International Journal of Molecular Sciences

Editorial

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2 pages, 165 KiB

Open AccessEditorial

Mesenchymal Stem Cells: A Hope or a Hype?

by Heba Abdelrazik

Int. J. Mol. Sci. 2023, 24(17), 13218; https://doi.org/10.3390/ijms241713218 - 25 Aug 2023

Viewed by 1119

Abstract

Mesenchymal Stem Cells (MSC) represent a captivating field of research attempting to address the vast variety of disease burdens, which at present lack efficient treatment [...] Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration)

Research

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20 pages, 2857 KiB

Open AccessArticle

Exploring the Molecular Crosstalk between Pancreatic Bud and Mesenchyme in Embryogenesis: Novel Signals Involved

by Ilaria Guerriero, Maria Teresa De Angelis, Fulvio D’Angelo, Rita Leveque, Eleonora Savignano, Luca Roberto, Valeria Lucci, Pellegrino Mazzone, Simona Laurino, Giovanni Storto, Anna Nardelli, Alessandro Sgambato, Michele Ceccarelli, Mario De Felice, Elena Amendola and Geppino Falco

Int. J. Mol. Sci. 2019, 20(19), 4900; https://doi.org/10.3390/ijms20194900 - 3 Oct 2019

Cited by 3 | Viewed by 3143

Abstract

Pancreatic organogenesis is a multistep process that requires the cooperation of several signaling pathways. In this context, the role of pancreatic mesenchyme is important to define the epithelium development; nevertheless, the precise space–temporal signaling activation still needs to be clarified. This study reports [...] Read more.

Pancreatic organogenesis is a multistep process that requires the cooperation of several signaling pathways. In this context, the role of pancreatic mesenchyme is important to define the epithelium development; nevertheless, the precise space–temporal signaling activation still needs to be clarified. This study reports a dissection of the pancreatic embryogenesis, highlighting the molecular network surrounding the epithelium–mesenchyme interaction. To investigate this crosstalk, pancreatic epithelium and surrounding mesenchyme, at embryonic day 10.5, were collected through laser capture microdissection (LCM) and characterized based on their global gene expression. We performed a bioinformatic analysis to hypothesize crosstalk interactions, validating the most promising genes and verifying the precise localization of their expression in the compartments, by RNA in situ hybridization (ISH). Our analyses pointed out also the c-Met gene, a very well-known factor involved in stimulating motility, morphogenesis, and organ regeneration. We also highlighted the potential crosstalk between Versican (Vcan) and Syndecan4 (Sdc4) since these genes are involved in pancreatic tissue repair, strengthening the concept that the same signaling pathways required during pancreatic embryogenesis are also involved in tissue repair. This finding leads to novel strategies for obtaining functional pancreatic stem cells for cell replacement therapies. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration)

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15 pages, 2020 KiB

Open AccessArticle

The Role of Prep1 in the Regulation of Mesenchymal Stromal Cells

by Giorgia Maroni, Daniele Panetta, Raffaele Luongo, Indira Krishnan, Federica La Rosa, Daniela Campani, Piero Salvadori, Patricia Iozzo, Francesco Blasi, Dmitry Penkov, Elena Levantini and Maria Cristina Magli

Int. J. Mol. Sci. 2019, 20(15), 3639; https://doi.org/10.3390/ijms20153639 - 25 Jul 2019

Cited by 4 | Viewed by 4115

Abstract

Molecular mechanisms governing cell fate decision events in bone marrow mesenchymal stromal cells (MSC) are still poorly understood. Herein, we investigated the homeobox gene Prep1 as a candidate regulatory molecule, by adopting Prep1 hypomorphic mice as a model to investigate the effects of [...] Read more.

Molecular mechanisms governing cell fate decision events in bone marrow mesenchymal stromal cells (MSC) are still poorly understood. Herein, we investigated the homeobox gene Prep1 as a candidate regulatory molecule, by adopting Prep1 hypomorphic mice as a model to investigate the effects of Prep1 downregulation, using in vitro and in vivo assays, including the innovative single cell RNA sequencing technology. Taken together, our findings indicate that low levels of Prep1 are associated to enhanced adipogenesis and a concomitant reduced osteogenesis in the bone marrow, suggesting Prep1 as a potential regulator of the adipo-osteogenic differentiation of mesenchymal stromal cells. Furthermore, our data suggest that in vivo decreased Prep1 gene dosage favors a pro-adipogenic phenotype and induces a “browning” effect in all fat tissues. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration)

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13 pages, 1913 KiB

Open AccessArticle

Thrombin Preconditioning Boosts Biogenesis of Extracellular Vesicles from Mesenchymal Stem Cells and Enriches Their Cargo Contents via Protease-Activated Receptor-Mediated Signaling Pathways

by Dong Kyung Sung, Se In Sung, So Yoon Ahn, Yun Sil Chang and Won Soon Park

Int. J. Mol. Sci. 2019, 20(12), 2899; https://doi.org/10.3390/ijms20122899 - 14 Jun 2019

Cited by 26 | Viewed by 3683

Abstract

We investigated the role of protease-activated receptor (PAR)-mediated signaling pathways in the biogenesis of human umbilical cord blood-derived mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) and the enrichment of their cargo content after thrombin preconditioning. Immunoblot analyses showed that MSCs expressed two PAR [...] Read more.

