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Mesenchymal Stem Cells and Their Derived Products as an Innovative Therapeutic Strategy in Acute Clinical Settings

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (15 December 2021) | Viewed by 41789

Special Issue Editor

Dr. Francisco J. Vizoso

E-Mail Website
Guest Editor
1. Unidad de Investigación, Fundación Hospital de Jove, 33290 Gijón, Spain
2. Fundación para la Investigación con Células Madre Uterinas (FICEMU), 33212 Gijón, Spain
Interests: mesenchymal stem cell

Special Issue Information

Dear Colleagues,

Acute clinical settings include acute heart failure, septic shock, neurovascular disorders, and acute lung and kidney failure, both from sepsis. These processes lead to complex mechanisms such as pro-inflammatory responses, endothelial activation, microcirculatory dysfunction, oxidative stress, and fibrosis, the handling strategies for all of which often collapse.

Mesenchymal stem cells (MSC), due to their properties (anti-inflammatory, immunomodulatory, anti-microbial, anti-oxidative stress, anti-fibrotic, regenerative and angiogenic), have demonstrated their potential usefulness in the treatment of several chronic diseases. Orienting research toward its applicability in urgent situations could be a catalyst to deepen our knowledge and revolutionize patient care and management of this array of acute illnesses. However, several aspects of cell therapy should be clarified, such as the mode of administration, dose or integrity, and viability of the cell once administered. On the other hand, cell-free therapies based on MSC-derived secretome products, such as conditioned medium or microvesicles, may contribute to abolish several safety problems associated to cell therapies (immunological incompatibility, tumorigenicity, the formation of emboli, transmission infections, and the potential entry of MSCs into senescence). Secretomes for therapies could also be prepared in advance in large quantities. Nevertheless, optimization strategies should be achieved by choosing the most adequate MSC type and the most satisfactory culture conditions for each imperative therapeutic implementation. In addition, most effective mass production and adequate functional tests are also necessary.

The investigations we will focus our attention on are fundamentally cellular/molecular studies, although scientific articles that incorporate clinical data in addition to cellular/molecular studies will be similarly accepted.

Dr. Francisco J. Vizoso
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Mesenchymal Stem Cells

Mesenchymal stromal cells

MSCs

Stromal cells derived products

MSC-derived therapeutics

Published Papers (15 papers)

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Editorial

Jump to: Research, Review

4 pages, 209 KiB  
Editorial
Mesenchymal Stem/Stromal Cells and Their Derivates in Acute Diseases: Emergency in the Post-COVID-19 Times
by Francisco J. Vizoso, Silvia Fernández-Francos and Noemi Eiro
Int. J. Mol. Sci. 2021, 22(16), 8395; https://doi.org/10.3390/ijms22168395 - 5 Aug 2021
Cited by 2 | Viewed by 1762
Abstract
The current coronavirus disease-19 (COVID-19) pandemic has strongly revived the pressing need to incorporate new therapeutic alternatives to deal with medical situations that result in a dramatic breakdown in the body’s normal homeostasis [...] Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells and Their Derived Products as an Innovative Therapeutic Strategy in Acute Clinical Settings)

