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Mechanisms and Therapeutic Potential of Mesenchymal Stem Cells (MSCs)

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Gene and Cell Therapy".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 21307

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Dr. Francisco José Vizoso

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Guest Editor

Research Unit, Fundación Hospital de Jove, Avda. Eduardo Castro, 161, 33290 Gijón, Spain
Interests: mesenchymal stem cells; secretome; hUCESC; cancer; inflammation

Dr. Noemí Eiró

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Guest Editor

Research Unit, Fundación Hospital de Jove, Av. Eduardo Castro, 161, 33290 Gijón, Spain
Interests: mesenchymal stem cells; secretome; hUCESC; cancer; inflammation
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Dear Colleagues,

Around 40% of the population will suffer from a disease that cannot be satisfactorily controlled with current therapies. For example, today, the worldwide number of diabetic patients is estimated at 537 million, and the global cancer incidence is on a steady rise at 19.3 million, with a resultant 10 million deaths annually as of 2020. In addition, population aging is rapidly accelerating, and this is accompanied by stages of physiological vulnerability and declining ability to maintain tissue homeostasis and respond to stress. On the other hand, the emergence of new threats, such as the coronavirus pandemic (SARS-CoV-2), due to their unusual and unforeseen virulence, is demanding new therapeutic strategies. Regarding this, and despite the considerable progress in therapeutic pharmacology in recent times, new perspectives must be pursued to handle the technological and scientific challenges of treating these catastrophic clinical situations more effectively. A conceptual axis of the change in therapeutic strategies may be the consideration of acting in a more global way on the complex pathophysiological mechanisms of these diseases, instead of the classical paradigm of “one disease, one drug”. An alternative for this proposal is represented by stem cells, particularly mesenchymal stem cells (MSCs), for which a growing body of evidence suggests their significant role in the regulation of tissue homeostasis.

In the proposed Special Issue of the journal Biomedicines, we plan to recruit related works that address the state of the art in strategies to transfer, as quickly as possible, the therapeutic potential of MSCs and the products derived from their secretome from the experimental setting to clinical practice.

Dr. Francisco José Vizoso
Dr. Noemí Eiró
Guest Editors

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Keywords

mesenchymal stem cells
MSC secretome/conditioned medium (media)
extracellular vesicles
translational studies
cancer
inflammation
aging
clinical application
regulatory aspects
scale-up technologies (mass production)

Published Papers (11 papers)

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12 pages, 21335 KiB

Open AccessArticle

The Efficacy of Transplanting Human Umbilical Cord Mesenchymal Stem Cell Sheets in the Treatment of Myocardial Infarction in Mice

by Thang Quoc Bui, Nguyen Trong Binh, Truc Le-Buu Pham, Trinh Le Van, Nhung Hai Truong, Dang Phu-Hai Nguyen, Thao Thi-Thu Luu, Trang Nguyen-Xuan Pham, Tu Cam Tran, Huyen Thuong-Thi Nguyen, Nhu Thuy-Trinh and Phong Anh Tran

Biomedicines 2023, 11(8), 2187; https://doi.org/10.3390/biomedicines11082187 - 3 Aug 2023

Viewed by 1578

Abstract

The transplantation of mesenchymal stem cell (MSC) sheets derived from human umbilical cords (hUCs) was investigated in this study as a potential application in treating myocardial infarction (MI). Two groups of hUC-MSC sheets were formed by populating LunaGel^TM, which are 3D scaffolds of photo-crosslinkable gelatin-based hydrogel with two different cell densities. An MI model was created by ligating the left anterior descending coronary artery of healthy BALB/c mice. After two weeks, the cell sheets were applied directly to the MI area and the efficacy of the treatment was evaluated over the next two weeks by monitoring the mice’s weight, evaluating the left ventricle ejection fraction, and assessing the histology of the heart tissue at the end of the experiment. Higher cell density showed significantly greater efficiency in MI mice treatment in terms of weight gain and the recovery of ejection fraction. The heart tissue of the groups receiving cell sheets showed human-CD44-positive staining and reduced fibrosis and apoptosis. In conclusion, the hUC-MSC sheets ameliorated heart MI injury in mice and the efficacy of the cell sheets improved as the number of cells increased. Full article