We investigated the role of protease-activated receptor (PAR)-mediated signaling pathways in the biogenesis of human umbilical cord blood-derived mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) and the enrichment of their cargo content after thrombin preconditioning. Immunoblot analyses showed that MSCs expressed two PAR subtypes: PAR-1 and PAR-3. Thrombin preconditioning significantly accelerated MSC-derived EV biogenesis more than five-fold and enriched their cargo contents by more than two-fold via activation of Rab5, early endosomal antigen (EEA)-1, and the extracellular signal regulated kinase (ERK)1/2 and AKT signaling pathways. Blockage of PAR-1 with the PAR-1-specific antagonist, SCH79797, significantly suppressed the activation of Rab5, EEA-1, and the ERK1/2 and AKT pathways and subsequently increased EV production and enriched EV cargo contents. Combined blockage of PAR-1 and PAR-3 further and significantly inhibited the activation of Rab5, EEA-1, and the ERK1/2 and AKT pathways, accelerated EV production, and enriched EV cargo contents. In summary, thrombin preconditioning boosted the biogenesis of MSC-derived EVs and enriched their cargo contents largely via PAR-1-mediated pathways and partly via PAR-1-independent, PAR-3-mediated activation of Rab5, EEA-1, and the ERK1/2 and AKT signaling pathways. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration)

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14 pages, 2533 KiB

Open AccessArticle

Differentiation of Motor Neuron-Like Cells from Tonsil-Derived Mesenchymal Stem Cells and Their Possible Application to Neuromuscular Junction Formation

by Saeyoung Park, Ji Yeon Kim, Seoha Myung, Namhee Jung, Yeonzi Choi and Sung-Chul Jung

Int. J. Mol. Sci. 2019, 20(11), 2702; https://doi.org/10.3390/ijms20112702 - 1 Jun 2019

Cited by 11 | Viewed by 4680

Abstract

Human tonsil-derived mesenchymal stem cells (T-MSCs) are newly identified MSCs and present typical features of MSCs, including having the differentiation capacity into the three germ layers and excellent proliferation capacity. They are easily sourced and are useful for stem cell therapy in various [...] Read more.

Human tonsil-derived mesenchymal stem cells (T-MSCs) are newly identified MSCs and present typical features of MSCs, including having the differentiation capacity into the three germ layers and excellent proliferation capacity. They are easily sourced and are useful for stem cell therapy in various disease states. We previously reported that T-MSCs could be differentiated into skeletal myocytes and Schwann-like cells; therefore, they are a promising candidate for cell therapies for neuromuscular disease. Motor neurons (MNs), which regulate spontaneous behavior, are affected by a wide range of MN diseases (MNDs) for which there are no effective remedies. We investigated the differentiation potential of MN-like cells derived from T-MSCs (T-MSC-MNCs) for application to therapy of MNDs. After the process of MN differentiation, the expression of MN-related markers, including Islet 1, HB9/HLXB9 (HB9), and choline acetyltransferase (ChAT), was increased when compared with undifferentiated T-MSCs. The secretion of acetylcholine to the conditioned medium was significantly increased after MN differentiation. We cocultured T-MSC-MNCs and human skeletal muscle cells, and confirmed the presence of the acetylcholine receptor clusters, which demonstrated the formation of neuromuscular junctions. The potential functional improvements afforded by these T-MSC-MNCs could be useful in the treatment of MNDs caused by genetic mutation, viral infection, or environmental problems. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration)

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21 pages, 31473 KiB

Open AccessArticle

Early Developmental Zebrafish Embryo Extract to Modulate Senescence in Multisource Human Mesenchymal Stem Cells

by Federica Facchin, Francesco Alviano, Silvia Canaider, Eva Bianconi, Martina Rossi, Laura Bonsi, Raffaella Casadei, Pier Mario Biava and Carlo Ventura

Int. J. Mol. Sci. 2019, 20(11), 2646; https://doi.org/10.3390/ijms20112646 - 29 May 2019

Cited by 4 | Viewed by 4532

Abstract

Stem cells undergo senescence both in vivo, contributing to the progressive decline in self-healing mechanisms, and in vitro during prolonged expansion. Here, we show that an early developmental zebrafish embryo extract (ZF1) could act as a modulator of senescence in human mesenchymal stem [...] Read more.

Stem cells undergo senescence both in vivo, contributing to the progressive decline in self-healing mechanisms, and in vitro during prolonged expansion. Here, we show that an early developmental zebrafish embryo extract (ZF1) could act as a modulator of senescence in human mesenchymal stem cells (hMSCs) isolated from both adult tissues, including adipose tissue (hASCs), bone marrow (hBM-MSCs), dental pulp (hDP-MSCs), and a perinatal tissue such as the Wharton’s Jelly (hWJ-MSCs). In all the investigated hMSCs, ZF1 decreased senescence-associated β-galactosidase (SA β-gal) activity and enhanced the transcription of TERT, encoding the catalytic telomerase core. In addition, it was associated, only in hASCs, with a transcriptional induction of BMI1, a pleiotropic repressor of senescence. In hBM-MSCs, hDP-MSCs, and hWJ-MSCs, TERT over-expression was concomitant with a down-regulation of two repressors of TERT, TP53 (p53), and CDKN1A (p21). Furthermore, ZF1 increased the natural ability of hASCs to perform adipogenesis. These results indicate the chance of using ZF1 to modulate stem cell senescence in a source-related manner, to be potentially used as a tool to affect stem cell senescence in vitro. In addition, its anti-senescence action could also set the basis for future in vivo approaches promoting tissue rejuvenation bypassing stem cell transplantation. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration)

