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1.
Cells ; 10(3)2021 03 07.
Artículo en Inglés | MEDLINE | ID: mdl-33799966

RESUMEN

The novel coronavirus severe acute respiratory syndrome-CoV-2 (SARS-CoV-2) is responsible for COVID-19 infection. The COVID-19 pandemic represents one of the worst global threats in the 21st century since World War II. This pandemic has led to a worldwide economic recession and crisis due to lockdown. Biomedical researchers, pharmaceutical companies, and premier institutes throughout the world are claiming that new clinical trials are in progress. During the severe phase of this disease, mechanical ventilators are used to assist in the management of outcomes; however, their use can lead to the development of pneumonia. In this context, mesenchymal stem cell (MSC)-derived exosomes can serve as an immunomodulation treatment for COVID-19 patients. Exosomes possess anti-inflammatory, pro-angiogenic, and immunomodulatory properties that can be explored in an effort to improve the outcomes of SARS-CoV-2-infected patients. Currently, only one ongoing clinical trial (NCT04276987) is specifically exploring the use of MSC-derived exosomes as a therapy to treat SARS-CoV-2-associated pneumonia. The purpose of this review is to provide insights of using exosomes derived from mesenchymal stem cells in management of the co-morbidities associated with SARS-CoV-2-infected persons in direction of improving their health outcome. There is limited knowledge of using exosomes in SARS-CoV-2; the clinicians and researchers should exploit exosomes as therapeutic regime.


Asunto(s)
/terapia , Exosomas/metabolismo , Vesículas Extracelulares/metabolismo , Inmunomodulación , Células Madre Mesenquimatosas/metabolismo , Neumonía Viral/terapia , /complicaciones , /patología , Citocinas/metabolismo , Citocinas/farmacología , Exosomas/química , Exosomas/genética , Humanos , Inflamación/inmunología , Inflamación/terapia , Inflamación/virología , Células Madre Mesenquimatosas/inmunología , Neovascularización Fisiológica/inmunología , Neumonía Viral/complicaciones , Neumonía Viral/virología , Infecciones del Sistema Respiratorio/complicaciones , Infecciones del Sistema Respiratorio/terapia , Infecciones del Sistema Respiratorio/virología
2.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33802220

RESUMEN

Metabolic glycoengineering enables a directed modification of cell surfaces by introducing target molecules to surface proteins displaying new features. Biochemical pathways involving glycans differ in dependence on the cell type; therefore, this technique should be tailored for the best results. We characterized metabolic glycoengineering in telomerase-immortalized human mesenchymal stromal cells (hMSC-TERT) as a model for primary hMSC, to investigate its applicability in TERT-modified cell lines. The metabolic incorporation of N-azidoacetylmannosamine (Ac4ManNAz) and N-alkyneacetylmannosamine (Ac4ManNAl) into the glycocalyx as a first step in the glycoengineering process revealed no adverse effects on cell viability or gene expression, and the in vitro multipotency (osteogenic and adipogenic differentiation potential) was maintained under these adapted culture conditions. In the second step, glycoengineered cells were modified with fluorescent dyes using Cu-mediated click chemistry. In these analyses, the two mannose derivatives showed superior incorporation efficiencies compared to glucose and galactose isomers. In time-dependent experiments, the incorporation of Ac4ManNAz was detectable for up to six days while Ac4ManNAl-derived metabolites were absent after two days. Taken together, these findings demonstrate the successful metabolic glycoengineering of immortalized hMSC resulting in transient cell surface modifications, and thus present a useful model to address different scientific questions regarding glycosylation processes in skeletal precursors.