(This article belongs to the Special Issue Mechanisms and Therapeutic Potential of Mesenchymal Stem Cells (MSCs))

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20 pages, 9014 KiB

Open AccessArticle

Regenerative Effect of Mesenchymal Stem Cell on Cartilage Damage in a Porcine Model

by Sheng-Chuan Lin, Sankar Panthi, Yu-Her Hsuuw, Shih-Hsien Chen, Ming-Ju Huang, Martin Sieber and Yan-Der Hsuuw

Biomedicines 2023, 11(7), 1810; https://doi.org/10.3390/biomedicines11071810 - 24 Jun 2023

Viewed by 1950

Abstract

Osteoarthritis (OA) is a major public and animal health challenge with significant economic consequences. Cartilage degradation plays a critical role in the initiation and progression of degenerative joint diseases, such as OA. Mesenchymal stem cells (MSCs) have become increasingly popular in the field of cartilage regeneration due to their promising results. The objective of this preclinical study was to evaluate the regenerative effects of mesenchymal stem cells (MSCs) in the repair of knee cartilage defects using a porcine model. Seven healthy LYD breed white pigs, aged 9–10 weeks and weighing approximately 20 ± 3 kg, were used in the experimental protocol. Full-thickness defects measuring 8 mm in diameter and 5 mm in depth were induced in the lateral femoral condyle of the posterior limbs in both knee joints using a sterile puncture technique while the knee was maximally flexed. Following a 1-week induction phase, the pig treatment groups received a 0.3 million/kg MSC transplant into the damaged knee region, while the placebo group received a control solution as a treatment. Magnetic resonance imaging (MRI), computerized tomography (CT), visual macroscopic examination, histological analysis, and cytokine concentration analysis were used to assess cartilage regeneration. The findings revealed that human adipose-derived mesenchymal stem cells (hADSCs) were more effective in repairing cartilage than pig umbilical cord-derived mesenchymal stem cells (pUCMSCs). These results suggest that MSC-based treatments hold promise as a treatment option for cartilage repair, which aid in the treatment of OA. However, further studies with larger sample sizes and longer follow-up periods are required to fully demonstrate the safety and efficacy of these therapies in both animals and humans. Full article

(This article belongs to the Special Issue Mechanisms and Therapeutic Potential of Mesenchymal Stem Cells (MSCs))

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15 pages, 13558 KiB

Open AccessArticle

Encapsulation of Human Umbilical Cord Mesenchymal Stem Cells in LunaGel Photocrosslinkable Extracellular Matrix and Subcutaneous Transplantation in Mice

by Truc Le-Buu Pham, Dang Phu-Hai Nguyen, Thao Thi-Thu Luu, Luong Si Nguyen, Nguyen Trong Binh, Quan Dang Nguyen and Phong Anh Tran

Biomedicines 2023, 11(4), 1158; https://doi.org/10.3390/biomedicines11041158 - 12 Apr 2023

Cited by 3 | Viewed by 1745

Abstract

Stem cells have significant potential in regenerative medicines. However, a major issue with implanting stem cells in the regeneration of new tissue is the methods to implant them and cell viability and functions before and after implantation. Here we developed a simple yet effective method that used photo-crosslinkable gelatin-based hydrogel (LunaGel^TM) as a scaffold for the encapsulation, expansion, and eventually, transplantation of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) into mice subcutaneously. We demonstrated the proliferation and maintenance of the original expression of mesenchymal stem cell markers as well as the ability to differentiate into mesoderm-derived cells. The hydrogel was highly stable with no signs of degradation after 20 days in PBS. The hUC-MSCs remained viable after transplantation into mice’s subcutaneous pockets and migrated to integrate with the surrounding tissues. We showed a collagen-rich layer surrounding the transplanted cell-laden scaffold indicating the effects of growth factors secreted by the hUC-MSCs. A connective tissue layer was found between the implanted cell-laden scaffold and the collagen layer, and immunohistochemical staining results suggested that this tissue was derived from the MSCs which migrated from within the scaffold. The results, thus, also suggested a protective effect the scaffold has on the encapsulated cells from the antibodies and cytotoxic cells of the host immune system. Full article

