Commentary - Journal of Experimental Pathology (2021) Volume 2, Issue 1
News About the Extracellular Vesicles from Mesenchymal Stem Cells: Functions, Therapy and Protection from COVID-19
Division of Neuroscience, San Raffaele Scientific Institute, and Vita-Salute San Raffaele University, via Olgettina 58, 20132 Milan, Italy
- *Corresponding Author:
- Jacopo Meldolesi
Received date: February 14, 2020; Accepted date: March 05, 2021
Citation: Meldolesi J. News About the Extracellular Vesicles from Mesenchymal Stem Cells: Functions, Therapy and Protection
from COVID-19. J Exp Pathol. 2021;2(1):47-52.
Copyright: © 2021 Meldolesi J. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
This is a Commentary of a review about extracellular vesicles of immune cells published two years ago in Clinical and Experimental
Immunology, a prestigious journal of the field. The aim is to establish whether, and to what extent, results in scientific area of the
review have been extended and strengthened by innovative findings of considerable interest. The analysis of the recently published
results has revealed that in various areas of the review developments have occurred. However, innovative findings have been only
about the extracellular vesicles secreted by mesenchymal stem cells, usually indicated as MSC-EVs. Based on these findings, the
Commentary has been focused on recent MSC-EVs findings presented in three Sections dealing with 1. recently appeared, relevant
functions of the latter vesicles; 2. therapeutic processes developed according well known criteria, however innovative in many
respects; and 3. protection of COVID-19 disease patients from organ lesions induced by the specific virus, SARS-CoV-2, during the
disease. As everybody knows, the COVID-19 pandemic started at the end of 2019, thus after the publication of the aforementioned
review. Data of Section 3 are therefore innovative, of great potential interest also at the clinical level, applied by translational medicine
to various organs, from lung to brain, heart, kidney, immune and other cells. In view of its relevance, the author expects that research
and medical use of MSC-EV, active at present, will be further developed, acquiring additional relevance in the near future.
The present Commentary is a critical follow-up of a previous review about “Extracellular vesicles, news about their role in immune cells: physiology, pathology and diseases”, appeared in Clinical and Experimental Immunology last June 2019 . During the last 5 years several reviews about the immune role of exosomes and extracellular vesicles (EVs, combinations of exosomes and ectosomes ) had already been published. Most such reviews, however, were specialized, reporting basic and/ or applicative effects induced in specific immune cells, operative alone or in cooperation with non-immune cells, including cells of cancer and cancer microenvironment. At variance with the specialized reviews, the aforementioned review had been planned in general terms, focused on the main effects induced by immune EVs on healthy, pathological, and diseased cells. In all reported studies the observed effects of EVs were variable, dependent on their heterogeneity and on the environment where their interaction with target cells was taking place. All together, these results had been conceived as tools, useful to increase knowledge about various diseases, dealing especially with their diagnosis and with the development of innovative therapies.
The immune studies about pathology and diseases, governed by various EVs, have been intensely pursued during the last two years, i.e. after the publication of author’s review . The conditions most often investigated have been those already mentioned, dealing with the interaction of two immune cells  and the co-operation of single immune cell with non-immune cells of cancer [4,5] or cancer microenvironment [6,7]. In many such recent studies, interest was mostly due to new cell types and/or new techniques employed. However, the general framework remained similar to the previous reviews. Therefore, these studies did not appear appropriate for a Commentary.
Another issue that, in contrast, appeared appropriate to author for the Commentary is related to mesenchymal stem cells (MSC), a family of multipotent cells discovered several decades ago. MSC cells, resident in the stroma of all body tissues, are competent for self-replication and multidirectional differentiation, favorable for culturing, manipulation and attenuation of inflammatory processes. Such properties of MSC do not depend only on their direct intercellular communication. In addition to the release of soluble and bioactive factors, such as cytokines and growth factors, MSCs undergo secretion of specific EVs, referred to as MSC-EVs. Investigated from 2015, such EVs have grown progressively to a maximum in 2020. In most cases the MSC-EVs have been found to induce effects analogous, but simpler and clinically more convenient, with respect to those of their parental cells. Among their functions, MSCEVs modulate immune responses. Recruitment in their proximity of needed cells may result in boosting immune response, associated in many cases to protective roles in infectious diseases. Examples concerning MSCs and diseases had been already included in author’s previous review [8-10]. At the time, however, relevant properties, concerning MSC-EV production and function had not been established.