Asunto(s)
Glicocálix , Hexosaminas , Células Madre Mesenquimatosas/metabolismo , Ingeniería Metabólica , Modelos Biológicos , Mioblastos Esqueléticos/metabolismo , Línea Celular Transformada , Glicocálix/química , Glicocálix/metabolismo , Hexosaminas/química , Hexosaminas/metabolismo , Humanos
3.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-33802984

RESUMEN

Hybrid composites of synthetic and natural polymers represent materials of choice for bone tissue engineering. Ulvan, a biologically active marine sulfated polysaccharide, is attracting great interest in the development of novel biomedical scaffolds due to recent reports on its osteoinductive properties. Herein, a series of hybrid polycaprolactone scaffolds containing ulvan either alone or in blends with κ-carrageenan and chondroitin sulfate was prepared and characterized. The impact of the preparation methodology and the polysaccharide composition on their morphology, as well as on their mechanical, thermal, water uptake and porosity properties was determined, while their osteoinductive potential was investigated through the evaluation of cell adhesion, viability, and osteogenic differentiation of seeded human adipose-derived mesenchymal stem cells. The results verified the osteoinductive ability of ulvan, showing that its incorporation into the polycaprolactone matrix efficiently promoted cell attachment and viability, thus confirming its potential in the development of biomedical scaffolds for bone tissue regeneration applications.


Asunto(s)
Organismos Acuáticos/química , Huesos/fisiología , Osteogénesis/efectos de los fármacos , Poliésteres/química , Polisacáridos/farmacología , Ingeniería de Tejidos , Andamios del Tejido/química , Huesos/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Elasticidad , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Polisacáridos/ultraestructura , Espectroscopía Infrarroja por Transformada de Fourier , Termogravimetría , Agua/química
4.
Int J Mol Sci ; 22(6)2021 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-33809632

RESUMEN

Over the past two decades, mesenchymal stromal cells (MSCs) have demonstrated great potential in the treatment of inflammation-related conditions. Numerous early stage clinical trials have suggested that this treatment strategy has potential to lead to significant improvements in clinical outcomes. While promising, there remain substantial regulatory hurdles, safety concerns, and logistical issues that need to be addressed before cell-based treatments can have widespread clinical impact. These drawbacks, along with research aimed at elucidating the mechanisms by which MSCs exert their therapeutic effects, have inspired the development of extracellular vesicles (EVs) as anti-inflammatory therapeutic agents. The use of MSC-derived EVs for treating inflammation-related conditions has shown therapeutic potential in both in vitro and small animal studies. This review will explore the current research landscape pertaining to the use of MSC-derived EVs as anti-inflammatory and pro-regenerative agents in a range of inflammation-related conditions: osteoarthritis, rheumatoid arthritis, Alzheimer's disease, cardiovascular disease, and preeclampsia. Along with this, the mechanisms by which MSC-derived EVs exert their beneficial effects on the damaged or degenerative tissues will be reviewed, giving insight into their therapeutic potential. Challenges and future perspectives on the use of MSC-derived EVs for the treatment of inflammation-related conditions will be discussed.


Asunto(s)
Vesículas Extracelulares/metabolismo , Inflamación/patología , Inflamación/terapia , Células Madre Mesenquimatosas/metabolismo , Animales , Humanos , Modelos Biológicos
5.
Int J Mol Sci ; 22(6)2021 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-33809663

RESUMEN

Specific stem cell populations within dental mesenchymal tissues guarantee tooth homeostasis and regeneration throughout life. The decision between renewal and differentiation of stem cells is greatly influenced by interactions with stromal cells and extracellular matrix molecules that form the tissue specific stem cell niches. The Cxcl12 chemokine is a general marker of stromal cells and plays fundamental roles in the maintenance, mobilization and migration of stem cells. The aim of this study was to exploit Cxcl12-GFP transgenic mice to study the expression patterns of Cxcl12 in putative dental niches of intact and injured teeth. We showed that endothelial and stromal cells expressed Cxcl12 in the dental pulp tissue of both intact molars and incisors. Isolated non-endothelial Cxcl12+ dental pulp cells cultured in different conditions in vitro exhibited expression of both adipogenic and osteogenic markers, thus suggesting that these cells possess multipotent fates. Taken together, our results show that Cxcl12 is widely expressed in intact and injured teeth and highlight its importance as a key component of the various dental mesenchymal stem cell niches.


