Review: MSCs and Exosomes Production

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MSCs and Extracellular Vesicle Production:
A Gateway to Regenerative Medicine
Mesenchymal stem / stromal cells (MSCs) have emerged as a promising tool in regenerative
medicine due to their unique properties, including self-renewal and differentiation capability.
One of the key mechanisms through which MSCs exert their therapeutic effects is via paracrine
signalling, which includes the production and secretion of Extracellular Vesicle (EVs), often
termed as exosomes or macrovesicles that play a crucial role in intercellular communication
and tissue repair. This article provides an overview of MSCs, their role in EVs production, and
the potential applications of MSC-derived EVs in regenerative medicine. In the scientific
community is a very active discussion regarding the appropriate nomenclature for
mesenchymal stem cells (MSCs): Some experts suggest MSCs should be more accurately
termed "stromal cells" to reflect their supportive role in tissue rather than their stem cell-like
qualities 24-27 . So here we will incorporate both names and refer to these cells mesenchymal
stem/stromal cells (MSCs) throughout this article.
Understanding MSCs
MSCs non-hematopoietic, multipotent, adult stem / stromal cells that can be isolated from
various biological sources such as bone marrow, adipose tissue, Wharton's jelly of the
umbilical cord, brain, spleen, kidneys, liver, placenta, dental pulp, neurons, lungs, skin, and
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breast milk. MSCs have further been defined by the International Society for Cellular Therapy
(ISCT) based on specific criteria outlined in a position statement from 2006. According to these
criteria, MSCs must exhibit certain characteristics to be classified as such. These include the
ability to adhere to plastic surfaces during in vitro culture, expression of specific surface
markers such as CD105, CD73, and CD90 while lacking CD45, CD34, CD14, or CD11b,
expression markers and the capacity to differentiate into osteoblasts, adipocytes, and
chondrocytes under specific in vitro conditions 22,23 . These criteria are crucial for the
identification and standardization of MSCs across various tissue sources. Importantly, the
tissue source of MSCs can influence their therapeutic potential, making it essential to
understand the differences between MSCs isolated from different tissues to predict their
behaviour and widen their clinical use 1 .
Extracellular Vesicles: Nature's Nanoscale Messengers
EVs, nanoscale membrane-bound vesicles released by various cell types, including MSCs, play
a vital role in an array of cellular functions, including intercellular communication, cell
differentiation, and proliferation, angiogenesis, stress response, and immune signalling. The
ability to carry out these different functions is because of the complexity of EVs. These vesicles
carry and transfer functional cargo like proteins, messenger RNAs, microRNAs, cytokines,
lipids, cell surface receptors, enzymes, and transcription factors from cells to the recipient cells.
Their sizes range from 30 to 150 nanometres, originating from a specialized biogenesis
pathway.
The composition of EVs is contingent on the donor cell type and the physiological context of
production. EVs interact with recipient cells through specific adhesion molecules and can be
internalized via multiple pathways, dependent on the proximity of the target cells. The nucleic
acid content in EVs is particularly influential in their functional capacity. They harbour distinct
markers including tetraspanins (CD9, CD63, CD81), integrins, MHC molecules, HSP70,
HSP90, Alix, TSG101, and GTPases. The lipid bilayer encapsulating EVs confers stability and
protection, facilitating their biological roles. MSCs release large amounts of EVs for cell-tocell
communication, maintaining a dynamic and homeostatic microenvironment for tissue
repair and regeneration 2,28 . Furthermore, EVs have been implicated in various physiological
and pathological processes, including cardiovascular diseases and neurogenesis 3,29-31 .
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MSC-Derived EVs: Key Agents in Regenerative Medicine
Past research has demonstrated that, despite positive effects in various settings, MSCs were
barely detected in affected tissues, resulting in the hypothesis that they mainly act via their
secretome rather than in a direct cellular manner 15 . Using the examples of an acute kidney
injury model and a myocardial infarction model that MSCs were found to exert their
therapeutic effects EVs 33 .
MSC-derived EVs have become key players in regenerative medicine, showcasing a broad
range of therapeutic effects. Originating from MSCs, these EVs carry immunomodulatory,
regenerative, and anti-inflammatory traits, making them highly effective in tissue repair,
angiogenesis, inflammation control, and wound healing. They contribute significantly to
critical cellular processes, including angiogenesis, fibrosis reduction, and remodelling of the
extracellular matrix. They are particularly promising for treating a spectrum of conditions such
as cardiovascular, renal, hepatic, pulmonary, and neurodegenerative diseases, and they also
exhibit antimicrobial effects.