At this point, the introduction of the Commentary on MSC-EVs and their role in immunities, is complete. The presentation of their recent developments is organized in three Sections dealing with the innovative role of MSCEVs, their therapeutic perspectives, and their promising role in the protection of severe lesions induced during the COVID-19 disease. In view of the recent appearance of the latter disease such a protective role of MSC-EVs was unexpected.
Innovative Role 0f MSC-EV
The general effects of MSC-EVs, in particular their suppression of inflammation, promotion of regeneration, and immunomodulation, remained as reported previously. However, the parallel investigation of EVs secreted by MSCs of different origin emphasized the heterogeneity of their effects. For example, EV regulation can make prominent both the innate and adaptive immune reactions; the EVinduced altered effects can appear in several immune cells, not only various lymphocytes but also natural killer cells, dendritic cells and especially macrophages; MSCEVs can govern immune-modulatory effectors or transmit active signal molecules, thus participating in various distinct processes such as differentiation, activation, proliferation and also suppression of immune cells [11-14]. Moreover, MSC-EVs from different tissues (bone marrow, adipose tissue, and umbilical cord) exhibit different cargo proteins . This difference is relevant also because
proteins and microRNAs (miRNAs) of such cargos induce different therapeutic effects. In addition, they operate as
biomarkers, relevant for the diagnosis and the treatment
of autoimmunity–related diseases [16,17].
Innovative results have been reported about MSC-EVs of specific origin. The immune cells of adipose origin, mostly stimulated by the above vesicles, are specific macrophages that induce regulations of immunomodulatory and inflammatory-mediated responses. For these effects macrophages are considered for therapy of immunemediated diseases . Analogously, the vesicles have been shown to ameliorate the conditions of a mouse model with immune mediated aplastic anemia  and to mitigate trained immunity in the brain . Moreover, the intranasal administration of MSC-EV meliorates the experimental autoimmune encephalomyelitis . The concomitant study of two diseases, multiple sclerosis and amyotrophic lateral sclerosis, demonstrated the expression in the MSC-EVs cargo of six miRNAs, two of which were found to dampen the pro-inflammatory phenotype of microglia, with ensuing decrease of its neuroinflammation . Moreover, the well-known, anti-apoptotic neutrophil effect of MSC is due to its MSC-EVs, reinforced if isolated from the Wharton’s jelly. With this action the EVs appear to induce protection on neutrophil function and lifespan .
An advanced therapeutic role of MSC-EVs, developed during the last few years, is based on their well-known immune-modulatory potential of vesicles processed by various treatments including their drug accumulation followed by intracellular target release. Exciting vesicles operate by their cargo components, with concomitant crossing of biological barriers and without immune rejections and lung entrapments, where antiinflammatory and/or regenerative actions are needed. MSC-EVs, administered both locally and systemically, induce multiple effects [24,25]. Together with reduction of inflammation and fibrosis associated with diseases they suppress the detrimental immune response of inflamed tissues and promote survival and regeneration of injured parenchymal cells . Moreover, the MSCEV modulation of immune responses is able to attack diseases by activation of autophagy and/or inhibition of apoptosis, necrosis, oxidative stress and other processes [27,28]. At clinical stage, the effect of many MSC-EVs closely resembles the responses to MSC, and the number of protected diseases is considerable. In some cases, the similarity between MSC and their EVs, initially limited, becomes stronger a few days later. Moreover, since the use of MSC-EVs have appeared safe in humans, with low risk of immune- and carcinogenicity, their use for therapy in translational medicine is expected to become more common in the near future [16,24,25,29-31].
Protection of the COVID-19 Disease
COVID-19 is a disease rapidly evolving into a pandemic, an unprecedented global health emergency, aggravated at present by the lack of effective therapies. In view of the time of its identification (in Italy the end of February 2020), presentation about the MSC-EV effects on the disease, absent from the author’s review , is presented here as a completely innovative area of MSC-EV function. The severe lesions of the lung, the brain and other organs, induced by the COVID-19 virus SARS-CoV-2, are well known [32,33]. The presentation of possible anti-COVID-19 tools attracts therefore great interest. During the last two decades MSCs have been tested for treatment of various pathologic conditions, including acute and chronic lung diseases. The MSC-EV protective results against COVID-19, obtained recently, are solid as documented by several clinical trials, recently initiated or planned in several Countries [34,35].
