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Stromal, Stem, Signaling Cells: The Multiple Roles and Applications of...
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Stromal, Stem, Signaling Cells: The Multiple Roles and Applications of Mesenchymal Cells, 2nd Edition

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Gene and Cell Therapy".

Deadline for manuscript submissions: closed (15 August 2024) | Viewed by 31716

Special Issue Editor

Dr. Bianca Vezzani

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Guest Editor
Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy
Interests: inflammation; perivascular stem cells; mesenchymal stem cells; regenerative medicine; adipose tissue biology; stem cell biology; skeletal muscle biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The characterization of Mesenchymal Stem Cells (MSCs) has challenged scientists since their first discovery. Initially defined by their differentiation ability and markers expression in culture, MSCs were then been classified as the in vitro counterpart of perivascular cells. This discovery shed light on the existence of multiple sub-groups of MSCs, highly heterogenous and characterized by different abilities and molecular signatures. The in vivo regenerative potential of MSCs has been challenged by many studies, and it is nowadays widely recognized that this ability resides in their capacity to orchestrate the regenerative processes by releasing bioactive factors. In fact, from their isolation, MSCs have been the centre of numerous clinical studies focused on cell-based therapies for tissue regeneration.

This Special Issue is designed to give a comprehensive overview of the studies involving MSCs, together with the new knowledge about their possible use as drug delivery systems based on exosome secretion. In this regard, we would like to invite review articles which address the above-mentioned topics or original research papers providing new evidence on MSCs characterization and clinical application.

I look forward to reading your contributions.

Dr. Bianca Vezzani
Guest Editor

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Keywords

  • mesenchymal stem cells (MSCs) applications
  • MSCs and the perivascular compartment
  • cell-based drug delivery systems
  • MSCs-based cell therapy
  • exosomes based drug delivery
  • perivascular niche and tissue homeostasis regulation
  • tissue repair and regeneration

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Related Special Issue

Published Papers (10 papers)