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16 pages, 2722 KiB

Open AccessArticle

Regenerative Features of Adipose Tissue for Osteoarthritis Treatment in a Rabbit Model: Enzymatic Digestion Versus Mechanical Disruption

by Giovanna Desando, Isabella Bartolotti, Lucia Martini, Gianluca Giavaresi, Nicolò Nicoli Aldini, Milena Fini, Alice Roffi, Francesco Perdisa, Giuseppe Filardo, Elizaveta Kon and Brunella Grigolo

Int. J. Mol. Sci. 2019, 20(11), 2636; https://doi.org/10.3390/ijms20112636 - 29 May 2019

Cited by 31 | Viewed by 4611

Abstract

Evaluating cell migration after cell-based treatment is important for several disorders, including osteoarthritis (OA), as it might influence the clinical outcome. This research explores migrating expanded-adipose stromal cells (ASCs) and adipose niches after enzymatic and mechanical processes. Bilateral anterior cruciate ligament transection induced [...] Read more.

Evaluating cell migration after cell-based treatment is important for several disorders, including osteoarthritis (OA), as it might influence the clinical outcome. This research explores migrating expanded-adipose stromal cells (ASCs) and adipose niches after enzymatic and mechanical processes. Bilateral anterior cruciate ligament transection induced a mild grade of OA at eight weeks in adult male New Zealand rabbits. ASCs, enzymatic stromal vascular fraction (SVF), and micro fragmented adipose tissue (MFAT) were intra-articularly injected in the knee joint. Assessments of cell viability and expression of specific markers, including CD-163 wound-healing macrophages, were done. Cell migration was explored through labelling with PKH26 dye at 7 and 30 days alongside co-localization analyses for CD-146. All cells showed good viability and high percentages of CD-90 and CD-146. CD-163 was significantly higher in MFAT compared to SVF. Distinct migratory potential and time-dependent effects were observed among cell-based treatments. At day 7, both ASCs and SVF migrated towards synovium, whereas for MFAT versus cartilage, a different migration pattern was noticed at day 30. The long-term distinct cell migration of ASCs, SVF, and MFAT open interesting clinical insights on their potential use for OA treatment. Moreover, the highest expression of CD-163 in MFAT, rather than SVF, might have an important role in directly mediating cartilage tissue repair responses. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration)

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19 pages, 2001 KiB

Open AccessArticle

Senescence Phenomena and Metabolic Alteration in Mesenchymal Stromal Cells from a Mouse Model of Rett Syndrome

by Tiziana Squillaro, Nicola Alessio, Stefania Capasso, Giovanni Di Bernardo, Mariarosa Anna Beatrice Melone, Gianfranco Peluso and Umberto Galderisi

Int. J. Mol. Sci. 2019, 20(10), 2508; https://doi.org/10.3390/ijms20102508 - 21 May 2019

Cited by 12 | Viewed by 4622

Abstract

Chromatin modifiers play a crucial role in maintaining cell identity through modulation of gene expression patterns. Their deregulation can have profound effects on cell fate and functions. Among epigenetic regulators, the MECP2 protein is particularly attractive. Mutations in the Mecp2 gene are responsible [...] Read more.

Chromatin modifiers play a crucial role in maintaining cell identity through modulation of gene expression patterns. Their deregulation can have profound effects on cell fate and functions. Among epigenetic regulators, the MECP2 protein is particularly attractive. Mutations in the Mecp2 gene are responsible for more than 90% of cases of Rett syndrome (RTT), a progressive neurodevelopmental disorder. As a chromatin modulator, MECP2 can have a key role in the government of stem cell biology. Previously, we showed that deregulated MECP2 expression triggers senescence in mesenchymal stromal cells (MSCs) from (RTT) patients. Over the last few decades, it has emerged that senescent cells show alterations in the metabolic state. Metabolic changes related to stem cell senescence are particularly detrimental, since they contribute to the exhaustion of stem cell compartments, which in turn determine the falling in tissue renewal and functionality. Herein, we dissect the role of impaired MECP2 function in triggering senescence along with other senescence-related aspects, such as metabolism, in MSCs from a mouse model of RTT. We found that MECP2 deficiencies lead to senescence and impaired mitochondrial energy production. Our results support the idea that an alteration in mitochondria metabolic functions could play an important role in the pathogenesis of RTT. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration)

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15 pages, 2843 KiB

Open AccessArticle

Thrombin Preconditioning Enhances Therapeutic Efficacy of Human Wharton’s Jelly–Derived Mesenchymal Stem Cells in Severe Neonatal Hypoxic Ischemic Encephalopathy

by Young Eun Kim, Se In Sung, Yun Sil Chang, So Yoon Ahn, Dong Kyung Sung and Won Soon Park

Int. J. Mol. Sci. 2019, 20(10), 2477; https://doi.org/10.3390/ijms20102477 - 20 May 2019

Cited by 31 | Viewed by 4791

Abstract

We investigated whether thrombin preconditioning of human Wharton’s jelly–derived mesenchymal stem cells (MSCs) improves paracrine potency and thus the therapeutic efficacy of naïve MSCs against severe hypoxic ischemic encephalopathy (HIE). Thrombin preconditioning significantly enhances the neuroprotective anti-oxidative, anti-apoptotic, and anti-cytotoxic effects of naïve [...] Read more.