Research

Jump to: Editorial, Review

16 pages, 2619 KiB  
Article
Antioxidants Attenuate Heat Shock Induced Premature Senescence of Bovine Mesenchymal Stem Cells
by Dana Nir, Ivana Ribarski-Chorev, Chen Shimoni, Carmit Strauss, Jan Frank and Sharon Schlesinger
Int. J. Mol. Sci. 2022, 23(10), 5750; https://doi.org/10.3390/ijms23105750 - 20 May 2022
Cited by 8 | Viewed by 2375
Abstract
Mesenchymal stem cells (MSC) have many roles that are important for the body’s proper functioning. When the MSC pool is damaged, it is often correlated with impaired development or health of the organism. MSC are known for their anti-inflammatory, immunomodulatory and trophic characteristics [...] Read more.
Mesenchymal stem cells (MSC) have many roles that are important for the body’s proper functioning. When the MSC pool is damaged, it is often correlated with impaired development or health of the organism. MSC are known for their anti-inflammatory, immunomodulatory and trophic characteristics that play an important role in the physiological homeostasis of many tissues. Heat shock impairs MSC capacity by inducing the generation of reactive oxygen species and mitochondrial dysfunction, which, in turn, send the cells into a state of premature senescence. Here, we pre-exposed MSC to melatonin, resveratrol, or curcumin, which are natural antioxidative compounds, and tested the protective effects of these substances from oxidative stress and aging. Our data showed that pre-exposure of MSC to antioxidants decreased reactive oxygen species while mitochondrial damage remained high. Additionally, although the proliferation of the cells was slow, antioxidants protected the cells from premature senescence, and subsequent cytokine release was prevented. We conclude that while elevated temperatures directly cause mitochondrial damage, senescence is induced by elevated ROS levels. We suggest that heat shock alters cell and tissue homeostasis by several independent mechanisms; however, reducing tissue senescence will reduce damage and provide a pathway to overcome physiological challenges in animals. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells and Their Derived Products as an Innovative Therapeutic Strategy in Acute Clinical Settings)
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18 pages, 2763 KiB  
Article
Effects of Cell Density and Microenvironment on Stem Cell Mitochondria Transfer among Human Adipose-Derived Stem Cells and HEK293 Tumorigenic Cells
by Shalise A. Burch and Carlos Luna Lopez
Int. J. Mol. Sci. 2022, 23(4), 2003; https://doi.org/10.3390/ijms23042003 - 11 Feb 2022
Cited by 3 | Viewed by 1855
Abstract
Stem cells (SC) are largely known for their potential to restore damaged tissue through various known mechanisms. Among these mechanisms is their ability to transfer healthy mitochondria to injured cells to rescue them. This mitochondrial transfer plays a critical role in the healing [...] Read more.
Stem cells (SC) are largely known for their potential to restore damaged tissue through various known mechanisms. Among these mechanisms is their ability to transfer healthy mitochondria to injured cells to rescue them. This mitochondrial transfer plays a critical role in the healing process. To determine the optimal parameters for inducing mitochondrial transfer between cells, we assessed mitochondrial transfer as a function of seeding density and in two-dimensional (2D) and semi three-dimensional (2.5D) culture models. Since mitochondrial transfer can occur through direct contact or secretion, the 2.5D culture model utilizes collagen to provide cells with a more physiologically relevant