The severity of COVID-19 seems to be mostly dependent on the patient responses. Over-activation of the immune system, developed by the system of the patients in the attempt to kill the SARS-CoV-2 virus, can cause a “cytokine storm” which in turn can induce an acute respiratory distress syndrome (ARDS), a well as multi-organ damage ultimately leading to death. It is known that, in COVID-19 patients, the immunomodulatory properties of MSCs ameliorate the cytokine-storm by providing a treatment through inhibiting or modulating the pathological events, especially those of severe cases [36,37]. Protection by MSCs is due to the release of their EVs, working through immunomodulatory effects, striking the COVID-19 balance in the immune cells of patients, with added advantages of increased safety and tissue penetration [38-39]. Interestingly, the MSC-EVs of mice were found stronger in their protection against ARDS if released from original cells pre-stimulated to release neurotrophic and immunomodulatory factors . The result obtained by MSC-EVs could regulate, in infected patients the inflammatory responses, promoting tissue-repair and regeneration of damaged organs [34,37-39]. Moreover, the MSC-EVs, active by molecules of their cargo, could also operate against weak antiviral antibodies, which contribute to dysfunctional responses .
Ongoing studies have been focused on the mechanisms by which MSC-EV, as a therapeutic option, induces alleviations of inflammatory responses and thus promote the restoring of injured tissues. Among the molecules of the vesicle cargos are miRNAs known to exacerbate cytokines and chemokines with stimulate cell death and coagulation cascade genes. Some miRNAs were found to modulate above processes, and thus to prevent tissue damage. Therefore, the heterogeneous cargo molecules of MSC-EVs are relevant for the survival of CAVID-19 patients . In other studies, SARS-CoV-2 was shown affected
by MSC-EVs in the brain hippocampus. Such EVs have a
cell-free action by which viruses are degraded apparently
by an adaptive antiviral function, possibly active against
the genes of various factors. The antiviral immunity of
brain MSC-EVs appears promising to fight not only SARSCoV-
2, but also other viruses .
The present Commentary has demonstrated, on the one hand, that the review on EVs of immune cells that the author published in 2019  covered ample biomedical issues, at the time highly interesting, which has been further developed in the two subsequent years; on the other hand, innovative findings in the same field, focused however on MSC-EVs, i.e. vesicles from a specific family of original cells, have been developed very intensely, reaching highest levels during the last two years. The areas of the latter research have been particularly interesting, emphasizing 1. the innovative role covered by MSC-EVs, different in many respects from those of other EVs, and 2. the therapeutic perspectives which, based on criteria and mechanisms typical of exosomes, offer various, much more innovative aspects, characterized by significant potentials. In the author’s presentation, however, the highest perspectives deal with an aspect, totally unexpected during the last two years, concerning the possible role of specific MSCEVs to participate in the defense of COVID-19 patients from the severe lesions induced by the SARS-CoV-2 virus. Such lesions are present in many organs, beginning with the lung and then with the brain, kidney and others. The extraordinary effects induced by MSC-EVs suggest, on the one hand, an impact much greater than those recently reported by other types of EVs; on the other hand, the possibility that MSC-EV protection is effective also after its direct administration in the tissues, starting with the brain, active not only against SARS-CoV-2 but also against other viruses.
A final aspect of the author’s presentation, until now left out from this Commentary, deals with the clinical aspects of MSC-EVs action, concerning in particular translational medicine. The MSC-EV therapy is produced by small structures, different from whole cells . Vesicles modulate immune responses as effectively as MSCs themselves, however with various advantages, including increased safety and faster tissue penetration. Knowledge about the numerous proteins involved in the complex interplay of MSC-EVs with immune cells, and about their function, promoted a good understanding of their functions [25,43]. MSC-EVs participate in intercellular
communication events. In addition to the diseases, they contribute to the healing of injured tissues and organs.