We investigated whether thrombin preconditioning of human Wharton’s jelly–derived mesenchymal stem cells (MSCs) improves paracrine potency and thus the therapeutic efficacy of naïve MSCs against severe hypoxic ischemic encephalopathy (HIE). Thrombin preconditioning significantly enhances the neuroprotective anti-oxidative, anti-apoptotic, and anti-cytotoxic effects of naïve MSCs against oxygen–glucose deprivation (OGD) of cortical neurons in vitro. Severe HIE was induced in vivo using unilateral carotid artery ligation and hypoxia for 2 h and confirmed using brain magnetic resonance imaging (MRI) involving >40% of ipsilateral hemisphere at postnatal day (P) 7 in newborn rats. Delayed intraventricular transplantation of 1 × 10⁵ thrombin preconditioned but not naïve MSCs at 24 h after hypothermia significantly enhanced observed anti-inflammatory, anti-astroglial, and anti-apoptotic effects and the ensuing brain infarction; behavioral tests, such as cylinder rearing and negative geotaxis tests, were conducted at P42. In summary, thrombin preconditioning of human Wharton’s jelly-derived MSCs significantly boosted the neuroprotective effects of naïve MSCs against OGD in vitro by enhancing their anti-oxidative, anti-apoptotic, and anti-cytotoxic effects, and significantly attenuated the severe HIE-induced brain infarction and improved behavioral function tests in vivo by maximizing their paracrine anti-inflammatory, anti-astroglial, and anti-apoptotic effects. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration)

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10 pages, 4676 KiB

Open AccessCommunication

Cyclophilin A in Arrhythmogenic Cardiomyopathy Cardiac Remodeling

by Erica Rurali, Chiara Assunta Pilato, Gianluca Lorenzo Perrucci, Alessandro Scopece, Ilaria Stadiotti, Donato Moschetta, Michela Casella, Elisa Cogliati, Elena Sommariva, Giulio Pompilio and Patrizia Nigro

Int. J. Mol. Sci. 2019, 20(10), 2403; https://doi.org/10.3390/ijms20102403 - 15 May 2019

Cited by 5 | Viewed by 3165

Abstract

Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder characterized by the progressive substitution of functional myocardium with noncontractile fibro-fatty tissue contributing to ventricular arrhythmias and sudden cardiac death. Cyclophilin A (CyPA) is a ubiquitous protein involved in several pathological mechanisms, which also characterize ACM [...] Read more.

Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder characterized by the progressive substitution of functional myocardium with noncontractile fibro-fatty tissue contributing to ventricular arrhythmias and sudden cardiac death. Cyclophilin A (CyPA) is a ubiquitous protein involved in several pathological mechanisms, which also characterize ACM (i.e., fibrosis, inflammation, and adipogenesis). Nevertheless, the involvement of CyPA in ACM cardiac remodeling has not been investigated yet. Thus, we first evaluated CyPA expression levels in the right ventricle (RV) tissue specimens obtained from ACM patients and healthy controls (HC) by immunohistochemistry. Then, we took advantage of ACM- and HC-derived cardiac mesenchymal stromal cells (C-MSC) to assess CyPA modulation during adipogenic differentiation. Interestingly, CyPA was more expressed in the RV sections obtained from ACM vs. HC subjects and positively correlated with the adipose replacement extent. Moreover, CyPA was upregulated at early stages of C-MSC adipogenic differentiation and was secreted at higher level over time in ACM- derived C-MSC. Our study provides novel ex vivo and in vitro information on CyPA expression in ACM remodeling paving the way for future C-MSC-based mechanistic and therapeutic investigations. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration)

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18 pages, 3894 KiB

Open AccessArticle

The Effect of Conditioned Media of Stem Cells Derived from Lipoma and Adipose Tissue on Macrophages’ Response and Wound Healing in Indirect Co-culture System In Vitro

by Sanja Stojanović and Stevo Najman

Int. J. Mol. Sci. 2019, 20(7), 1671; https://doi.org/10.3390/ijms20071671 - 3 Apr 2019

Cited by 33 | Viewed by 5608

Abstract

Immunomodulatory and wound healing activities of adipose-derived stem cells (ADSCs) have been reported in various in vitro and in vivo experimental models suggesting their beneficial role in regenerative medicine and treatments of inflammatory-related disorders. Lipoma-derived stem cells (LDSCs) were reported as a potential [...] Read more.