Asunto(s)
Quimiocina CXCL12/genética , Regulación de la Expresión Génica , Células Madre Mesenquimatosas/metabolismo , Nicho de Células Madre/genética , Traumatismos de los Dientes/genética , Diente/patología , Animales , Quimiocina CXCL12/metabolismo , Pulpa Dental/metabolismo , Incisivo/metabolismo , Ratones Transgénicos , Diente Molar/metabolismo , Receptores CXCR4/metabolismo
6.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33808970

RESUMEN

Cell-free therapy using extracellular vesicles (EVs) from adipose-derived mesenchymal stromal/stem cells (ASCs) seems to be a safe and effective therapeutic option to support tissue and organ regeneration. The application of EVs requires particles with a maximum regenerative capability and hypoxic culture conditions as an in vitro preconditioning regimen has been shown to alter the molecular composition of released EVs. Nevertheless, the EV cargo after hypoxic preconditioning has not yet been comprehensively examined. The aim of the present study was the characterization of EVs from hypoxic preconditioned ASCs. We investigated the EV proteome and their effects on renal tubular epithelial cells in vitro. While no effect of hypoxia was observed on the number of released EVs and their protein content, the cargo of the proteins was altered. Proteomic analysis showed 41 increased or decreased proteins, 11 in a statistically significant manner. Furthermore, the uptake of EVs in epithelial cells and a positive effect on oxidative stress in vitro were observed. In conclusion, culture of ASCs under hypoxic conditions was demonstrated to be a promising in vitro preconditioning regimen, which alters the protein cargo and increases the anti-oxidative potential of EVs. These properties may provide new potential therapeutic options for regenerative medicine.


Asunto(s)
Vesículas Extracelulares/genética , Proteoma/genética , Proteómica , Medicina Regenerativa/métodos , Tratamiento Basado en Trasplante de Células y Tejidos/tendencias , Células Cultivadas , Células Epiteliales/citología , Células Epiteliales/metabolismo , Humanos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , MicroARNs/genética , Regeneración/genética
7.
Int J Mol Sci ; 22(6)2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33809214

RESUMEN

Extracellular vesicles (EVs) are generated and secreted by cells into the circulatory system. Stem cell-derived EVs have a therapeutic effect similar to that of stem cells and are considered an alternative method for cell therapy. Accordingly, research on the characteristics of EVs is emerging. EVs were isolated from human epidural fat-derived mesenchymal stem cells (MSCs) and human fibroblast culture media by ultracentrifugation. The characterization of EVs involved the typical evaluation of cluster of differentiation (CD antigens) marker expression by fluorescence-activated cell sorting, size analysis with dynamic laser scattering, and morphology analysis with transmission electron microscopy. Lastly, the secreted levels of cytokines and chemokines in EVs were determined by a cytokine assay. The isolated EVs had a typical size of approximately 30-200 nm, and the surface proteins CD9 and CD81 were expressed on human epidural fat MSCs and human fibroblast cells. The secreted levels of cytokines and chemokines were compared between human epidural fat MSC-derived EVs and human fibroblast-derived EVs. Human epidural fat MSC-derived EVs showed anti-inflammatory effects and promoted macrophage polarization. In this study, we demonstrated for the first time that human epidural fat MSC-derived EVs exhibit inflammatory suppressive potency relative to human fibroblast-derived EVs, which may be useful for the treatment of inflammation-related diseases.