Therefore, they can be manipulated and applied to establish
novel cell-free therapeutic approaches for treatment of
a variety of pathological conditions, distinct from those
induced by viruses mentioned previously. In comparison
with their donor cells, MSC-EVs offer more stable
events, with diminished safety risks of microvasculature
occlusion [44,45]. The author conclude that MSC-EVs
possesses most of the functional and therapeutic activities
recognized to their original cells during the decades of
their employment. In view of their relevance during the
intense research, the author expect these activities to be
further developed in the near future.
This work has been funded by Telethon (grant GGP09066), a Foundation supported by EU. The author thank Palma Gallana for her contribution in the presentation of this Commentary.
- Meldolesi J. Extracellular vesicles, news about
their role in immune cells: physiology, pathology and
diseases. Clinical & Experimental Immunology. 2019
- Meldolesi J. Exosomes and ectosomes in intercellular
communication. Current Biology. 2018 Apr 23;28(8):R435-
- Tavasolian F, Hosseini AZ, Rashidi M, Soudi S,
Abdollahi E, Momtazi-Borojeni AA, et al. The Impact of
Immune Cell-derived Exosomes on Immune Response
Initiation and Immune System Function. Current
Pharmaceutical Design. 2021;27(2):197-205
- Xu Z, Zeng S, Gong Z, Yan Y. Exosome-based
immunotherapy: a promising approach for cancer
treatment. Molecular Cancer. 2020 Nov 12;19(1):160.
- Kugeratski FG, Kalluri R. Exosomes as mediators of
immune regulation and immunotherapy in cancer. The
FEBS Journal. 2021 Jan;288(1):10-35.
- Dragomir MP, Moisoiu V, Manaila R, Pardini B, Knutsen
E, Anfossi S, et al. A Holistic Perspective: Exosomes
Shuttle between Nerves and Immune Cells in the Tumor
Microenvironment. Journal of Clinical Medicine. 2020
- Dou D, Ren X, Han M, Xu X, Ge X, Gu Y, et al. Cancer-
Associated Fibroblasts-Derived Exosomes Suppress
Immune Cell Function in Breast Cancer via the miR-92/
PD-L1 Pathway. Frontiers in Immunology. 2020 Oct 9;11:2026.
- Börger V, Bremer M, Ferrer-Tur R, Gockeln L, Stambouli
O, Becic A, et al. Mesenchymal stem/stromal cellderived
extracellular vesicles and their potential as novel
immunomodulatory therapeutic agents. International
Journal of Molecular Sciences. 2017 Jul;18(7):1450.
- Mardpour S, Hamidieh AA, Taleahmad S, Sharifzad
F, Taghikhani A, Baharvand H. Interaction between
mesenchymal stromal cell-derived extracellular vesicles
and immune cells by distinct protein content. Journal of
Cellular Physiology. 2019 Jun;234(6):8249-58.
- Laso-García F, Ramos-Cejudo J, Carrillo-Salinas
FJ, Otero-Ortega L, Feliú A, Gómez-de Frutos M, et al.
Therapeutic potential of extracellular vesicles derived from
human mesenchymal stem cells in a model of progressive
multiple sclerosis. PloS One. 2018 Sep 19;13(9):e0202590.
- Bazzoni R, Kamga PT, Tanasi I, Krampera M.
Extracellular vesicle-dependent communication between
mesenchymal stromal cells and immune effector cells.
Frontiers in Cell and Developmental Biology. 2020;8.
- Qian X, An N, Ren Y, Yang C, Zhang X, Li L.
Immunosuppressive Effects of Mesenchymal Stem Cellsderived
Exosomes. Stem Cell Reviews and Reports. 2020
- Wang C, Börger V, Sardari M, Murke F, Skuljec J,
Pul R, et al. Mesenchymal Stromal Cell–Derived Small
Extracellular Vesicles Induce Ischemic Neuroprotection
by Modulating Leukocytes and Specifically Neutrophils.
Stroke. 2020 Jun;51(6):1825-34.
- Wang J, Xia J, Huang R, Hu Y, Fan J, Shu Q, et al.
Mesenchymal stem cell-derived extracellular vesicles
alter disease outcomes via endorsement of macrophage
polarization. Stem Cell Research & Therapy. 2020
- Wang ZG, He ZY, Liang S, Yang Q, Cheng P, Chen AM.