Unlike MSCs themselves, which can pose challenges related to cell viability, potential for
immune rejection, and the complexity of direct use in regenerative therapies, MSC-EVs offer
a safer, more stable, and potentially more effective alternative. In contrast to cell therapies,
EVs are not self-replicating, and they lack endogenous tumour formation potentials. EVs do
not seem to sense environmental conditions, and thus, their biological activity can be predicted
more reliably than that of cells. Preconditioning and engineering techniques have enhanced the
efficacy of MSC-EVs, paving the way for improved outcomes in cell-free therapeutic
interventions 8 . This evolution emphasizes the strategic advantage of utilizing MSC-EVs over
direct MSC therapies, as they represent an innovative method for harnessing the full
regenerative potential of mesenchymal stem cells, setting a new standard in medical treatments.
Culture and Expansion of MSCs for Extracellular Vesicle
Production
The origin, culture, and expansion of MSCs are crucial for EVs production. The choice of
expansion method significantly impacts EVs yield and quality.
The field of MSC research faces challenges due to the inherent tendency of primary MSCs to
undergo senescence during culture expansion. This limitation has prompted researchers to
explore the generation and characterization of immortalized MSC (iMSC) lines as a potential
solution. IMSC lines, such as those created by inducing the expression of human telomerase
reverse transcriptase (hTERT), have been investigated for their ability to offer a reliable and
scalable source of MSCs for EVs production 17 . Studies have indicated that iMSC lines could
serve as a consistent resource for EVs production, which is crucial for various therapeutic
applications. However, it is important to note that iMSCs may exhibit functional alterations
compared to primary MSCs 18 .
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This difference in functionality raises concerns about the suitability of iMSCs for certain
applications and underscores the importance of further research to understand the implications
of iMSC behaviour and characteristics. Moreover, the source of MSCs, whether primary,
induced pluripotent stem cell (iPSC)-derived, or immortalized, can influence EVs production.
While iPSC derived MSCs have shown promise for specific applications, primary MSCs are
still preferred in many cases due to their superior supportive capabilities in co-culture
systems 19 . The choice of MSC source is a critical consideration in EVs production, as it can
impact the quantity and quality of EVs generated for therapeutic purposes.
The culture media used for MSC expansion can also influence EVs production and
functionality. The use of defined media has been suggested as advantageous for maintaining
the desired characteristics of MSCs and their derived EVs 20 . Additionally, it may be necessary
to add special lipid cocktails for high EVs production. The balance between high
proliferation/expansion rates and EVs production is a critical consideration. While high
proliferation rates are desirable for obtaining large quantities of MSCs, it may lead to
competition for resources, such as lipids, which are essential for both proliferation and EVs
biogenesis 21 . Studies have indicated that the efficiency of EVs production may inversely
correlate with the developmental maturity of the MSC donor, further highlighting the
importance of donor selection for optimal EVs yield 21 .
Moreover, the choice of having serum in the cell culture, such as FBS, hPL, or AB serum, can
introduce both variability in proliferation, and expansion. Utilizing defined media can help to
overcome these batch-to-batch variabilities and ensure consistent functional EVs production 20 .
In conclusion, the culture and expansion of MSCs for EVs production involve various factors
that influence the quantity and quality of EVs. Careful consideration of expansion methods,
culture media, cell source, proliferation rates, and serum choice is essential to optimize EVs
production for therapeutic applications. Special lipid cocktails may be necessary to enhance
EVs production efficiency and yield, further emphasizing the importance of optimizing culture
conditions for successful EVs-based therapies.
Isolation Techniques for MSC-Derived EVs
Isolating EVs from MSCs is a noteworthy area of research, essential for obtaining pure EVs
samples for applications ranging from therapeutic use, drug delivery, regenerative medicine,
and tissue engineering. Various methods such as ultracentrifugation, differential
ultracentrifugation, and tangential flow filtration are employed, each with its distinct
advantages and limitations 4 .
• Ultracentrifugation: Ultracentrifugation is one of the most traditional and widely used
methods for Extracellular Vesicles isolation. This technique relies on the application of
extremely high centrifugal forces, typically ranging from 100,000 to 200,000g to
sediment EVs from MSC culture media or other biological fluids. The process involves
multiple centrifugation steps at varying speeds and durations to progressively remove
cells, cell debris, and larger vesicles, culminating in the sedimentation of EVs.
o
Advantages:
Widely available: The equipment required for ultracentrifugation is available in
most research laboratories.
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Scalable: It can be adapted for large-volume preparations, making it suitable for
both research and clinical applications.
o
Limitations:
Time-consuming: The process is labor-intensive and requires several hours to
complete.
Potential for contamination: Co-isolation of protein aggregates or other vesicles
of similar density can occur.
Sample integrity: The high forces applied can potentially damage the EVs or
alter their functional properties.
• Differential Ultracentrifugation
Differential ultracentrifugation refines the basic ultracentrifugation process by
employing a series of centrifugation steps at gradually increasing speeds. This method
allows for more precise separation of EVs from other components based on their size
and density.
o
o
Advantages:
Improved purity: By carefully adjusting the centrifugation parameters, it is
possible to enhance the purity of the isolated EVs.