Asunto(s)
Diferenciación Celular/genética , Vesículas Extracelulares/genética , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Animales , Polaridad Celular/genética , Tratamiento Basado en Trasplante de Células y Tejidos , Quimiocinas/genética , Citocinas/genética , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/trasplante , Fibroblastos/citología , Fibroblastos/metabolismo , Regulación de la Expresión Génica/genética , Humanos , Inflamación/genética , Inflamación/terapia , Macrófagos/metabolismo , Células Madre Mesenquimatosas/metabolismo
8.
Int J Mol Sci ; 22(7)2021 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-33810326

RESUMEN

Musashi-1 (MSI1) is an RNA-binding protein that regulates progenitor cells in adult and developing organisms to maintain self-renewal capacities. The role of musashi-1 in the bone healing environment and its relation with other osteogenic factors is unknown. In the current study, we analyze the expression of MSI1 in an experimental model of rat femoral bone fractures. We also analyze the relation between MSI1 expression and the expression of two osteogenic markers: periostin (POSTN) and runt-related transcription factor 2 (RUNX2). We use histological, immunohistochemical, and qPCR techniques to evaluate bone healing and the expression of MSI1, POSTN, and RUNX2 over time (4, 7, and 14 days). We compare our findings with non-fractured controls. We find that in bone calluses, the number of cells expressing MSI1 and RUNX2 increase over time and the intensity of POSTN expression decreases over time. Within bone calluses, we find the presence of MSI1 expression in mesenchymal stromal cells, osteoblasts, and osteocytes but not in hypertrophic chondrocytes. After 14 days, the expression of MSI1, POSTN, and RUNX2 was significantly correlated. Thus, we conclude that musashi-1 potentially serves in the osteogenic differentiation of mesenchymal stromal cells and bone healing. Therefore, further studies are needed to determine the possibility of musashi-1's role as a clinical biomarker of bone healing and therapeutic agent for bone regeneration.


Asunto(s)
Curación de Fractura , Proteínas del Tejido Nervioso/metabolismo , Osteogénesis , Proteínas de Unión al ARN/metabolismo , Animales , Callo Óseo/citología , Callo Óseo/metabolismo , Callo Óseo/fisiología , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Condrocitos/metabolismo , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Masculino , Células Madre Mesenquimatosas/metabolismo , Proteínas del Tejido Nervioso/genética , Osteoblastos/metabolismo , Osteocitos/metabolismo , Proteínas de Unión al ARN/genética , Ratas , Ratas Wistar
9.
Int J Mol Sci ; 22(7)2021 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-33810359

RESUMEN

Despite the strong evidence for the immunomodulatory activity of mesenchymal stromal cells (MSCs), clinical trials have so far failed to clearly show benefit, likely reflecting methodological shortcomings and lack of standardization. MSC-mediated tissue repair is commonly believed to occur in a paracrine manner, and it has been stated that extracellular vesicles (EVs) secreted by MSCs (EVMSC) are able to recapitulate the immunosuppressive properties of parental cells. As a next step, clinical trials to corroborate preclinical studies should be performed. However, effective dose in large mammals, including humans, is quite high and EVs industrial production is hindered by the proliferative senescence that affects MSCs during massive cell expansion. We generated a genetically modified MSC cell line overexpressing hypoxia-inducible factor 1-alpha and telomerase to increase the therapeutic potency of EVMSC and facilitate their large-scale production. We also developed a cytokine-based preconditioning culture medium to prime the immunomodulatory response of secreted EVs (EVMSC-T-HIFc). We tested the efficacy of this system in vitro and in a delayed-type hypersensitivity mouse model. MSC-T with an HIF-1α-GFP lentiviral vector (MSC-T-HIF) can be effectively expanded to obtain large amounts of EVs without major changes in cell phenotype and EVs composition. EVMSC-T-HIFc suppressed the proliferation of activated T-cells more effectively than did EVs from unmodified MSC in vitro, and significantly blunted the ear-swelling response in vivo by inhibiting cell infiltration and improving tissue integrity. We have developed a long-lived EV source that secretes high quantities of immunosuppressive EVs, facilitating a more standard and cost-effective therapeutic product.