Comprehensive proteomic analysis of exosomes derived
from human bone marrow, adipose tissue, and umbilical
cord mesenchymal stem cells. Stem Cell Research &
Therapy. 2020 Dec;11(1):1-1.
- Cai J, Wu J, Wang J, Li Y, Hu X, Luo S, et al. Extracellular
vesicles derived from different sources of mesenchymal
stem cells: therapeutic effects and translational potential.
Cell & Bioscience. 2020 Dec;10:1-4.
- Wang JH, Liu XL, Sun JM, Yang JH, Xu DH, Yan
SS. Role of mesenchymal stem cell derived extracellular
vesicles in autoimmunity: A systematic review. World
Journal of Stem Cells. 2020 Aug 26;12(8):879-96.
- Heo JS, Choi Y, Kim HO. Adipose-derived
mesenchymal stem cells promote M2 macrophage
phenotype through exosomes. Stem Cells International.
2019 Nov 5;2019.
- Gholampour MA, Abroun S, Nieuwland R, Mowla
SJ, Soudi S. Mesenchymal stem cell-derived extracellular
vesicles conditionally ameliorate bone marrow failure
symptoms in an immune-mediated aplastic anemia mouse
model. Journal of Cellular Physiology. 2021 Jan 25.
- Feng Y, Guo M, Zhao H, Han S, Dong Q, Cui M.
Mesenchymal-Stem-Cell–Derived Extracellular Vesicles
Mitigate Trained Immunity in the Brain. Frontiers in
Bioengineering and Biotechnology. 2020 Nov 19;8:1321.
- Fathollahi A, Hashemi SM, Hoseini MH, Tavakoli
S, Farahani E, Yeganeh F. Intranasal administration of
small extracellular vesicles derived from mesenchymal
stem cells ameliorated the experimental autoimmune
encephalomyelitis. International Immunopharmacology.
2021 Jan 1;90:107207.
- Giunti D, Marini C, Parodi B, Usai C, Milanese
M, Bonanno G, et al. Role of miRNAs shuttled by
mesenchymal stem cell-derived small extracellular vesicles
in modulating neuroinflammation. Scientific Reports.
2021 Jan 18;11(1):1-7.
- Taghavi-Farahabadi M, Mahmoudi M, Rezaei N,
Hashemi SM. Wharton’s Jelly Mesenchymal Stem cells
exosomes and conditioned media increased Neutrophil
lifespan and phagocytosis capacity. Immunological
investigations. 2020 Aug 12:1-16.
- Joo HS, Suh JH, Lee HJ, Bang ES, Lee JM. Current
knowledge and future perspectives on mesenchymal
stem cell-derived exosomes as a new therapeutic agent.
International Journal of Molecular Sciences. 2020
- Massa M, Croce S, Campanelli R, Abbà C, Lenta E,
Valsecchi C, et al. Clinical Applications of Mesenchymal
Stem/Stromal Cell Derived Extracellular Vesicles:
Therapeutic Potential of an Acellular Product. Diagnostics.
- Harrell CR, Jovicic N, Djonov V, Arsenijevic N,
Volarevic V. Mesenchymal stem cell-derived exosomes and
other extracellular vesicles as new remedies in the therapy
of inflammatory diseases. Cells. 2019 Dec;8(12):1605.
- Kahmini FR, Shahgaldi S. Therapeutic potential of
mesenchymal stem cell-derived extracellular vesicles
as novel cell-free therapy for treatment of autoimmune
disorders. Experimental and Molecular Pathology. 2020
- Fu DL, Jiang H, Li CY, Gao T, Liu MR, Li HW.
MicroRNA-338 in MSCs-derived exosomes inhibits
cardiomyocyte apoptosis in myocardial infarction.
European Review for Medical and Pharmacological
Sciences. 2020 Oct 1;24(19):10107-17.
- Khoei SG, Dermani FK, Malih S, Fayazi N,
Sheykhhasan M. The use of mesenchymal stem cells
and their derived extracellular vesicles in cardiovascular
disease treatment. Current Stem Cell Research & Therapy.
