From Mesenchymal Stromal Cells to Engineered Extracellular Vesicles: A New Therapeutic Paradigm

Abstract

Mesenchymal stromal cells (MSCs) are multipotent cells obtained from many tissues including bone marrow, adipose tissue, umbilical cord, amniotic fluid, and placenta. MSCs are the leading cell source for stem cell therapy due to their regenerative and immunomodulatory properties, their low risk of tumorigenesis and lack of ethical constraints. However, clinical applications of MSCs remain limited. MSC therapeutic development continues to pose challenges in terms of preparation, purity, consistency, efficiency, reproducibility, processing time and scalability. Additionally, there are issues with their poor engraftment and survival in sites of disease or damage that limit their capacity to directly replace damaged cells. A key recent development in MSC research, however, is the now widely accepted view that MSCs primarily exert therapeutic effects via paracrine factor secretion. One of the major paracrine effectors are extracellular vesicles (EVs). EVs represent a potential cell-free alternative to stem cell therapy but are also rapidly emerging as a novel therapeutic platform in their own right, particularly in the form of engineered EVs (EEVs) tailored to target a broad range of clinical indications. However, the development of EVs and EEVs for therapeutic application still faces a number of hurdles, including the establishment of a consistent, scalable cell source, and the development of robust GMP-compliant upstream and downstream manufacturing processes. In this review we will highlight the clinical challenges of MSC therapeutic development and discuss how EVs and EEVs can overcome the challenges faced in the clinical application of MSCs.

Increasing the Therapeutic Efficacy of Extracellular Vesicles From the Antigen-Specific Antibody and Light Chain Perspective

“…Recent studies and clinical trials uncovered a number of hurdles that are faced by the cell-based therapies. The widely described obstacles affecting the efficacy of stem cell therapies result mainly from a lack of standardized treatment procedures, low percentage of cells that reach the desired tissue/organ, the poor survival of engrafted cells that often rapidly undergo apoptosis in targeted tissues, and finally from the diversity of yielded cell populations between individual donors ( Hassanzadeh et al, 2021 ; Johnson et al, 2021 ; Wang et al, 2021 ). In addition, stem cell therapies raise concerns about possible adverse events of the treatment that are associated with the risk of tumorigenesis, the possibility of disrupted or abnormal maturation of infused cells as well as with their eventual differentiation in undesirable tissue ( Lukomska et al, 2019 ).…”

“…Abovementioned obstacles and concerns prompted researchers to search for safer alternatives that could efficiently replace the living cells for therapeutic purposes. Consequently, EVs released by these cells become considered main promising candidates for cell-free therapies ( Tang et al, 2015 ; Johnson et al, 2021 ; Wang et al, 2021 ; Yao et al, 2021 ).…”

“…This assumption is supported by the fact that the cargo is sorted into EVs, exosomes especially, in a very sophisticated manner, and represents a unique content of proteins, RNAs, and lipids, usually differing from the parental cell ( Wei et al, 2021 ). Thus, stem cell-derived EVs cannot differentiate but can promote immune tolerance ( Wang et al, 2021 ), and tissue regeneration ( Johnson et al, 2021 ) instead of tumorigenesis ( Lukomska et al, 2019 ), since they do not carry full genomic DNA material. Moreover, EVs can carry and present antigens as do dendritic cells, but they are unable to switch their phenotype ( Yao et al, 2021 ).…”

“…The latter EV feature together with still expanding knowledge about their biology and functions opened up a new research area attempting both to improve the properties of cell-derived EVs and to design and manufacture their artificial counterparts ( García-Manrique et al, 2018 ) in order to design the most appropriate therapeutic modality, for example in personalized medicine. Such possibilities support the consideration of either manipulated or engineered EVs as next generation biotherapeutics with almost unlimited therapeutic activities and indications that would be easy to produce, handle, and distribute ( Johnson et al, 2021 ). Obviously, as discussed below, selecting the best cellular source of EVs for each considered application is the first crucial step on the way to personalize the EV-based therapeutics ( Campanella et al, 2019 ; Logozzi et al, 2021a ).…”

“…Furthermore, EVs could be used by pathogens for infection spreading, and thus one can speculate that they may transfer virulence factors, which has to be taken into consideration while manipulating EVs for therapeutic applications ( Pironti et al, 2021 ). On the other hand, attempts to solve the challenges of stem cell therapy allowed to discover that EVs are the main paracrine factors that actually mediate the effects induced by administration of their parental cells ( Johnson et al, 2021 ; Wang et al, 2021 ). However, despite having many advantages over such approaches, EV-based therapeutics usually achieve lower or almost the same therapeutic efficacy than releasing cells ( Kalluri and LeBleu, 2020 ).…”