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Research

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18 pages, 4488 KiB  
Article
Enhancing Anticancer Efficacy of Chemotherapeutics Using Targeting Ligand-Functionalized Synthetic Antigen Receptor-Mesenchymal Stem Cells
by Susheel Kumar Nethi, Xiaolei Li, Shubhmita Bhatnagar and Swayam Prabha
Pharmaceutics 2023, 15(6), 1742; https://doi.org/10.3390/pharmaceutics15061742 - 15 Jun 2023
Cited by 3 | Viewed by 1878
Abstract
Mesenchymal stem cells (MSCs) have been studied for their potential in facilitating tumor-targeted delivery of chemotherapeutics due to their tumor-homing characteristics. We hypothesized that targeting effectiveness of MSCs can be further enhanced by incorporating tumor-targeting ligands on MSC surfaces that will allow for [...] Read more.
Mesenchymal stem cells (MSCs) have been studied for their potential in facilitating tumor-targeted delivery of chemotherapeutics due to their tumor-homing characteristics. We hypothesized that targeting effectiveness of MSCs can be further enhanced by incorporating tumor-targeting ligands on MSC surfaces that will allow for enhanced arrest and binding within the tumor tissue. We utilized a unique strategy of modifying MSCs with synthetic antigen receptors (SARs), targeting specific antigens overexpressed on cancer cells. MSCs were surface-functionalized by first incorporating recombinant protein G (PG) on the surface, followed by binding of the targeting antibody to the PG handle. We functionalized MSCs with antibodies targeting a tyrosine kinase transmembrane receptor protein, epidermal growth factor receptor (EGFR), overexpressed in non-small-cell lung cancer (NSCLC). The efficacy of MSCs functionalized with anti-EGFR antibodies (cetuximab and D8) was determined in murine models of NSCLC. Cetuximab-functionalized MSCs demonstrated improved binding to EGFR protein and to EGFR overexpressing A549 lung adenocarcinoma cells. Further, cetuximab-functionalized MSCs loaded with paclitaxel nanoparticles were efficient in slowing orthotopic A549 tumor growth and improving the overall survival relative to that of other controls. Biodistribution studies revealed a six-fold higher retention of EGFR-targeted MSCs than non-targeted MSCs. Based on these results, we conclude that targeting ligand functionalization could be used to enhance the concentration of therapeutic MSC constructs at the tumor tissue and to achieve improved antitumor response. Full article
(This article belongs to the Special Issue Stromal, Stem, Signaling Cells: The Multiple Roles and Applications of Mesenchymal Cells, 2nd Edition)
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16 pages, 5956 KiB  
Article
The Secretome of Mesenchymal Stromal Cells in Treating Intracerebral Hemorrhage: The First Step to Bedside
by Stalik Dzhauari, Nataliya Basalova, Alexandra Primak, Vadim Balabanyan, Anastasia Efimenko, Mariya Skryabina, Vladimir Popov, Arkadiy Velichko, Kirill Bozov, Zhanna Akopyan, Pavel Malkov, Dmitry Stambolsky, Vsevolod Tkachuk and Maxim Karagyaur
Pharmaceutics 2023, 15(6), 1608; https://doi.org/10.3390/pharmaceutics15061608 - 29 May 2023
Cited by 5 | Viewed by 1791
Abstract
Intracerebral hemorrhage is an unmet medical need that often leads to the disability and death of a patient. The lack of effective treatments for intracerebral hemorrhage makes it necessary to look for them. Previously, in our proof-of-concept study (Karagyaur M et al. Pharmaceutics, [...] Read more.