Immunomodulatory and wound healing activities of adipose-derived stem cells (ADSCs) have been reported in various in vitro and in vivo experimental models suggesting their beneficial role in regenerative medicine and treatments of inflammatory-related disorders. Lipoma-derived stem cells (LDSCs) were reported as a potential tool in regenerative medicine due to the similarity with ADSCs but we have previously shown that LDSCs have different differentiation capacity than ADSCs despite a similar mesenchymal phenotype. To further analyze the potential differences and/or similarities between those two stem cell types, in the present study we examined the macrophages (MΦs)’ response, immunomodulatory and wound healing effect of conditioned media (CM) of LDSCs and ADSCs in indirect co-culture system in vitro. We confirmed similar mesenchymal phenotype and stemness state of LDSCs and ADSCs but indicated differences in expression of some inflammatory-related genes. Anti-inflammatory potential of CM of LDSCs and ADSCs, with pronounced effect of LDSCs, in unstimulated RAW 264.7 MΦs was evaluated by decrease in Tnf and increase in Il10 gene expression, which was confirmed by corresponding cytokines’ secretion analysis. Conditioned media of both LDSCs and ADSCs led to the functional activation of MΦs, with slightly more pronounced effect of CM of LDSCs, while both stimulated wound healing in vitro in a similar manner. Results of this study suggest that LDSCs secrete soluble factors like ADSCs and therefore may have a potential for application in regenerative medicine, due to immunomodulatory and wound healing activity, and indicate that LDSCs through secretome may interact with other cells in lipoma tissue. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration)

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15 pages, 2475 KiB

Open AccessArticle

miR-31-5p Is a LIPUS-Mechanosensitive MicroRNA that Targets HIF-1α Signaling and Cytoskeletal Proteins

by Viviana Costa, Valeria Carina, Alice Conigliaro, Lavinia Raimondi, Angela De Luca, Daniele Bellavia, Francesca Salamanna, Stefania Setti, Riccardo Alessandro, Milena Fini and Gianluca Giavaresi

Int. J. Mol. Sci. 2019, 20(7), 1569; https://doi.org/10.3390/ijms20071569 - 28 Mar 2019

Cited by 20 | Viewed by 3786

Abstract

The roles of low-intensity pulsed ultrasound (LIPUS) and microRNAs (miRNAs) on hMSCs commitments have already been investigated; however, the effects of the application of their co-treatments in an in vitro cell model are still unknown. Our previous studies demonstrated that (i) LIPUS modulated [...] Read more.

The roles of low-intensity pulsed ultrasound (LIPUS) and microRNAs (miRNAs) on hMSCs commitments have already been investigated; however, the effects of the application of their co-treatments in an in vitro cell model are still unknown. Our previous studies demonstrated that (i) LIPUS modulated hMSCs cytoskeletal organization and (ii) miRNA-675-5p have a role in HIF-1α signaling modulation during hMSCs osteoblast commitment. We investigated for the first time the role of LIPUS as promoter tool for miRNA expression. Thanks to bioinformatic analysis, we identified miR-31-5p as a LIPUS-induced miRNA and investigated its role through in vitro studies of gain and loss of function. Results highlighted that LIPUS stimulation induced a hypoxia adaptive cell response, which determines a reorganization of cell membrane and cytoskeleton proteins. MiR-31-5p gain and loss of function studies, demonstrated as miR-31-5p overexpression, were able to induce hypoxic and cytoskeletal responses. Moreover, the co-treatments LIPUS and miR-31-5p inhibitor abolished the hypoxic responses including angiogenesis and the expression of Rho family proteins. MiR-31-5p was identified as a LIPUS-mechanosensitive miRNAs and may be considered a new therapeutic option to promote or abolish hypoxic response and cytoskeletal organization on hMSCs during the bone regeneration process. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration)

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15 pages, 22920 KiB

Open AccessArticle

In Vitro Induction of Tendon-Specific Markers in Tendon Cells, Adipose- and Bone Marrow-Derived Stem Cells is Dependent on TGFβ3, BMP-12 and Ascorbic Acid Stimulation

by Carlotta Perucca Orfei, Marco Viganò, John R. Pearson, Alessandra Colombini, Paola De Luca, Enrico Ragni, Leonor Santos-Ruiz and Laura De Girolamo

Int. J. Mol. Sci. 2019, 20(1), 149; https://doi.org/10.3390/ijms20010149 - 3 Jan 2019

Cited by 37 | Viewed by 5605

Abstract

Mesenchymal Stem Cells (MSCs) and tissue-specific progenitors have been proposed as useful tools for regenerative medicine approaches in bone, cartilage and tendon-related pathologies. The differentiation of cells towards the desired, target tissue-specific lineage has demonstrated advantages in the application of cell therapies and [...] Read more.