extracellular matrix and offers a more realistic representation of cell attachment and movement. Results demonstrate the dependence of mitochondrial transfer on cell density and the distance between donor and recipient cell. Furthermore, the differences found between the transfer of mitochondria in 2D and 2.5D microenvironments suggest an optimal mode of mitochondria transport. Using these parameters, we explored the effects on mitochondrial transfer between SCs and tumorigenic cells. HEK293 (HEK) is an immortalized cell line derived from human embryonic kidney cells which grow rapidly and form tumors in culture. Consequently, HEKs have been deemed tumorigenic and are widely used in cancer research. We observed mitochondrial transfer from SCs to HEK cells at significantly higher transfer rates when compared to a SC–SC co-culture system. Interestingly, our results also revealed an increase in the migratory ability of HEK cells when cultured with SCs. As more researchers find co-localization of stem cells and tumors in the human body, these results could be used to better understand their biological relationship and lead to enhanced therapeutic applications. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells and Their Derived Products as an Innovative Therapeutic Strategy in Acute Clinical Settings)
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23 pages, 5489 KiB  
Article
Mesenchymal Stem Cells Delivery in Individuals with Different Pathologies: Multimodal Tracking, Safety and Future Applications
by Carolina Belmar-López, Georges Vassaux, Ana Medel-Martinez, Jerome Burnet, Miguel Quintanilla, Santiago Ramón y Cajal, Javier Hernandez-Losa, Antonio De la Vieja and Pilar Martin-Duque
Int. J. Mol. Sci. 2022, 23(3), 1682; https://doi.org/10.3390/ijms23031682 - 31 Jan 2022
Cited by 4 | Viewed by 2562
Abstract
Due to their ease of isolation and their properties, mesenchymal stem cells (MSCs) have been widely investigated. MSCs have been proved capable of migration towards areas of inflammation, including tumors. Therefore, they have been suggested as vectors to carry therapies, specifically to neoplasias. [...] Read more.
Due to their ease of isolation and their properties, mesenchymal stem cells (MSCs) have been widely investigated. MSCs have been proved capable of migration towards areas of inflammation, including tumors. Therefore, they have been suggested as vectors to carry therapies, specifically to neoplasias. As most of the individuals joining clinical trials that use MSCs for cancer and other pathologies are carefully recruited and do not suffer from other diseases, here we decided to study the safety and application of iv-injected MSCs in animals simultaneously induced with different inflammatory pathologies (diabetes, wound healing and tumors). We studied this by in vitro and in vivo approaches using different gene reporters (GFP, hNIS, and f-Luc) and non-invasive techniques (PET, BLI, or fluorescence). Our results found that MSCs reached different organs depending on the previously induced pathology. Moreover, we evaluated the property of MSCs to target tumors as vectors to deliver adenoviruses, including the interaction between tumor microenvironment and MSCs on their arrival. Mechanisms such as transdifferentiation, MSC fusion with cells, or paracrine processes after MSCs homing were studied, increasing the knowledge and safety of this new therapy for cancer. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells and Their Derived Products as an Innovative Therapeutic Strategy in Acute Clinical Settings)
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Graphical abstract

