 : Ratajczak, M.Z. et al. (2012) ‘Pivotal role of paracrine effects in stem cell therapies in regenerative medicine: can we translate stem cell-secreted paracrine factors and microvesicles into better therapeutic strategies?’, Leukemia, 26(6), pp. 1166–1173. Available at: https://doi.org/10.1038/leu.2011.389.
 : Lai, R.C., Chen, T.S. and Lim, S.K. (2011) ‘Mesenchymal stem cell exosome: a novel stem cell-based therapy for cardiovascular disease’, Regenerative Medicine, 6(4), pp. 481–492. Available at: https://doi.org/10.2217/rme.11.35.
 : Yuan, Y. et al. (2018) ‘Stem Cell-Derived Exosome in Cardiovascular Diseases: Macro Roles of Micro Particles’, Frontiers in Pharmacology, 9, p. 547. Available at: https://doi.org/10.3389/fphar.2018.00547.
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