Intracerebral hemorrhage is an unmet medical need that often leads to the disability and death of a patient. The lack of effective treatments for intracerebral hemorrhage makes it necessary to look for them. Previously, in our proof-of-concept study (Karagyaur M et al. Pharmaceutics, 2021), we have shown that the secretome of multipotent mesenchymal stromal cells (MSC) provides neuroprotection of the brain in a model of intracerebral hemorrhage in rats. Here, we have conducted a systematic study of the therapeutic potential of the MSC secretome in the model of hemorrhagic stroke and provided answers to the questions that need to be addressed in order to translate the secretome-based drug into clinical practice: routes and multiplicity of administration, optimal dose and door-to-treatment time. We have found that MSC secretome reveals prominent neuroprotective activity when administered intranasally or intravenously within 1–3 h after hemorrhage modeling, even in aged rats, and its multiple injections (even within 48 h) are able to reduce the delayed negative effects of hemorrhagic stroke. To our knowledge, this study provides the first systematic investigation of the therapeutic activity of a biomedical MSC-based cell-free drug in intracerebral hemorrhage and is an integral part of its preclinical studies. Full article
(This article belongs to the Special Issue Stromal, Stem, Signaling Cells: The Multiple Roles and Applications of Mesenchymal Cells, 2nd Edition)
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13 pages, 2191 KiB  
Article
Mesenchymal Stem/Stromal Cells in Skeletal Muscle Are Pro-Angiogenic, and the Effect Is Potentiated by Erythropoietin
by Yoshitaka Iso, Sayaka Usui and Hiroshi Suzuki
Pharmaceutics 2023, 15(4), 1049; https://doi.org/10.3390/pharmaceutics15041049 - 24 Mar 2023
Cited by 3 | Viewed by 1545
Abstract
The aim of this study was to investigate the angiogenic potential of skeletal muscle mesenchymal stem/stromal cells (mMSCs). Platelet-derived growth factor receptor (PDGFR)-α positive mMSCs secreted vascular endothelial growth factor (VEGF) and hepatocyte growth factor when cultured in an ELISA assay. The mMSC-medium [...] Read more.
The aim of this study was to investigate the angiogenic potential of skeletal muscle mesenchymal stem/stromal cells (mMSCs). Platelet-derived growth factor receptor (PDGFR)-α positive mMSCs secreted vascular endothelial growth factor (VEGF) and hepatocyte growth factor when cultured in an ELISA assay. The mMSC-medium significantly induced endothelial tube formation in an in vitro angiogenesis assay. The mMSC implantation promoted capillary growth in rat limb ischemia models. Upon identifying the erythropoietin receptor (Epo-R) in the mMSCs, we examined how Epo affected the cells. Epo stimulation enhanced the phosphorylation of Akt and STAT3 in the mMSCs and significantly promoted cellular proliferation. Next, Epo was directly administered into the rats’ ischemic hindlimb muscles. PDGFR-α positive mMSCs in the interstitial area of muscles expressed VEGF and proliferating cell markers. The proliferating cell index was significantly higher in the ischemic limbs of Epo-treated rats than in untreated controls. Investigations by laser Doppler perfusion imaging and immunohistochemistry demonstrated significantly improved perfusion recovery and capillary growth in the Epo-treated groups versus the control groups. Taken together, the results of this study demonstrated that mMSCs possessed a pro-angiogenic property, were activated by Epo, and potentially contributed to capillary growth in skeletal muscle after ischemic injury. Full article
(This article belongs to the Special Issue Stromal, Stem, Signaling Cells: The Multiple Roles and Applications of Mesenchymal Cells, 2nd Edition)
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19 pages, 4690 KiB  
Article
Basic Properties of Adipose-Derived Mesenchymal Stem Cells of Rheumatoid Arthritis and Osteoarthritis Patients
by Ewa Kuca-Warnawin, Weronika Kurowska, Magdalena Plebańczyk, Anna Wajda, Anna Kornatka, Tomasz Burakowski, Iwona Janicka, Piotr Syrówka and Urszula Skalska
Pharmaceutics 2023, 15(3), 1003; https://doi.org/10.3390/pharmaceutics15031003 - 20 Mar 2023
Cited by 4 | Viewed by 2509
Abstract
Rheumatoid arthritis (RA) and osteoarthritis (OA) are destructive joint diseases, the development of which are associated with the expansion of pathogenic T lymphocytes. Mesenchymal stem cells may be an attractive therapeutic option for patients with RA or OA due to the regenerative and [...] Read more.