Versatility: It can be used in conjunction with other purification steps to further
increase the yield and purity of EVs.
Limitations:
Complexity: The process requires meticulous optimization of centrifugation
speeds and times for each specific sample type.
Sample loss: Each centrifugation step may lead to a loss of EVs yield.
• Tangential Flow Filtration (TFF) 32
Tangential flow filtration is a more modern approach that utilizes a crossflow
mechanism, where the sample fluid flows tangentially across the surface of a membrane
filter. This method effectively separates EVs based on their size, allowing them to pass
through the membrane while larger particles are retained.
o
o
Advantages:
Efficiency: TFF can process large volumes of samples in a relatively short
amount of time.
Gentle on samples: The technique is less likely to damage EVs compared to
ultracentrifugation.
Scalability and reproducibility: TFF is easily scalable and offers high
reproducibility, making it suitable for clinical applications.
Limitations:
Equipment cost: The initial investment for TFF systems can be high.
Membrane maintenance: Over time, the membrane may become clogged with
particles, requiring regular maintenance or replacement.
The choice of an EVs isolation technique depends on various factors, including the source of
MSCs, the volume of the sample, the desired purity and yield of EVs, and the available
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resources. Each method has its trade-offs; thus, a combination of techniques should be used to
achieve the best results. Continuous advancements in EVs isolation technologies are expected
to enhance the efficiency, yield, and purity of EVs preparations.
Enhancing EVs Production from MSCs
Optimizing the production of EVs from MSCs can significantly lead to more effective application
possibilities by ensuring that enough potent, high-quality EVs are available for research and clinical
therapy.
Currently, several strategies are being developed to boost EVs production:
• Culturing with Bioactive Glass (BG) Ion Products: Culturing MSCs with BG ion productenriched
medium significantly increases Extracellular Vesicles production without altering
their inherent characteristics 5 .
• Use of Small Molecules: Identified specific small molecules capable of enhancing
Extracellular Vesicles production in MSCs, with ongoing research exploring their effects on
the EVs composition and regenerative capacity 6 .
• Preconditioning and Engineering: Innovative strategies such as preconditioning MSCs and
engineering EVs are being investigated to amplify the therapeutic activity of MSC-EVs 7 .
Navigating the Evolving Landscape of Engineered EVs Therapies:
Opportunity and Challenges in Clinical Translation
The landscape of EV-based therapies growing exponentially, with over 150 clinical trials,
spanning various domains such as respiratory disorders, infectious diseases, and oncology 9 .
Notably, MSC-EVs are particularly promising, offering a compelling alternative to traditional
stem cell therapies. As we have talked earlier, MSC-EVs can replicate the therapeutic impacts
of their source MSCs, with added benefits like reduced size, increased stability, and more
versatile administration routes 10 . Various companies are at the forefront of advancing the
therapeutic potential of EVs through the engineering of EVs membrane proteins. These
developments have led to innovative treatments, such as the creation of inhalable COVID-19
vaccines utilizing EVs derived from lung stem cells. The contributions from multiple
companies have played a significant role in driving progress in this field. The exciting world
of engineered Extracellular Vesicles therapy is on the brink of transforming how we approach
healing, opening a whole new world of medical possibilities 11 . Despite the promise of MSC-
EVs, challenges persist in translating these therapies from bench to bedside. Issues concerning
safety, standardized isolation protocols, and EVs characterization require resolution 12 .
Additionally, the heterogeneity of EVs populations, influenced by extracellular environmental
factors, complicates their therapeutic application 13 . A deeper understanding of exosomal cargo
and its disease-specific roles is imperative for the full realization of exosomal potential in
clinical settings.
Lastly, the scale-up of MSC-EVs production for clinical applications encounters significant
difficulties, primarily due to the substantial volume required to treat a single patient. Traditional
volume reduction methods, such as ultracentrifugation, are notably inefficient for this scale,
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with the maximum processing volume per run capped at under 500 mL, starkly inadequate for
the quantities needed for EV-based therapeutics. This limitation highlights a critical bottleneck
in the transition from laboratory-scale research to clinical applications. Key challenges include
maintaining the purity and functionality of EVs, ensuring consistent quality across batches,
source of EVs, isolation methods, and biodistribution, which are crucial for the successful
translation of MSC-EVs into clinical use.
In summary, the synergy between MSCs and EVs is illuminating new frontiers in regenerative
medicine. As we unravel the complexities of MSC-EVs, we edge closer to a new epoch of
therapeutic interventions that are safer, more efficacious, and transformative. These diminutive
vesicles, emerging from the intricacies of cellular communication, hold the potential to redefine
medical treatments, offering renewed hope for patients worldwide.
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