(This article belongs to the Special Issue Mechanisms and Therapeutic Potential of Mesenchymal Stem Cells (MSCs))

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11 pages, 3209 KiB

Open AccessArticle

An Effect of Cyclosporin A in a Treatment of Temporal Bone Defect Using hBM-MSCs

by Lukas Skoloudik, Viktor Chrobok, Jan Laco, Jana Dedkova, Daniel Diaz Garcia and Stanislav Filip

Biomedicines 2022, 10(11), 2918; https://doi.org/10.3390/biomedicines10112918 - 14 Nov 2022

Viewed by 1108

Abstract

Background. The treatment of middle ear cholesteatoma requires surgical treatment and the reconstruction of the temporal bone, which represents an ongoing problem. Otologists have focused on the research of materials allowing an airy middle ear and the preservation of hearing function to reconstruct the temporal bone. Methods. This study evaluated the effect of cyclosporin A (CsA) and a combined biomaterial in the healing process of postoperative temporal bone defects in an animal model. Cultured human Bone Marrow Mesenchymal Stromal Cells (hBM-MSCs) were mixed with hydroxyapatite (Cem-Ostetic^®), and subsequently applied as a bone substitute after middle ear surgery, showing that the therapeutic potential of hBM-MSCs associated with bone regeneration and replacement is directly influenced by CsA, confirming that it promotes the survival of MSCs in vivo. Results. The therapeutic efficacy of the combination of MSCs with CsA is greater than the sole application of MSCs in a hydroxyapatite carrier. Conclusion. The reconstruction of a temporal bone defect using hBM-MSCs requires an immunosuppressant to improve the results of treatment. Full article

(This article belongs to the Special Issue Mechanisms and Therapeutic Potential of Mesenchymal Stem Cells (MSCs))

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16 pages, 2999 KiB

Open AccessArticle

Therapeutic Potential of Adipose Stem Cell-Derived Conditioned Medium on Scar Contraction Model

by Yukiko Imai, Nobuhito Mori, Yuma Nihashi, Yutaro Kumagai, Yoichiro Shibuya, Junya Oshima, Masahiro Sasaki, Kaoru Sasaki, Yukiko Aihara, Mitsuru Sekido and Yasuyuki S. Kida

Biomedicines 2022, 10(10), 2388; https://doi.org/10.3390/biomedicines10102388 - 24 Sep 2022

Cited by 5 | Viewed by 2203

Abstract

Scars are composed of stiff collagen fibers, which contract strongly owing to the action of myofibroblasts. To explore the substances that modulate scar contracture, the fibroblast-populated collagen lattice (FPCL) model has been used. However, the molecular signature of the patient-derived FPCL model has not been verified. Here, we examined whether the patient-derived keloid FPCL model reflects scar contraction, analyzing detailed gene expression changes using comprehensive RNA sequencing and histological morphology, and revealed that these models are consistent with the changes during human scar contracture. Moreover, we examined whether conditioned media derived from adipose stem cells (ASC-CM) suppress the scar contracture of the collagen disc. Detailed time-series measurements of changes in disc area showed that the addition of ASC-CM significantly inhibited the shrinkage of collagen discs. In addition, a deep sequencing data analysis revealed that ASC-CM suppressed inflammation-related gene expression in the early phase of contraction; in the later phase, this suppression was gradually replaced by extracellular matrix (ECM)-related gene expression. These lines of data suggested the effectiveness of ASC-CM in suppressing scar contractures. Therefore, the molecular analysis of the ASC-CM actions found in this study will contribute to solving medical problems regarding pathological scarring in wound prognosis. Full article