18 pages, 1542 KiB  
Article
Human Amnion-Derived Mesenchymal Stromal Cells: A New Potential Treatment for Carbapenem-Resistant Enterobacterales in Decompensated Cirrhosis
by Mariangela Pampalone, Giampiero Vitale, Salvatore Gruttadauria, Giandomenico Amico, Gioacchin Iannolo, Bruno Douradinha, Alessandra Mularoni, Pier Giulio Conaldi and Giada Pietrosi
Int. J. Mol. Sci. 2022, 23(2), 857; https://doi.org/10.3390/ijms23020857 - 13 Jan 2022
Cited by 2 | Viewed by 1591
Abstract
Background: Spontaneous bacterial peritonitis (SBP) is a severe and often fatal infection in patients with decompensated cirrhosis and ascites. The only cure for SBP is antibiotic therapy, but the emerging problem of bacterial resistance requires novel therapeutic strategies. Human amniotic mesenchymal stromal cells [...] Read more.
Background: Spontaneous bacterial peritonitis (SBP) is a severe and often fatal infection in patients with decompensated cirrhosis and ascites. The only cure for SBP is antibiotic therapy, but the emerging problem of bacterial resistance requires novel therapeutic strategies. Human amniotic mesenchymal stromal cells (hA-MSCs) possess immunomodulatory and anti-inflammatory properties that can be harnessed as a therapy in such a context. Methods: An in vitro applications of hA-MSCs in ascitic fluid (AF) of cirrhotic patients, subsequently infected with carbapenem-resistant Enterobacterales, was performed. We evaluated the effects of hA-MSCs on bacterial load, innate immunity factors, and macrophage phenotypic expression. Results: hA-MSCs added to AF significantly reduce the proliferation of both bacterial strains at 24 h and diversely affect M1 and M2 polarization, C3a complement protein, and ficolin 3 concentrations during the course of infection, in a bacterial strain-dependent fashion. Conclusion: This study shows the potential usefulness of hA-MSC in treating ascites infected with carbapenem-resistant bacteria and lays the foundation to further investigate antibacterial and anti-inflammatory roles of hA-MSC in in vivo models. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells and Their Derived Products as an Innovative Therapeutic Strategy in Acute Clinical Settings)
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16 pages, 4911 KiB  
Article
MSC Pretreatment for Improved Transplantation Viability Results in Improved Ventricular Function in Infarcted Hearts
by Mark F. Pittenger, Saman Eghtesad, Pablo G. Sanchez, Xiaoyan Liu, Zhongjun Wu, Ling Chen and Bartley P. Griffith
Int. J. Mol. Sci. 2022, 23(2), 694; https://doi.org/10.3390/ijms23020694 - 8 Jan 2022
Cited by 2 | Viewed by 1740
Abstract
Many clinical studies utilizing MSCs (mesenchymal stem cells, mesenchymal stromal cells, or multipotential stromal cells) are underway in multiple clinical settings; however, the ideal approach to prepare these cells in vitro and to deliver them to injury sites in vivo with maximal effectiveness [...] Read more.
Many clinical studies utilizing MSCs (mesenchymal stem cells, mesenchymal stromal cells, or multipotential stromal cells) are underway in multiple clinical settings; however, the ideal approach to prepare these cells in vitro and to deliver them to injury sites in vivo with maximal effectiveness remains a challenge. Here, pretreating MSCs with agents that block the apoptotic pathways were compared with untreated MSCs. The treatment effects were evaluated in the myocardial infarct setting following direct injection, and physiological parameters were examined at 4 weeks post-infarct in a rat permanent ligation model. The prosurvival treated MSCs were detected in the hearts in greater abundance at 1 week and 4 weeks than the untreated MSCs. The untreated MSCs improved ejection fraction in infarcted hearts from 61% to 77% and the prosurvival treated MSCs further improved ejection fraction to 83% of normal. The untreated MSCs improved fractional shortening in the infarcted heart from 52% to 68%, and the prosurvival treated MSCs further improved fractional shortening to 77% of normal. Further improvements in survival of the MSC dose seems possible. Thus, pretreating MSCs for improved in vivo survival has implications for MSC-based cardiac therapies and in other indications where improved cell survival may improve effectiveness. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells and Their Derived Products as an Innovative Therapeutic Strategy in Acute Clinical Settings)
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14 pages, 4415 KiB  
Article
Treatment with Mesenchymal Stromal Cells Overexpressing Fas-Ligand Ameliorates Acute Graft-versus-Host Disease in Mice