Asunto(s)
Vesículas Extracelulares/trasplante , Hipersensibilidad Retardada/terapia , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Inmunomodulación , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/metabolismo , Linfocitos T/inmunología , Animales , Línea Celular , Proliferación Celular , Células Cultivadas , Citocinas/farmacología , Pulpa Dental/citología , Vesículas Extracelulares/inmunología , Vectores Genéticos/genética , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Lentivirus/genética , Masculino , Células Madre Mesenquimatosas/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ingeniería de Proteínas/métodos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Linfocitos T/fisiología , Telomerasa/genética , Telomerasa/metabolismo , Adulto Joven
10.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-33800912

RESUMEN

Arrhythmogenic Cardiomyopathy (ACM) is characterized by the replacement of the myocardium with fibrotic or fibro-fatty tissue and inflammatory infiltrates in the heart. To date, while ACM adipogenesis is a well-investigated differentiation program, ACM-related fibrosis remains a scientific gap of knowledge. In this study, we analyze the fibrotic process occurring during ACM pathogenesis focusing on the role of cardiac mesenchymal stromal cells (C-MSC) as a source of myofibroblasts. We performed the ex vivo studies on plasma and right ventricular endomyocardial bioptic samples collected from ACM patients and healthy control donors (HC). In vitro studies were performed on C-MSC isolated from endomyocardial biopsies of both groups. Our results revealed that circulating TGF-ß1 levels are significantly higher in the ACM cohort than in HC. Accordingly, fibrotic markers are increased in ACM patient-derived cardiac biopsies compared to HC ones. This difference is not evident in isolated C-MSC. Nevertheless, ACM C-MSC are more responsive than HC ones to TGF-ß1 treatment, in terms of pro-fibrotic differentiation and higher activation of the SMAD2/3 signaling pathway. These results provide the novel evidence that C-MSC are a source of myofibroblasts and participate in ACM fibrotic remodeling, being highly responsive to ACM-characteristic excess TGF-ß1.


Asunto(s)
Displasia Ventricular Derecha Arritmogénica/fisiopatología , Endocardio/patología , Células Madre Mesenquimatosas/patología , Miofibroblastos/patología , Factor de Crecimiento Transformador beta1/fisiología , Adulto , Displasia Ventricular Derecha Arritmogénica/sangre , Displasia Ventricular Derecha Arritmogénica/patología , Diferenciación Celular , Endocardio/metabolismo , Femenino , Fibrosis , Humanos , Masculino , Células Madre Mesenquimatosas/metabolismo , Persona de Mediana Edad , ARN Mensajero/biosíntesis , Transducción de Señal/fisiología , Proteína Smad2/fisiología , Proteína smad3/fisiología , Factor de Crecimiento Transformador beta1/sangre
11.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-33806897

RESUMEN

Adipose tissue and more specifically micro-fragmented adipose tissue (MFAT) obtained from liposuction has recently been shown to possess interesting medicinal properties whereby its application supports pain reduction and may enhance tissue regeneration particularly in osteoarthritis. Here we have characterised samples of MFAT produced using the Lipogems® International Spa system from eight volunteer individuals in order to understand the critical biological mechanisms through which they act. A variation was found in the MFAT cluster size between individual samples and this translated into a similar variation in the ability of purified mesenchymal stem cells (MSCs) to form colony-forming units. Almost all of the isolated cells were CD105/CD90/CD45+ indicating stemness. An analysis of the secretions of cytokines from MFAT samples in a culture using targeted arrays and an enzyme-linked immunosorbent assay (ELISA) showed a long-term specific and significant expression of proteins associated with anti-inflammation (e.g., interleukin-1 receptor alpha (Il-1Rα) antagonist), pro-regeneration (e.g., hepatocyte growth factor), anti-scarring and pro-angiogenesis (e.g., transforming growth factor beta 1 and 2 (TGFß1/2) and anti-bacterial (e.g., chemokine C-X-C motif ligand-9 (CXCL-9). Angiogenesis and angiogenic signalling were notably increased in primary bovine aortic endothelial cells (BAEC) to a different extent in each individual sample of the conditioned medium whilst a direct capacity of the conditioned medium to block inflammation induced by lipopolysaccharides was shown. This work characterises the biological mechanisms through which a strong, long-lasting, and potentially beneficial effect can be observed regarding pain reduction, protection and regeneration in osteoarthritic joints treated with MFAT.