(This article belongs to the Special Issue Mechanisms and Therapeutic Potential of Mesenchymal Stem Cells (MSCs))

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18 pages, 9983 KiB

Open AccessArticle

Immunomodulation of Pluripotent Stem Cell-Derived Mesenchymal Stem Cells in Rotator Cuff Tears Model

by Jieun Baek, Bokyeong Ryu, Jin Kim, Seul-Gi Lee, Min-Seok Oh, Ki-Sung Hong, Eun-Young Kim, C-Yoon Kim and Hyung-Min Chung

Biomedicines 2022, 10(7), 1549; https://doi.org/10.3390/biomedicines10071549 - 29 Jun 2022

Cited by 2 | Viewed by 1735

Abstract

Background: Rotator cuff tears (RCTs) induce chronic muscle weakness and shoulder pain. Treatment of RCT using surgery or drugs causes lipid infiltration and fibrosis, which hampers tissue regeneration and complete recovery. The pluripotent stem cell-derived multipotent mesenchymal stem cells (M-MSCs) represent potential candidate next-generation therapies for RCT. Methods: The difference between M-MSCs and adult-MSCs was compared and analyzed using next-generation sequencing (NGS). In addition, using a rat model of RCT, the muscle recovery ability of M-MSCs and adult-MSCs was evaluated by conducting a histological analysis and monitoring the cytokine expression level. Results: Using NGS, it was confirmed that M-MSC was suitable for transplantation because of its excellent ability to regulate inflammation that promotes tissue repair and reduced apoptosis and rejection during transplantation. In addition, while M-MSCs persisted for up to 8 weeks in vivo, they significantly reduced inflammation and adipogenesis-related cytokine levels in rat muscle. Significant differences were also confirmed in histopathological remission. Conclusions: M-MSCs remain in the body longer to modulate immune responses in RCTs and have a greater potential to improve muscle recovery by alleviating acute inflammatory responses. This indicates that M-MSCs could be used in potential next-generation RCT therapies. Full article

(This article belongs to the Special Issue Mechanisms and Therapeutic Potential of Mesenchymal Stem Cells (MSCs))

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16 pages, 2734 KiB

Open AccessArticle

Intrapericardial Administration of Secretomes from Menstrual Blood-Derived Mesenchymal Stromal Cells: Effects on Immune-Related Genes in a Porcine Model of Myocardial Infarction

by María Ángeles de Pedro, María Pulido, Federica Marinaro, Verónica Álvarez, Claudia Báez-Díaz, Virginia Blanco, Juan Carlos Silla-Castro, Fátima Sanchez-Cabo, Francisco Miguel Sánchez-Margallo, Verónica Crisóstomo, Javier G. Casado and Esther López

Biomedicines 2022, 10(5), 1117; https://doi.org/10.3390/biomedicines10051117 - 11 May 2022

Cited by 5 | Viewed by 2414

Abstract

Acute myocardial infarction (AMI) is a manifestation of ischemic heart disease where the immune system plays an important role in the re-establishment of homeostasis. We hypothesize that the anti-inflammatory activity of secretomes from menstrual blood-derived mesenchymal stromal cells (S-MenSCs) and IFNγ/TNFα-primed MenSCs (S-MenSCs*) may be considered a therapeutic option for the treatment of AMI. To assess this hypothesis, we have evaluated the effect of S-MenSCs and S-MenSCs* on cardiac function parameters and the involvement of immune-related genes using a porcine model of AMI. Twelve pigs were randomly divided into three biogroups: AMI/Placebo, AMI/S-MenSCs, and AMI/S-MenSCs*. AMI models were generated using a closed chest coronary occlusion-reperfusion procedure and, after 72 h, the different treatments were intrapericardially administered. Cardiac function parameters were monitored by magnetic resonance imaging before and 7 days post-therapy. Transcriptomic analyses in the infarcted tissue identified 571 transcripts associated with the Gene Ontology term Immune response, of which 57 were differentially expressed when different biogroups were compared. Moreover, a prediction of the interactions between differentially expressed genes (DEGs) and miRNAs from secretomes revealed that some DEGs in the infarction area, such as STAT3, IGFR1, or BCL6 could be targeted by previously identified miRNAs in secretomes from MenSCs. In conclusion, the intrapericardial administration of secretome early after infarction has a significant impact on the expression of immune-related genes in the infarcted myocardium. This confirms the immunomodulatory potential of intrapericardially delivered secretomes and opens new therapeutic perspectives in myocardial infarction treatment. Full article