Rheumatoid arthritis (RA) and osteoarthritis (OA) are destructive joint diseases, the development of which are associated with the expansion of pathogenic T lymphocytes. Mesenchymal stem cells may be an attractive therapeutic option for patients with RA or OA due to the regenerative and immunomodulatory abilities of these cells. The infrapatellar fat pad (IFP) is a rich and easily available source of mesenchymal stem cells (adipose-derived stem cells, ASCs). However, the phenotypic, potential and immunomodulatory properties of ASCs have not been fully characterised. We aimed to evaluate the phenotype, regenerative potential and effects of IFP-derived ASCs from RA and OA patients on CD4+ T cell proliferation. The MSC phenotype was assessed using flow cytometry. The multipotency of MSCs was evaluated on the basis of their ability to differentiate into adipocytes, chondrocytes and osteoblasts. The immunomodulatory activities of MSCs were examined in co-cultures with sorted CD4+ T cells or peripheral blood mononuclear cells. The concentrations of soluble factors involved in ASC-dependent immunomodulatory activities were assessed in co-culture supernatants using ELISA. We found that ASCs with PPIs from RA and OA patients maintain the ability to differentiate into adipocytes, chondrocytes and osteoblasts. ASCs from RA and OA patients also showed a similar phenotype and comparable abilities to inhibit CD4+ T cell proliferation, which was dependent on the induction of soluble factors The results of our study constitute the basis for further research on the therapeutic potential of ASCs in the treatment of patients with RA and OA. Full article
(This article belongs to the Special Issue Stromal, Stem, Signaling Cells: The Multiple Roles and Applications of Mesenchymal Cells, 2nd Edition)
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19 pages, 4338 KiB  
Article
CD73-Positive Cell Spheroid Transplantation Attenuates Colonic Atrophy
by Daisuke Hisamatsu, Natsumi Itakura, Yo Mabuchi, Rion Ozaki, Eriko Grace Suto, Yuna Naraoka, Akari Ikeda, Lisa Ito and Chihiro Akazawa
Pharmaceutics 2023, 15(3), 845; https://doi.org/10.3390/pharmaceutics15030845 - 4 Mar 2023
Cited by 2 | Viewed by 2258
Abstract
The incidence of inflammatory bowel diseases (IBD) is increasing worldwide. Mesenchymal stem/stromal cells (MSCs) have immunomodulatory functions and are a promising source for cell transplantation therapy for IBD. However, owing to their heterogeneous nature, their therapeutic efficacy in colitis is controversial and depends [...] Read more.
The incidence of inflammatory bowel diseases (IBD) is increasing worldwide. Mesenchymal stem/stromal cells (MSCs) have immunomodulatory functions and are a promising source for cell transplantation therapy for IBD. However, owing to their heterogeneous nature, their therapeutic efficacy in colitis is controversial and depends on the delivery route and form of transplanted cells. Cluster of differentiation (CD) 73 is widely expressed in MSCs and used to obtain a homogeneous MSC population. Herein, we determined the optimal method for MSC transplantation using CD73+ cells in a colitis model. mRNA sequencing analysis showed that CD73+ cells exhibited a downregulation of inflammatory gene expression and an upregulation of extracellular matrix-related gene expression. Furthermore, three-dimensional CD73+ cell spheroids showed enhanced engraftment at the injured site through the enteral route, facilitated extracellular matrix remodeling, and downregulated inflammatory gene expression in fibroblasts, leading to the attenuation of colonic atrophy. Therefore, the interaction between intestinal fibroblasts and exogenous MSCs via tissue remodeling is one mechanism that can be exploited for colitis prevention. Our results highlight that the transplantation of homogeneous cell populations with well-characterized properties is beneficial for IBD treatment. Full article
(This article belongs to the Special Issue Stromal, Stem, Signaling Cells: The Multiple Roles and Applications of Mesenchymal Cells, 2nd Edition)
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Review