2020 Oct 1;15(7):623-38.
- Bulut O, Gürsel I. Mesenchymal stem cell derived
extracellular vesicles: promising immunomodulators
against autoimmune, autoinflammatory disorders and
SARS-CoV-2 infection. Turkish Journal of Biology. 2020
- Askenase PW. COVID-19 therapy with mesenchymal
stromal cells (MSC) and convalescent plasma must consider
exosome involvement: Do the exosomes in convalescent
plasma antagonize the weak immune antibodies?. Journal
of Extracellular Vesicles. 2020 Oct;10(1):e12004.
- Wang F, Kream RM, Stefano GB. Long-term
respiratory and neurological sequelae of COVID-19.
Medical Science Monitor: International Medical Journal
of Experimental and Clinical Research. 2020;26:e928996-
- Tsuchiya A, Takeuchi S, Iwasawa T, Kumagai M, Sato
T, Motegi S, et al. Therapeutic potential of mesenchymal
stem cells and their exosomes in severe novel coronavirus
disease 2019 (COVID-19) cases. Inflammation and
Regeneration. 2020 Dec;40(1):1-6.
- Rezakhani L, Kelishadrokhi AF, Soleimanizadeh A.
Mesenchymal stem cell (MSC)-derived exosomes as a cellfree
therapy for Patients Infected with COVID-19: Real
Opportunities and Range of Promises. Chemistry and
Physics of Lipids. 2020 Nov 12:105009.
- Jayaramayya K, Mahalaxmi I, Subramaniam MD, Raj
N, Dayem AA, Lim KM, et al. Immunomodulatory effect
of mesenchymal stem cells and mesenchymal stem-cellderived
exosomes for COVID-19 treatmen. BMB Reports.
2020 Aug 31;53(8):400-412.
- Kassem DH, Kamal MM. Mesenchymal Stem Cells and
Their Extracellular Vesicles: A Potential Game Changer for
the COVID-19 Crisis. Frontiers in Cell and Developmental
- Akbari A, Rezaie J. Potential therapeutic application
of mesenchymal stem cell-derived exosomes in SARSCoV-
2 pneumonia. Stem Cell Research & Therapy. 2020
- Jamshidi E, Babajani A, Soltani P, Niknejad
H. Proposed Mechanisms of Targeting COVID-19 by
Delivering Mesenchymal Stem Cells and Their Exosomes
to Damaged Organs. Stem Cell Reviews and Reports. 2021
- Muraca M, Pessina A, Pozzobon M, Dominici M,
Galderisi U, Lazzari L, et al. Mesenchymal stromal cells
and their secreted extracellular vesicles as therapeutic
tools for COVID-19 pneumonia?. Journal of Controlled
Release. 2020 Sep 10;325:135-40.
- Kaspi H, Semo J, Abramov N, Dekel C, Lindborg S,
Kern R, et al. MSC-NTF (NurOwn®) exosomes: a novel
therapeutic modality in the mouse LPS-induced ARDS
model. Stem Cell Research & Therapy. 2021 Dec;12(1):1-0.
- Schultz IC, Bertoni AP, Wink MR. Mesenchymal Stem
Cell-Derived Extracellular Vesicles Carrying miRNA as a
Potential Multi Target Therapy to COVID-19: an In Silico
Analysis. Stem Cell Reviews and Reports. 2021 Jan 28:1-
- Yu B, Ikhlas S, Ruan C, Zhong X, Cai D. Innate and
adaptive immunity of murine neural stem cell-derived
piRNA exosomes/microvesicles against pseudotyped
SARS-CoV-2 and HIV-based lentivirus. Iscience. 2020
- Ipinmoroti AO, Matthews QL. Extracellular Vesicles:
Roles in Human Viral Infections, Immune-Diagnostic,
and Therapeutic Applications. Pathogens. 2020
- Nazari-Shafti TZ, Neuber S, Garcia Duran A, Xu Z,
Beltsios E, Seifert M, et al. Human mesenchymal stromal
cells and derived extracellular vesicles: Translational
strategies to increase their proangiogenic potential for
the treatment of cardiovascular disease. STEM CELLS
Translational Medicine. 2020 Dec;9(12):1558-1569.
- Nikfarjam S, Rezaie J, Zolbanin NM, Jafari R.
Mesenchymal stem cell derived-exosomes: a modern
approach in translational medicine. Journal of
Translational Medicine. 2020 Dec;18(1):1-21.