(This article belongs to the Special Issue Mechanisms and Therapeutic Potential of Mesenchymal Stem Cells (MSCs))

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16 pages, 3101 KiB

Open AccessArticle

Potential Anti-Inflammatory Effects of a New Lyophilized Formulation of the Conditioned Medium Derived from Periodontal Ligament Stem Cells

by Agnese Gugliandolo, Francesca Diomede, Jacopo Pizzicannella, Luigi Chiricosta, Oriana Trubiani and Emanuela Mazzon

Biomedicines 2022, 10(3), 683; https://doi.org/10.3390/biomedicines10030683 - 16 Mar 2022

Cited by 3 | Viewed by 2597

Abstract

The mesenchymal stem cells’ (MSCs) secretome includes the bioactive molecules released in the conditioned medium (CM), such as soluble proteins, free nucleic acids, lipids and extracellular vesicles. The secretome is known to mediate some of the beneficial properties related to MSCs, such as anti-inflammatory, anti-apoptotic and regenerative capacities. In this work, we aim to evaluate the anti-inflammatory potential of a new lyophilized formulation of CM derived from human periodontal ligament stem cells (hPDLSCs). With this aim, we treat hPDLSCs with lipopolysaccharide (LPS) and test the anti-inflammatory potential of lyophilized CM (LYO) through the evaluation of wound closure, transcriptomic and immunofluorescence analysis. LPS treatment increased the expression of TLR4 and of genes involved in its signaling and in p38 and NF-κB activation, also increasing the expression of cytokines and chemokines. Interestingly, LYO downregulated the expression of genes involved in Toll-like receptor 4 (TLR-4), nuclear factor kappa light chain enhancer of activated B cells (NF-κB) and p38 signaling. As a consequence, the genes encoding for cytokines and chemokines were also downregulated. Immunofluorescence acquisitions confirmed the downregulation of TLR-4 and NF-κB with the LYO treatment. Moreover, the LYO treatment also increased hPDLSCs’ migration. LYO was demonstrated to contain transforming growth factor (TGF)-β3 and vascular endothelial growth factor (VEGF). These results suggest that LYO represents an efficacious formulation with anti-inflammatory potential and highlights lyophilization as a valid method to produce stable formulations of MSCs’ secretome. Full article

(This article belongs to the Special Issue Mechanisms and Therapeutic Potential of Mesenchymal Stem Cells (MSCs))

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Review

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66 pages, 3620 KiB

Open AccessReview

A Supportive Role of Mesenchymal Stem Cells on Insulin-Producing Langerhans Islets with a Specific Emphasis on The Secretome

by Ronit Vogt Sionov and Ronit Ahdut-HaCohen

Biomedicines 2023, 11(9), 2558; https://doi.org/10.3390/biomedicines11092558 - 18 Sep 2023