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24 pages, 443 KiB  
Review
Clinical Prospect of Mesenchymal Stromal/Stem Cell-Derived Extracellular Vesicles in Kidney Disease: Challenges and the Way Forward
by Maja Kosanović, Bojana Milutinović, Tanja J. Kutzner, Yanis Mouloud and Milica Bozic
Pharmaceutics 2023, 15(7), 1911; https://doi.org/10.3390/pharmaceutics15071911 - 9 Jul 2023
Cited by 5 | Viewed by 2833
Abstract
Kidney disease is a growing public health problem worldwide, including both acute and chronic forms. Existing therapies for kidney disease target various pathogenic mechanisms; however, these therapies only slow down the progression of the disease rather than offering a cure. One of the [...] Read more.
Kidney disease is a growing public health problem worldwide, including both acute and chronic forms. Existing therapies for kidney disease target various pathogenic mechanisms; however, these therapies only slow down the progression of the disease rather than offering a cure. One of the potential and emerging approaches for the treatment of kidney disease is mesenchymal stromal/stem cell (MSC) therapy, shown to have beneficial effects in preclinical studies. In addition, extracellular vesicles (EVs) released by MSCs became a potent cell-free therapy option in various preclinical models of kidney disease due to their regenerative, anti-inflammatory, and immunomodulatory properties. However, there are scarce clinical data available regarding the use of MSC-EVs in kidney pathologies. This review article provides an outline of the renoprotective effects of MSC-EVs in different preclinical models of kidney disease. It offers a comprehensive analysis of possible mechanisms of action of MSC-EVs with an emphasis on kidney disease. Finally, on the journey toward the implementation of MSC-EVs into clinical practice, we highlight the need to establish standardized methods for the characterization of an EV-based product and investigate the adequate dosing, safety, and efficacy of MSC-EVs application, as well as the development of suitable potency assays. Full article
(This article belongs to the Special Issue Stromal, Stem, Signaling Cells: The Multiple Roles and Applications of Mesenchymal Cells, 2nd Edition)
34 pages, 1511 KiB  
Review
Mesenchymal Stem Cell-Derived Exosomes in Ophthalmology: A Comprehensive Review
by Kevin Y. Wu, Hamza Ahmad, Grace Lin, Marjorie Carbonneau and Simon D. Tran
Pharmaceutics 2023, 15(4), 1167; https://doi.org/10.3390/pharmaceutics15041167 - 6 Apr 2023
Cited by 12 | Viewed by 6381
Abstract
Over the past decade, the field of mesenchymal stem cell (MSC) therapy has exhibited rapid growth. Due to their regenerative, reparatory, and immunomodulatory capacities, MSCs have been widely investigated as therapeutic agents in the cell-based treatment of chronic ophthalmic pathologies. However, the applicability [...] Read more.
Over the past decade, the field of mesenchymal stem cell (MSC) therapy has exhibited rapid growth. Due to their regenerative, reparatory, and immunomodulatory capacities, MSCs have been widely investigated as therapeutic agents in the cell-based treatment of chronic ophthalmic pathologies. However, the applicability of MSC-based therapy is limited by suboptimal biocompatibility, penetration, and delivery to the target ocular tissues. An emerging body of research has elucidated the role of exosomes in the biological functions of MSCs, and that MSC-derived extracellular vesicles (EVs) possess anti-inflammatory, anti-apoptotic, tissue repairing, neuroprotective, and immunomodulatory properties similar to MSCs. The recent advances in MSCs-derived exosomes can serve as solutions to the challenges faced by MSCs-therapy. Due to their nano-dimensions, MSC-derived exosomes can rapidly penetrate biological barriers and reach immune-privileged organs, allowing for efficient delivery of therapeutic factors such as trophic and immunomodulatory agents to ocular tissues that are typically challenging to target by conventional therapy and MSCs transplantation. In addition, the use of EVs minimizes the risks associated with mesenchymal stem cell transplantation. In this literature review, we focus on the studies published between 2017 and 2022, highlighting the characteristics of EVs derived from MSCs and their biological functions in treating anterior and posterior segment ocular diseases. Additionally, we discuss the potential use of EVs in clinical settings. Rapid advancements in regenerative medicine and exosome-based drug delivery, in conjunction with an increased understanding of ocular pathology and pharmacology, hold great promise for the treatment of ocular diseases. The potential of exosome-based therapies is exciting and can revolutionize the way we approach these ocular conditions. Full article
(This article belongs to the Special Issue Stromal, Stem, Signaling Cells: The Multiple Roles and Applications of Mesenchymal Cells, 2nd Edition)
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15 pages, 6010 KiB  
Review
Current Evidence on Bisphenol A Exposure and the Molecular Mechanism Involved in Related Pathological Conditions
by Ylenia Della Rocca, Enrico Matteo Traini, Francesca Diomede, Luigia Fonticoli, Oriana Trubiani, Alessia Paganelli, Jacopo Pizzicannella and Guya Diletta Marconi
Pharmaceutics 2023, 15(3), 908; https://doi.org/10.3390/pharmaceutics15030908 - 10 Mar 2023
Cited by 9 | Viewed by 4130
Abstract