Mesenchymal Stem Cells (MSCs) and tissue-specific progenitors have been proposed as useful tools for regenerative medicine approaches in bone, cartilage and tendon-related pathologies. The differentiation of cells towards the desired, target tissue-specific lineage has demonstrated advantages in the application of cell therapies and tissue engineering. Unlike osteogenic and chondrogenic differentiation, there is no consensus on the best tenogenic induction protocol. Many growth factors have been proposed for this purpose, including BMP-12, b-FGF, TGF-β3, CTGF, IGF-1 and ascorbic acid (AA). In this study, different combinations of these growth factors have been tested in the context of a two-step differentiation protocol, in order to define their contribution to the induction and maintenance of tendon marker expression in adipose tissue and bone marrow derived MSCs and tendon cells (TCs), respectively. Our results demonstrate that TGF-β3 is the main inducer of scleraxis, an early expressed tendon marker, while at the same time inhibiting tendon markers normally expressed later, such as decorin. In contrast, we find that decorin is induced by BMP-12, b-FGF and AA. Our results provide new insights into the effect of different factors on the tenogenic induction of MSCs and TCs, highlighting the importance of differential timing in TGF-β3 stimulation. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration)

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Review

Jump to: Editorial, Research

29 pages, 962 KiB

Open AccessReview

Substantial Overview on Mesenchymal Stem Cell Biological and Physical Properties as an Opportunity in Translational Medicine

by Heba Abdelrazik, Emanuele Giordano, Giovanni Barbanti Brodano, Cristiana Griffoni, Elena De Falco and Alessandra Pelagalli

Int. J. Mol. Sci. 2019, 20(21), 5386; https://doi.org/10.3390/ijms20215386 - 29 Oct 2019

Cited by 22 | Viewed by 4977

Abstract

Mesenchymal stem cells (MSC) have piqued worldwide interest for their extensive potential to treat a large array of clinical indications, their unique and controversial immunogenic and immune modulatory properties allowing ample discussions and debates for their possible applications. Emerging data demonstrating that the [...] Read more.

Mesenchymal stem cells (MSC) have piqued worldwide interest for their extensive potential to treat a large array of clinical indications, their unique and controversial immunogenic and immune modulatory properties allowing ample discussions and debates for their possible applications. Emerging data demonstrating that the interaction of biomaterials and physical cues with MSC can guide their differentiation into specific cell lineages also provide new interesting insights for further MSC manipulation in different clinical applications. Moreover, recent discoveries of some regulatory molecules and signaling pathways in MSC niche that may regulate cell fate to distinct lineage herald breakthroughs in regenerative medicine. Although the advancement and success in the MSC field had led to an enormous increase in the amount of ongoing clinical trials, we still lack defined clinical therapeutic protocols. This review will explore the exciting opportunities offered by human and animal MSC, describing relevant biological properties of these cells in the light of the novel emerging evidence mentioned above while addressing the limitations and challenges MSC are still facing. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration)

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23 pages, 920 KiB

Open AccessReview

Mesenchymal Stem Cells in Homeostasis and Systemic Diseases: Hypothesis, Evidences, and Therapeutic Opportunities

by Francisco J. Vizoso, Noemi Eiro, Luis Costa, Paloma Esparza, Mariana Landin, Patricia Diaz-Rodriguez, Jose Schneider and Roman Perez-Fernandez

Int. J. Mol. Sci. 2019, 20(15), 3738; https://doi.org/10.3390/ijms20153738 - 31 Jul 2019

Cited by 76 | Viewed by 6458

Abstract

Mesenchymal stem cells (MSCs) are present in all organs and tissues, playing a well-known function in tissue regeneration. However, there is also evidence indicating a broader role of MSCs in tissue homeostasis. In vivo studies have shown MSC paracrine mechanisms displaying proliferative, immunoregulatory, [...] Read more.

Mesenchymal stem cells (MSCs) are present in all organs and tissues, playing a well-known function in tissue regeneration. However, there is also evidence indicating a broader role of MSCs in tissue homeostasis. In vivo studies have shown MSC paracrine mechanisms displaying proliferative, immunoregulatory, anti-oxidative, or angiogenic activity. In addition, recent studies also demonstrate that depletion and/or dysfunction of MSCs are associated with several systemic diseases, such as lupus, diabetes, psoriasis, and rheumatoid arthritis, as well as with aging and frailty syndrome. In this review, we hypothesize about the role of MSCs as keepers of tissue homeostasis as well as modulators in a variety of inflammatory and degenerative systemic diseases. This scenario opens the possibility for the use of secretome-derived products from MSCs as new therapeutic agents in order to restore tissue homeostasis, instead of the classical paradigm “one disease, one drug”. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration)

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17 pages, 1795 KiB

Open AccessReview

Adapting and Surviving: Intra and Extra-Cellular Remodeling in Drug-Resistant Gastric Cancer Cells

by Sabino Russi, Henu Kumar Verma, Simona Laurino, Pellegrino Mazzone, Giovanni Storto, Anna Nardelli, Pietro Zoppoli, Giovanni Calice, Francesco La Rocca, Alessandro Sgambato, Valeria Lucci, Geppino Falco and Vitalba Ruggieri

Int. J. Mol. Sci. 2019, 20(15), 3736; https://doi.org/10.3390/ijms20153736 - 31 Jul 2019

Cited by 44 | Viewed by 5024

Abstract

Despite the significant recent advances in clinical practice, gastric cancer (GC) represents a leading cause of cancer-related deaths in the world. In fact, occurrence of chemo-resistance still remains a daunting hindrance to effectiveness of the current approach to GC therapy. There is accumulating [...] Read more.