by Andrei Mircea Vacaru, Ana-Maria Mazilu, Madalina Dumitrescu, Ioana Madalina Fenyo, Anca Violeta Gafencu and Ana-Maria Vacaru
Int. J. Mol. Sci. 2022, 23(1), 534; https://doi.org/10.3390/ijms23010534 - 4 Jan 2022
Cited by 4 | Viewed by 1709
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) has the potential to cure malignant and non-malignant hematological disorders, but because of the serious side effects of this intervention its applications are limited to a restricted number of diseases. Graft-versus-host disease (GvHD) is the most frequent complication [...] Read more.
Allogeneic hematopoietic cell transplantation (allo-HCT) has the potential to cure malignant and non-malignant hematological disorders, but because of the serious side effects of this intervention its applications are limited to a restricted number of diseases. Graft-versus-host disease (GvHD) is the most frequent complication and the leading cause of mortality and morbidity following allo-HCT. It results from the attack of the transplanted T cells from the graft against the cells of the recipient. There is no clear treatment for this severe complication. Due to their immunomodulatory properties, mesenchymal stromal cells (MSC) have been proposed to treat GvHD, but the results did not meet expectations. We have previously showed that the immunomodulatory effect of the MSC was significantly enhanced through adenoviral-mediated overexpression of FasL. In this study, we have tested the properties of FasL-overexpressing MSC in vivo, in a mouse model for acute GvHD. We found that treatment with FasL-overexpressing MSC delayed the onset of the disease and increased survival of the mice. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells and Their Derived Products as an Innovative Therapeutic Strategy in Acute Clinical Settings)
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12 pages, 2330 KiB  
Article
ASC and SVF Cells Synergistically Induce Neovascularization in Ischemic Hindlimb Following Cotransplantation
by Hong Zhe Zhang, Dong-Sik Chae and Sung-Whan Kim
Int. J. Mol. Sci. 2022, 23(1), 185; https://doi.org/10.3390/ijms23010185 - 24 Dec 2021
Cited by 6 | Viewed by 2751
Abstract
Previously, we reported the angio-vasculogenic properties of human stromal vascular fraction (SVF) and adipose tissue-derived mesenchymal stem cells (ASCs). In this study, we investigated whether the combination of ASCs and SVF cells exhibited synergistic angiogenic properties. We conducted quantitative (q)RT-PCR, Matrigel plug, tube [...] Read more.
Previously, we reported the angio-vasculogenic properties of human stromal vascular fraction (SVF) and adipose tissue-derived mesenchymal stem cells (ASCs). In this study, we investigated whether the combination of ASCs and SVF cells exhibited synergistic angiogenic properties. We conducted quantitative (q)RT-PCR, Matrigel plug, tube formation assays, and in vivo therapeutic assays using an ischemic hind limb mouse model. Immunohistochemical analysis was also conducted. qRT-PCR results revealed that FGF-2 was highly upregulated in ASCs compared with SVF, while PDGF-b and VEGF-A were highly upregulated in SVF. Conditioned medium from mixed cultures of ASCs and SVF (A+S) cells showed higher Matrigel tube formation and endothelial cell proliferation in vitro. A+S cell transplantation into ischemic mouse hind limbs strongly prevented limb loss and augmented blood perfusion compared with SVF cell transplantation. Transplanted A+S cells also showed high capillary density, cell proliferation, angiogenic cytokines, and anti-apoptotic potential in vivo compared with transplanted SVF. Our data indicate that A+S cell transplantation results in synergistic angiogenic therapeutic effects. Accordingly, A+S cell injection could be an alternative therapeutic strategy for treating ischemic diseases. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells and Their Derived Products as an Innovative Therapeutic Strategy in Acute Clinical Settings)
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19 pages, 1955 KiB  
Article
Therapeutic Effects of Hypoxic and Pro-Inflammatory Priming of Mesenchymal Stem Cell-Derived Extracellular Vesicles in Inflammatory Arthritis
by Alasdair G. Kay, Kane Treadwell, Paul Roach, Rebecca Morgan, Rhys Lodge, Mairead Hyland, Anna M. Piccinini, Nicholas R. Forsyth and Oksana Kehoe
Int. J. Mol. Sci. 2022, 23(1), 126; https://doi.org/10.3390/ijms23010126 - 23 Dec 2021
Cited by 14 | Viewed by 2938
Abstract