Viewed by 1301

Abstract

Type 1 Diabetes (T1D) is a chronic autoimmune disease characterized by a gradual destruction of insulin-producing β-cells in the endocrine pancreas due to innate and specific immune responses, leading to impaired glucose homeostasis. T1D patients usually require regular insulin injections after meals to maintain normal serum glucose levels. In severe cases, pancreas or Langerhans islet transplantation can assist in reaching a sufficient β-mass to normalize glucose homeostasis. The latter procedure is limited because of low donor availability, high islet loss, and immune rejection. There is still a need to develop new technologies to improve islet survival and implantation and to keep the islets functional. Mesenchymal stem cells (MSCs) are multipotent non-hematopoietic progenitor cells with high plasticity that can support human pancreatic islet function both in vitro and in vivo and islet co-transplantation with MSCs is more effective than islet transplantation alone in attenuating diabetes progression. The beneficial effect of MSCs on islet function is due to a combined effect on angiogenesis, suppression of immune responses, and secretion of growth factors essential for islet survival and function. In this review, various aspects of MSCs related to islet function and diabetes are described. Full article

(This article belongs to the Special Issue Mechanisms and Therapeutic Potential of Mesenchymal Stem Cells (MSCs))

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19 pages, 1415 KiB

Open AccessReview

To Explore the Stem Cells Homing to GBM: The Rise to the Occasion

by Sergey Tsibulnikov, Natalya M. Drefs, Peter S. Timashev and Ilya V. Ulasov

Biomedicines 2022, 10(5), 986; https://doi.org/10.3390/biomedicines10050986 - 24 Apr 2022

Cited by 3 | Viewed by 2174

Abstract

Multiple efforts are currently underway to develop targeted therapeutic deliveries to the site of glioblastoma progression. The use of carriers represents advancement in the delivery of various therapeutic agents as a new approach in neuro-oncology. Mesenchymal stem cells (MSCs) and neural stem cells (NSCs) are used because of their capability in migrating and delivering therapeutic payloads to tumors. Two of the main properties that carrier cells should possess are their ability to specifically migrate from the bloodstream and low immunogenicity. In this article, we also compared the morphological and molecular features of each type of stem cell that underlie their migration capacity to glioblastoma. Thus, the major focus of the current review is on proteins and lipid molecules that are released by GBM to attract stem cells. Full article

(This article belongs to the Special Issue Mechanisms and Therapeutic Potential of Mesenchymal Stem Cells (MSCs))

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Other

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15 pages, 1066 KiB

Open AccessSystematic Review

A Systematic Review of the Evidence of Hematopoietic Stem Cell Differentiation to Fibroblasts

by Bernard J. Smilde, Esmée Botman, Teun J. de Vries, Ralph de Vries, Dimitra Micha, Ton Schoenmaker, Jeroen J. W. M. Janssen and Elisabeth M. W. Eekhoff

Biomedicines 2022, 10(12), 3063; https://doi.org/10.3390/biomedicines10123063 - 28 Nov 2022

Viewed by 1456

Abstract

Fibroblasts have an important role in the maintenance of the extracellular matrix of connective tissues by producing and remodelling extracellular matrix proteins. They are indispensable for physiological processes, and as such also associate with many pathological conditions. In recent years, a number of studies have identified donor-derived fibroblasts in various tissues of bone marrow transplant recipients, while others could not replicate these findings. In this systematic review, we provide an overview of the current literature regarding the differentiation of hematopoietic stem cells into fibroblasts in various tissues. PubMed, Embase, and Web of Science (Core Collection) were systematically searched for original articles concerning fibroblast origin after hematopoietic stem cell transplantation in collaboration with a medical information specialist. Our search found 5421 studies, of which 151 were analysed for full-text analysis by two authors independently, resulting in the inclusion of 104 studies. Only studies in animals and humans, in which at least one marker was used for fibroblast identification, were included. The results were described per organ of fibroblast engraftment. We show that nearly all mouse and human organs show evidence of fibroblasts of hematopoietic stem cell transfer origin. Despite significant heterogeneity in the included studies, most demonstrate a significant presence of fibroblasts of hematopoietic lineage in non-hematopoietic tissues. This presence appears to increase after the occurrence of tissue damage. Full article

(This article belongs to the Special Issue Mechanisms and Therapeutic Potential of Mesenchymal Stem Cells (MSCs))

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