Despite the significant recent advances in clinical practice, gastric cancer (GC) represents a leading cause of cancer-related deaths in the world. In fact, occurrence of chemo-resistance still remains a daunting hindrance to effectiveness of the current approach to GC therapy. There is accumulating evidence that a plethora of cellular and molecular factors is implicated in drug-induced phenotypical switching of GC cells. Among them, epithelial-mesenchymal transition (EMT), autophagy, drug detoxification, DNA damage response and drug target alterations, have been reported as major determinants. Intriguingly, resistant GC phenotype may be the result of GC cell-induced tumor microenvironment (TME) remodeling, which is currently emerging as a key player in promoting drug resistance and overcoming cytotoxic effects of drugs. In this review, we discuss the possible mechanisms of drug resistance and their involvement in determining current GC therapies failure. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration)

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20 pages, 312 KiB

Open AccessReview

Genetically Engineered-MSC Therapies for Non-unions, Delayed Unions and Critical-size Bone Defects

by Jaime Freitas, Susana Gomes Santos, Raquel Madeira Gonçalves, José Henrique Teixeira, Mário Adolfo Barbosa and Maria Inês Almeida

Int. J. Mol. Sci. 2019, 20(14), 3430; https://doi.org/10.3390/ijms20143430 - 12 Jul 2019

Cited by 32 | Viewed by 5416

Abstract

The normal bone regeneration process is a complex and coordinated series of events involving different cell types and molecules. However, this process is impaired in critical-size/large bone defects, with non-unions or delayed unions remaining a major clinical problem. Novel strategies are needed to [...] Read more.

The normal bone regeneration process is a complex and coordinated series of events involving different cell types and molecules. However, this process is impaired in critical-size/large bone defects, with non-unions or delayed unions remaining a major clinical problem. Novel strategies are needed to aid the current therapeutic approaches. Mesenchymal stem/stromal cells (MSCs) are able to promote bone regeneration. Their beneficial effects can be improved by modulating the expression levels of specific genes with the purpose of stimulating MSC proliferation, osteogenic differentiation or their immunomodulatory capacity. In this context, the genetic engineering of MSCs is expected to further enhance their pro-regenerative properties and accelerate bone healing. Herein, we review the most promising molecular candidates (protein-coding and non-coding transcripts) and discuss the different methodologies to engineer and deliver MSCs, mainly focusing on in vivo animal studies. Considering the potential of the MSC secretome for bone repair, this topic has also been addressed. Furthermore, the promising results of clinical studies using MSC for bone regeneration are discussed. Finally, we debate the advantages and limitations of using MSCs, or genetically-engineered MSCs, and their potential as promoters of bone fracture regeneration/repair. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration)

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17 pages, 691 KiB

Open AccessReview

Mesenchymal Stem Cells Empowering Tendon Regenerative Therapies

by Raquel Costa-Almeida, Isabel Calejo and Manuela E. Gomes

Int. J. Mol. Sci. 2019, 20(12), 3002; https://doi.org/10.3390/ijms20123002 - 19 Jun 2019

Cited by 103 | Viewed by 13873

Abstract

Tendon tissues have limited healing capacity. The incidence of tendon injuries and the unsatisfactory functional outcomes of tendon repair are driving the search for alternative therapeutic approaches envisioning tendon regeneration. Cellular therapies aim at delivering adequate, regeneration-competent cell types to the injured tendon [...] Read more.

Tendon tissues have limited healing capacity. The incidence of tendon injuries and the unsatisfactory functional outcomes of tendon repair are driving the search for alternative therapeutic approaches envisioning tendon regeneration. Cellular therapies aim at delivering adequate, regeneration-competent cell types to the injured tendon and toward ultimately promoting its reconstruction and recovery of functionality. Mesenchymal stem cells (MSCs) either obtained from tendons or from non-tendon sources, like bone marrow (BM-MSCs) or adipose tissue (ASCs), have been receiving increasing attention over the years toward enhancing tendon healing. Evidences from in vitro and in vivo studies suggest MSCs can contribute to accelerate and improve the quality of tendon healing. Nonetheless, the exact mechanisms underlying these repair events are yet to be fully elucidated. This review provides an overview of the main challenges in the field of cell-based regenerative therapies, discussing the role of MSCs in boosting tendon regeneration, particularly through their capacity to enhance the tenogenic properties of tendon resident cells. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration)

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28 pages, 1997 KiB

Open AccessReview

Current Trends and Future Perspective of Mesenchymal Stem Cells and Exosomes in Corneal Diseases

by Hassan Mansoor, Hon Shing Ong, Andri K. Riau, Tisha P. Stanzel, Jodhbir S. Mehta and Gary Hin-Fai Yam

Int. J. Mol. Sci. 2019, 20(12), 2853; https://doi.org/10.3390/ijms20122853 - 12 Jun 2019

Cited by 83 | Viewed by 15112

Abstract

The corneal functions (transparency, refractivity and mechanical strength) deteriorate in many corneal diseases but can be restored after corneal transplantation (penetrating and lamellar keratoplasties). However, the global shortage of transplantable donor corneas remains significant and patients are subject to life-long risk of immune [...] Read more.