Mesenchymal stem cells (MSCs) immunomodulate inflammatory responses through paracrine signalling, including via secretion of extracellular vesicles (EVs) in the cell secretome. We evaluated the therapeutic potential of MSCs-derived small EVs in an antigen-induced model of arthritis (AIA). EVs isolated from MSCs cultured normoxically [...] Read more.
Mesenchymal stem cells (MSCs) immunomodulate inflammatory responses through paracrine signalling, including via secretion of extracellular vesicles (EVs) in the cell secretome. We evaluated the therapeutic potential of MSCs-derived small EVs in an antigen-induced model of arthritis (AIA). EVs isolated from MSCs cultured normoxically (21% O2, 5% CO2), hypoxically (2% O2, 5% CO2) or with a pro-inflammatory cytokine cocktail were applied into the AIA model. Disease pathology was assessed post-arthritis induction through swelling and histopathological analysis of synovial joint structure. Activated CD4+ T cells from healthy mice were cultured with EVs or MSCs to assess deactivation capabilities prior to application of standard EVs in vivo to assess T cell polarisation within the immune response to AIA. All EVs treatments reduced knee-joint swelling whilst only normoxic and pro-inflammatory primed EVs improved histopathological outcomes. In vitro culture with EVs did not achieve T cell deactivation. Polarisation towards CD4+ helper cells expressing IL17a (Th17) was reduced when normoxic and hypoxic EV treatments were applied in vitro. Normoxic EVs applied into the AIA model reduced Th17 polarisation and improved Regulatory T cell (Treg):Th17 homeostatic balance. Normoxic EVs present the optimal strategy for broad therapeutic benefit. EVs present an effective novel technology with the potential for cell-free therapeutic translation. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells and Their Derived Products as an Innovative Therapeutic Strategy in Acute Clinical Settings)
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20 pages, 3309 KiB  
Article
IFN-Gamma and TNF-Alpha as a Priming Strategy to Enhance the Immunomodulatory Capacity of Secretomes from Menstrual Blood-Derived Stromal Cells
by María Ángeles de Pedro, María Gómez-Serrano, Federica Marinaro, Esther López, María Pulido, Christian Preußer, Elke Pogge von Strandmann, Francisco Miguel Sánchez-Margallo, Verónica Álvarez and Javier G. Casado
Int. J. Mol. Sci. 2021, 22(22), 12177; https://doi.org/10.3390/ijms222212177 - 10 Nov 2021
Cited by 12 | Viewed by 3648
Abstract
Mesenchymal stromal cells isolated from menstrual blood (MenSCs) exhibit a potent pro-angiogenic and immunomodulatory capacity. Their therapeutic effect is mediated by paracrine mediators released by their secretomes. In this work, we aimed to evaluate the effect of a specific priming condition on the [...] Read more.
Mesenchymal stromal cells isolated from menstrual blood (MenSCs) exhibit a potent pro-angiogenic and immunomodulatory capacity. Their therapeutic effect is mediated by paracrine mediators released by their secretomes. In this work, we aimed to evaluate the effect of a specific priming condition on the phenotype and secretome content of MenSCs. Our results revealed that the optimal condition for priming MenSCs was the combination of interferon gamma (IFNγ) and tumor necrosis factor alpha (TNFα) that produced a synergistic and additive effect on IDO1 release and immune-related molecule expression. The analyses of MenSC-derived secretomes after IFNγ and TNFα priming also revealed an increase in EV release and in the differentially expressed miRNAs involved in the immune response and inflammation. Proliferation assays on lymphocyte subsets demonstrated a decrease in CD4+ T cells and CD8+ T cells co-cultured with secretomes, especially in the lymphocytes co-cultured with secretomes from primed cells. Additionally, the expression of immune checkpoints (PD-1 and CTLA-4) was increased in the CD4+ T cells co-cultured with MenSC-derived secretomes. These findings demonstrate that the combination of IFNγ and TNFα represents an excellent priming strategy to enhance the immunomodulatory capacity of MenSCs. Moreover, the secretome derived from primed MenSCs may be postulated as a therapeutic option for the regulation of adverse inflammatory reactions. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells and Their Derived Products as an Innovative Therapeutic Strategy in Acute Clinical Settings)
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15 pages, 4438 KiB  
Article
BDNF-Overexpressing Engineered Mesenchymal Stem Cells Enhances Their Therapeutic Efficacy against Severe Neonatal Hypoxic Ischemic Brain Injury
by So Yoon Ahn, Dong Kyung Sung, Yun Sil Chang, Se In Sung, Young Eun Kim, Hyo-Jin Kim, Soon Min Lee and Won Soon Park
