About this Research Topic

Background

The anti-inflammatory, immuno-modulatory, and tissue progenitor activating features of mesenchymal stem/stromal cells (MSCs) have made them a promising therapeutic tool in cellular therapy for regenerative medicine. This has sparked multiple clinical studies about their applications for different medical conditions and diseases, including degenerative, traumatic, immune/inflammatory-related, and ischemic disorders. It is nowadays appreciated that MSCs exert their effects via the release of bioactive factors collectively referred to as the MSC secretome. Bioactive factors within the secretome can be “free-floating” or packaged within extracellular vesicles (EVs). The MSC secretome can regulate different physiological processes, such as cellular proliferation, differentiation, and migration, and most importantly it has been shown to possess comparable in vitro functional properties and in vivo therapeutic benefits with respect to their cellular counterparts. Consistently, clinical trials have recently started using MSC-EVs. Overall, the use of the secretome/EVs in therapy may have relevant advantages, including: i) storage at low temperatures without the need to use potentially toxic cryopreservation agents; ii) increased safety related with the reduced risks of potential cell differentiation events; iii) the ability to circulate through thin capillaries and thus reach distant places; iv) the ability to cross the blood-brain barrier; v) potentially less-stringent regulatory requirements; vi) the possibility to have a defined “off-the-shelf” product with predictive potency and dosage testing.

Among the several challenges associated to the production of the MSC secretome or purified components such as EVs, two correlated and crucial points have to be unraveled: the choice of the most affordable and effective MSC source and the molecular fingerprint of the released factors. In fact, MSCs may be obtained from several sources, fetal or adult, including tissue progenitors potentially having clinically-relevant features. In addition, the array of secreted molecules and EVs with their cargo, that altogether defines secretome potency and is dependent on the source type, must be defined to better understand the disease-targeted mechanisms of action. Also, the identification of secreted factors or the EV cargo can be specifically designed by genetic engineering of the sourcing cells or by modulating by the culture conditions. Additionally, the methodology to isolate and purify the secretome, and especially EVs, must be highly controlled and optimized. Eventually, the secretome/EVs fingerprint will be crucial to develop release and disease-driven potency assays for future clinical batches. Therefore, the translation into clinical application remains difficult since, to date, there is both lack of a profound molecular characterization and great heterogeneity in study design, including quality control, for the release of the entire or fractionated (e.g. EVs) secretome.

The purpose of this Research Topic is to introduce recent advances in the study of MSCs secretome or purified EVs. We welcome the submission of Reviews, Original Research articles, Case Report that cover, but are not limited to, the following topics:
1. Characterization of secretome/EVs molecular fingerprint from both fetal and adult MSCs, including tissue progenitors
2. Bioengineered secretome/EVs as delivery vehicles for therapeutic drugs and molecules, including priming culturing conditions to enhance therapeutic properties
3. in vitro and in vivo studies defining secretome/EVs potency, with particular focus on tissue regeneration and immunomodulation
4. Applications of secretome/EVs as cell-free products in regenerative medicine including clinical trials.
6. Identification of molecular markers and release/potency assays for secretome/EVs batches quality control
7. Pros and cons of off-the-shelf secretome/EVs based products
8. Regulatory aspects, including standardization, GMP-compliance and legislation involving secretome and EV-based therapeutics

Prof. Diego Correa is Founder of Lumos Biomed Consulting, LLC. The rest of the Topic Editors declare no conflicts of interest with regards to this Research Topic.

Keywords: Mesenchymal Stem/Stromal Cells, Regenerative Medicine, Extracellular Vesicles, Cell-Free, Translation

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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