The corneal functions (transparency, refractivity and mechanical strength) deteriorate in many corneal diseases but can be restored after corneal transplantation (penetrating and lamellar keratoplasties). However, the global shortage of transplantable donor corneas remains significant and patients are subject to life-long risk of immune response and graft rejection. Various studies have shown the differentiation of multipotent mesenchymal stem cells (MSCs) into various corneal cell types. With the unique properties of immunomodulation, anti-angiogenesis and anti-inflammation, they offer the advantages in corneal reconstruction. These effects are widely mediated by MSC differentiation and paracrine signaling via exosomes. Besides the cell-free nature of exosomes in circumventing the problems of cell-fate control and tumorigenesis, the vesicle content can be genetically modified for optimal therapeutic affinity. The pharmacology and toxicology, xeno-free processing with sustained delivery, scale-up production in compliant to Good Manufacturing Practice regulations, and cost-effectiveness are the current foci of research. Routes of administration via injection, topical and/or engineered bioscaffolds are also explored for its applicability in treating corneal diseases. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration)

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26 pages, 1597 KiB

Open AccessReview

Mesenchymal Stem Cells for Spinal Cord Injury: Current Options, Limitations, and Future of Cell Therapy

by Fabio Cofano, Marina Boido, Matteo Monticelli, Francesco Zenga, Alessandro Ducati, Alessandro Vercelli and Diego Garbossa

Int. J. Mol. Sci. 2019, 20(11), 2698; https://doi.org/10.3390/ijms20112698 - 31 May 2019

Cited by 256 | Viewed by 18132

Abstract

Spinal cord injury (SCI) constitutes an inestimable public health issue. The most crucial phase in the pathophysiological process of SCI concerns the well-known secondary injury, which is the uncontrolled and destructive cascade occurring later with aberrant molecular signaling, inflammation, vascular changes, and secondary [...] Read more.

Spinal cord injury (SCI) constitutes an inestimable public health issue. The most crucial phase in the pathophysiological process of SCI concerns the well-known secondary injury, which is the uncontrolled and destructive cascade occurring later with aberrant molecular signaling, inflammation, vascular changes, and secondary cellular dysfunctions. The use of mesenchymal stem cells (MSCs) represents one of the most important and promising tested strategies. Their appeal, among the other sources and types of stem cells, increased because of their ease of isolation/preservation and their properties. Nevertheless, encouraging promise from preclinical studies was followed by weak and conflicting results in clinical trials. In this review, the therapeutic role of MSCs is discussed, together with their properties, application, limitations, and future perspectives. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration)

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15 pages, 839 KiB

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Adult Stem Cell Functioning in the Tumor Micro-Environment

by Yuhan Jiang, Alan Wells, Kyle Sylakowski, Amanda M. Clark and Bo Ma

Int. J. Mol. Sci. 2019, 20(10), 2566; https://doi.org/10.3390/ijms20102566 - 25 May 2019

Cited by 16 | Viewed by 5619

Abstract

Tumor progression from an expanded cell population in a primary location to disseminated lethal growths subverts attempts at cures. It has become evident that these steps are driven in a large part by cancer cell-extrinsic signaling from the tumor microenvironment (TME), one cellular [...] Read more.

Tumor progression from an expanded cell population in a primary location to disseminated lethal growths subverts attempts at cures. It has become evident that these steps are driven in a large part by cancer cell-extrinsic signaling from the tumor microenvironment (TME), one cellular component of which is becoming more appreciated for potential modulation of the cancer cells directly and the TME globally. That cell is a heterogenous population referred to as adult mesenchymal stem cells/multipotent stromal cells (MSCs). Herein, we review emerging evidence as to how these cells, both from distant sources, mainly the bone marrow, or local resident cells, can impact the progression of solid tumors. These nascent investigations raise more questions than they answer but paint a picture of an orchestrated web of signals and interactions that can be modulated to impact tumor progression. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration)

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26 pages, 3775 KiB

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Genetic Stability of Mesenchymal Stromal Cells for Regenerative Medicine Applications: A Fundamental Biosafety Aspect

by Simona Neri

Int. J. Mol. Sci. 2019, 20(10), 2406; https://doi.org/10.3390/ijms20102406 - 15 May 2019

Cited by 115 | Viewed by 9430

Abstract

Mesenchymal stem/stromal cells (MSC) show widespread application for a variety of clinical conditions; therefore, their use necessitates continuous monitoring of their safety. The risk assessment of mesenchymal stem cell-based therapies cannot be separated from an accurate and deep knowledge of their biological properties [...] Read more.

Mesenchymal stem/stromal cells (MSC) show widespread application for a variety of clinical conditions; therefore, their use necessitates continuous monitoring of their safety. The risk assessment of mesenchymal stem cell-based therapies cannot be separated from an accurate and deep knowledge of their biological properties and in vitro and in vivo behavior. One of the most relevant safety issues is represented by the genetic stability of MSCs, that can be altered during in vitro manipulation, frequently required before clinical application. MSC genetic stability has the potential to influence the transformation and the therapeutic effect of these cells. At present, karyotype evaluation represents the definitely prevailing assessment of MSC stability, but DNA alterations of smaller size should not be underestimated. This review will focus on current scientific knowledge about the genetic stability of mesenchymal stem cells. The techniques used and possible improvements together with regulatory aspects will also be discussed. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration)

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