Int. J. Mol. Sci. 2021, 22(21), 11395; https://doi.org/10.3390/ijms222111395 - 22 Oct 2021
Cited by 17 | Viewed by 2179
Abstract
We investigated whether irradiated brain-derived neurotropic factor (BDNF)-overexpressing engineered human mesenchymal stem cells (BDNF-eMSCs) improve paracrine efficiency and, thus, the beneficial potency of naïve MSCs against severe hypoxic ischemic (HI) brain injury in newborn rats. Irradiated BDNF-eMSCs hyper-secreted BDNF > 10 fold and [...] Read more.
We investigated whether irradiated brain-derived neurotropic factor (BDNF)-overexpressing engineered human mesenchymal stem cells (BDNF-eMSCs) improve paracrine efficiency and, thus, the beneficial potency of naïve MSCs against severe hypoxic ischemic (HI) brain injury in newborn rats. Irradiated BDNF-eMSCs hyper-secreted BDNF > 10 fold and were >5 fold more effective than naïve MSCs in attenuating the oxygen-glucose deprivation-induced increase in cytotoxicity, oxidative stress, and cell death in vitro. Only the irradiated BDNF-eMSCs, but not naïve MSCs, showed significant attenuating effects on severe neonatal HI-induced short-term brain injury scores, long-term progress of brain infarct, increased apoptotic cell death, astrogliosis and inflammatory responses, and impaired negative geotaxis and rotarod tests in vivo. Our data, showing better paracrine potency and the resultant better therapeutic efficacy of the irradiated BDNF-eMSCs, compared to naïve MSCs, suggest that MSCs transfected with the BDNF gene might represent a better, new therapeutic strategy against severe neonatal HI brain injury. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells and Their Derived Products as an Innovative Therapeutic Strategy in Acute Clinical Settings)
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21 pages, 4689 KiB  
Article
HIF-Overexpression and Pro-Inflammatory Priming in Human Mesenchymal Stromal Cells Improves the Healing Properties of Extracellular Vesicles in Experimental Crohn’s Disease
by Marta Gómez-Ferrer, Elena Amaro-Prellezo, Akaitz Dorronsoro, Rafael Sánchez-Sánchez, Ángeles Vicente, Jesús Cosín-Roger, María Dolores Barrachina, María Carmen Baquero, Jaris Valencia and Pilar Sepúlveda
Int. J. Mol. Sci. 2021, 22(20), 11269; https://doi.org/10.3390/ijms222011269 - 19 Oct 2021
Cited by 31 | Viewed by 3692
Abstract
Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) have therapeutic potential in the treatment of several immune disorders, including ulcerative colitis, owing to their regenerative and immunosuppressive properties. We recently showed that MSCs engineered to overexpress hypoxia-inducible factor 1-alpha and telomerase (MSC-T-HIF) [...] Read more.
Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) have therapeutic potential in the treatment of several immune disorders, including ulcerative colitis, owing to their regenerative and immunosuppressive properties. We recently showed that MSCs engineered to overexpress hypoxia-inducible factor 1-alpha and telomerase (MSC-T-HIF) and conditioned with pro-inflammatory stimuli release EVs (EVMSC-T-HIFC) with potent immunomodulatory activity. We tested the efficacy of EVMSC-T-HIFC to repolarize M1 macrophages (Mφ1) to M2-like macrophages (Mφ2-like) by analyzing surface markers and cytokines and performing functional assays in co-culture, including efferocytosis and T-cell proliferation. We also studied the capacity of EVMSC-T-HIFC to dampen the inflammatory response of activated endothelium and modulate fibrosis. Finally, we tested the therapeutic capacity of EVMSC-T-HIFC in an acute colitis model. EVMSC-T-HIFc induced the repolarization of monocytes from Mφ1 to an Mφ2-like phenotype, which was accompanied by reduced inflammatory cytokine release. EVMSC-T-HIFc-treated Mφ1 had similar effects of immunosuppression on activated peripheral blood mononuclear cells (PBMC) as Mφ2, and reduced the adhesion of PBMCs to activated endothelium. EVMSC-T-HIFc also prevented myofibroblast differentiation of TGF-β-treated fibroblasts. Finally, administration of EVMSC-T-HIFc promoted healing in a TNBS-induced mouse colitis model in terms of preserving colon length and intestinal mucosa architecture and altering the ratio of Mφ1/ Mφ2 infiltration. In conclusion, EVMSC-T-HIFC have effective anti-inflammatory properties, making them potential therapeutic agents in cell free-based therapies for the treatment of Crohn’s disease and likely other immune-mediated inflammatory diseases. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells and Their Derived Products as an Innovative Therapeutic Strategy in Acute Clinical Settings)
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Review