Bisphenol A (BPA) is one of the so-called endocrine disrupting chemicals (EDCs) and is thought to be involved in the pathogenesis of different morbid conditions: immune-mediated disorders, type-2 diabetes mellitus, cardiovascular diseases, and cancer. The purpose of this review is to analyze the [...] Read more.
Bisphenol A (BPA) is one of the so-called endocrine disrupting chemicals (EDCs) and is thought to be involved in the pathogenesis of different morbid conditions: immune-mediated disorders, type-2 diabetes mellitus, cardiovascular diseases, and cancer. The purpose of this review is to analyze the mechanism of action of bisphenol A, with a special focus on mesenchymal stromal/stem cells (MSCs) and adipogenesis. Its uses will be assessed in various fields: dental, orthopedic, and industrial. The different pathological or physiological conditions altered by BPA and the related molecular pathways will be taken into consideration. Full article
(This article belongs to the Special Issue Stromal, Stem, Signaling Cells: The Multiple Roles and Applications of Mesenchymal Cells, 2nd Edition)
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15 pages, 1289 KiB  
Review
Plausible Role of Stem Cell Types for Treating and Understanding the Pathophysiology of Depression
by Punya Sachdeva, Seongmin Ji, Shampa Ghosh, Soumya Ghosh, Manchala Raghunath, Hyunjin Kim, Rakesh Bhaskar, Jitendra Kumar Sinha and Sung Soo Han
Pharmaceutics 2023, 15(3), 814; https://doi.org/10.3390/pharmaceutics15030814 - 2 Mar 2023
Cited by 6 | Viewed by 4915
Abstract
Major Depressive Disorder (MDD), colloquially known as depression, is a debilitating condition affecting an estimated 3.8% of the population globally, of which 5.0% are adults and 5.7% are above the age of 60. MDD is differentiated from common mood changes and short-lived emotional [...] Read more.
Major Depressive Disorder (MDD), colloquially known as depression, is a debilitating condition affecting an estimated 3.8% of the population globally, of which 5.0% are adults and 5.7% are above the age of 60. MDD is differentiated from common mood changes and short-lived emotional responses due to subtle alterations in gray and white matter, including the frontal lobe, hippocampus, temporal lobe, thalamus, striatum, and amygdala. It can be detrimental to a person’s overall health if it occurs with moderate or severe intensity. It can render a person suffering terribly to perform inadequately in their personal, professional, and social lives. Depression, at its peak, can lead to suicidal thoughts and ideation. Antidepressants manage clinical depression and function by modulating the serotonin, norepinephrine, and dopamine neurotransmitter levels in the brain. Patients with MDD positively respond to antidepressants, but 10–30% do not recuperate or have a partial response accompanied by poor life quality, suicidal ideation, self-injurious behavior, and an increased relapse rate. Recent research shows that mesenchymal stem cells and iPSCs may be responsible for lowering depression by producing more neurons with increased cortical connections. This narrative review discusses the plausible functions of various stem cell types in treating and understanding depression pathophysiology. Full article
(This article belongs to the Special Issue Stromal, Stem, Signaling Cells: The Multiple Roles and Applications of Mesenchymal Cells, 2nd Edition)
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34 pages, 2459 KiB  
Review
Potential of Mesenchymal Stromal Cell-Derived Extracellular Vesicles as Natural Nanocarriers: Concise Review
by Florian Draguet, Cyril Bouland, Nathan Dubois, Dominique Bron, Nathalie Meuleman, Basile Stamatopoulos and Laurence Lagneaux
Pharmaceutics 2023, 15(2), 558; https://doi.org/10.3390/pharmaceutics15020558 - 7 Feb 2023
Cited by 7 | Viewed by 2436
Abstract
Intercellular communication, through direct and indirect cell contact, is mandatory in multicellular organisms. These last years, the microenvironment, and in particular, transfer by extracellular vesicles (EVs), has emerged as a new communication mechanism. Different biological fluids and cell types are common sources of [...] Read more.
Intercellular communication, through direct and indirect cell contact, is mandatory in multicellular organisms. These last years, the microenvironment, and in particular, transfer by extracellular vesicles (EVs), has emerged as a new communication mechanism. Different biological fluids and cell types are common sources of EVs. EVs play different roles, acting as signalosomes, biomarkers, and therapeutic agents. As therapeutic agents, MSC-derived EVs display numerous advantages: they are biocompatible, non-immunogenic, and stable in circulation, and they are able to cross biological barriers. Furthermore, EVs have a great potential for drug delivery. Different EV isolation protocols and loading methods have been tested and compared. Published and ongoing clinical trials, and numerous preclinical studies indicate that EVs are safe and well tolerated. Moreover, the latest studies suggest their applications as nanocarriers. The current review will describe the potential for MSC-derived EVs as drug delivery systems (DDS) in disease treatment, and their advantages. Thereafter, we will outline the different EV isolation methods and loading techniques, and analyze relevant preclinical studies. Finally, we will describe ongoing and published clinical studies. These elements will outline the benefits of MSC-derived EV DDS over several aspects. Full article
(This article belongs to the Special Issue Stromal, Stem, Signaling Cells: The Multiple Roles and Applications of Mesenchymal Cells, 2nd Edition)
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