Jump to: Editorial, Research

23 pages, 2685 KiB  
Review
New Perspectives to Improve Mesenchymal Stem Cell Therapies for Drug-Induced Liver Injury
by Fernando Ezquer, Ya-Lin Huang and Marcelo Ezquer
Int. J. Mol. Sci. 2022, 23(5), 2669; https://doi.org/10.3390/ijms23052669 - 28 Feb 2022
Cited by 10 | Viewed by 3094
Abstract
Drug-induced liver injury (DILI) is one of the leading causes of acute liver injury. Many factors may contribute to the susceptibility of patients to this condition, making DILI a global medical problem that has an impact on public health and the pharmaceutical industry. [...] Read more.
Drug-induced liver injury (DILI) is one of the leading causes of acute liver injury. Many factors may contribute to the susceptibility of patients to this condition, making DILI a global medical problem that has an impact on public health and the pharmaceutical industry. The use of mesenchymal stem cells (MSCs) has been at the forefront of regenerative medicine therapies for many years, including MSCs for the treatment of liver diseases. However, there is currently a huge gap between these experimental approaches and their application in clinical practice. In this concise review, we focus on the pathophysiology of DILI and highlight new experimental approaches conceived to improve cell-based therapy by the in vitro preconditioning of MSCs and/or the use of cell-free products as treatment for this liver condition. Finally, we discuss the advantages of new approaches, but also the current challenges that must be addressed in order to develop safer and more effective procedures that will allow cell-based therapies to reach clinical practice, enhancing the quality of life and prolonging the survival time of patients with DILI. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells and Their Derived Products as an Innovative Therapeutic Strategy in Acute Clinical Settings)
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12 pages, 598 KiB  
Review
Protease Activated Receptors: A Pathway to Boosting Mesenchymal Stromal Cell Therapeutic Efficacy in Acute Respiratory Distress Syndrome?
by Naveen Gupta
Int. J. Mol. Sci. 2022, 23(3), 1277; https://doi.org/10.3390/ijms23031277 - 24 Jan 2022
Viewed by 2880
Abstract
Acute Respiratory Distress Syndrome is the most common cause of respiratory failure among critically ill patients, and its importance has been heightened during the COVID-19 pandemic. Even with the best supportive care, the mortality rate in the most severe cases is 40–50%, and [...] Read more.
Acute Respiratory Distress Syndrome is the most common cause of respiratory failure among critically ill patients, and its importance has been heightened during the COVID-19 pandemic. Even with the best supportive care, the mortality rate in the most severe cases is 40–50%, and the only pharmacological agent shown to be of possible benefit has been steroids. Mesenchymal stromal cells (MSCs) have been tested in several pre-clinical models of lung injury and been found to have significant therapeutic benefit related to: (a) potent immunomodulation; (b) secretion of epithelial and endothelial growth factors; and (c) augmentation of host defense to infection. Initial translational efforts have shown signs of promise, but the results have not yielded the anticipated outcomes. One potential reason is the relatively low survival of MSCs in inflammatory conditions as shown in several studies. Therefore, strategies to boost the survival of MSCs are needed to enhance their therapeutic effect. Protease-activated receptors (PARs) may represent one such possibility as they are G-protein coupled receptors expressed by MSCs and control several facets of cell behavior. This review summarizes some of the existing literature about PARs and MSCs and presents possible future areas of investigation in order to develop potential, PAR-modified MSCs with enhanced therapeutic efficiency. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells and Their Derived Products as an Innovative Therapeutic Strategy in Acute Clinical Settings)
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28 pages, 1000 KiB  
Review
Mesenchymal Stem Cell-Based Therapy as an Alternative to the Treatment of Acute Respiratory Distress Syndrome: Current Evidence and Future Perspectives
by Silvia Fernández-Francos, Noemi Eiro, Natalia González-Galiano and Francisco J. Vizoso
Int. J. Mol. Sci. 2021, 22(15), 7850; https://doi.org/10.3390/ijms22157850 - 22 Jul 2021
Cited by 37 | Viewed by 5422
Abstract
Acute respiratory distress syndrome (ARDS) represents a current challenge for medicine due to its incidence, morbidity and mortality and, also, the absence of an optimal treatment. The COVID-19 outbreak only increased the urgent demand for an affordable, safe and effective treatment for this [...] Read more.
Acute respiratory distress syndrome (ARDS) represents a current challenge for medicine due to its incidence, morbidity and mortality and, also, the absence of an optimal treatment. The COVID-19 outbreak only increased the urgent demand for an affordable, safe and effective treatment for this process. Early clinical trials suggest the therapeutic usefulness of mesenchymal stem cells (MSCs) in acute lung injury (ALI) and ARDS. MSC-based therapies show antimicrobial, anti-inflammatory, regenerative, angiogenic, antifibrotic, anti-oxidative stress and anti-apoptotic actions, which can thwart the physiopathological mechanisms engaged in ARDS. In addition, MSC secretome and their derived products, especially exosomes, may reproduce the therapeutic effects of MSC in lung injury. This last strategy of treatment could avoid several safety issues potentially associated with the transplantation of living and proliferative cell populations and may be formulated in different forms. However, the following diverse limitations must be addressed: (i) selection of the optimal MSC, bearing in mind both the heterogeneity among donors and across different histological origins, (ii) massive obtention of these biological products through genetic manipulations of the most appropriate MSC, (iii) bioreactors that allow their growth in 3D, (iv) ideal culture conditions and (v) adequate functional testing of these obtaining biological products before their clinical application. Full article
(This article belongs to the Special Issue Mesenchymal Stem Cells and Their Derived Products as an Innovative Therapeutic Strategy in Acute Clinical Settings)
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