Asunto(s)
Tejido Adiposo/química , Inductores de la Angiogénesis/química , Inductores de la Angiogénesis/farmacología , Antiinflamatorios/química , Antiinflamatorios/farmacología , Inductores de la Angiogénesis/aislamiento & purificación , Animales , Antiinflamatorios/aislamiento & purificación , Bovinos , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Medios de Cultivo Condicionados/química , Medios de Cultivo Condicionados/farmacología , Citocinas/biosíntesis , Células Endoteliales , Inmunofenotipificación , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Transducción de Señal/efectos de los fármacos
12.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-33806895

RESUMEN

Skeletal muscle regeneration is highly dependent on the inflammatory response. A wide variety of innate and adaptive immune cells orchestrate the complex process of muscle repair. This review provides information about the various types of immune cells and biomolecules that have been shown to mediate muscle regeneration following injury and degenerative diseases. Recently developed cell and drug-based immunomodulatory strategies are highlighted. An improved understanding of the immune response to injured and diseased skeletal muscle will be essential for the development of therapeutic strategies.


Asunto(s)
Inmunidad Adaptativa , Inmunidad Innata , Músculo Esquelético/fisiología , Regeneración/inmunología , Factores de Edad , Animales , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Susceptibilidad a Enfermedades , Humanos , Inmunomodulación , Leucocitos/inmunología , Leucocitos/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Desarrollo de Músculos/genética , Desarrollo de Músculos/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo
13.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-33806988

RESUMEN

The effect of perinatal asphyxia (PA) on oligodendrocyte (OL), neuroinflammation, and cell viability was evaluated in telencephalon of rats at postnatal day (P)1, 7, and 14, a period characterized by a spur of neuronal networking, evaluating the effect of mesenchymal stem cell (MSCs)-treatment. The issue was investigated with a rat model of global PA, mimicking a clinical risk occurring under labor. PA was induced by immersing fetus-containing uterine horns into a water bath for 21 min (AS), using sibling-caesarean-delivered fetuses (CS) as controls. Two hours after delivery, AS and CS neonates were injected with either 5 µL of vehicle (10% plasma) or 5 × 104 MSCs into the lateral ventricle. Samples were assayed for myelin-basic protein (MBP) levels; Olig-1/Olig-2 transcriptional factors; Gglial phenotype; neuroinflammation, and delayed cell death. The main effects were observed at P7, including: (i) A decrease of MBP-immunoreactivity in external capsule, corpus callosum, cingulum, but not in fimbriae of hippocampus; (ii) an increase of Olig-1-mRNA levels; (iii) an increase of IL-6-mRNA, but not in protein levels; (iv) an increase in cell death, including OLs; and (v) MSCs treatment prevented the effect of PA on myelination, OLs number, and cell death. The present findings show that PA induces regional- and developmental-dependent changes on myelination and OLs maturation. Neonatal MSCs treatment improves survival of mature OLs and myelination in telencephalic white matter.


Asunto(s)
Asfixia/metabolismo , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/metabolismo , Vaina de Mielina/metabolismo , Animales , Animales Recién Nacidos , Puntaje de Apgar , Asfixia/etiología , Biomarcadores , Encéfalo/metabolismo , Encéfalo/patología , Diferenciación Celular , Supervivencia Celular , Citocinas/genética , Citocinas/metabolismo , Expresión Génica , Hipocampo/metabolismo , Hipocampo/patología , Inmunohistoquímica , Mediadores de Inflamación , Células Madre Mesenquimatosas/citología , Vaina de Mielina/patología , Neuroglía/inmunología , Neuroglía/metabolismo , Oligodendroglía/metabolismo , ARN Mensajero , Ratas
14.
Int J Mol Sci ; 22(4)2021 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-33672879

RESUMEN

Osteosarcoma has a poor survival rate due to relapse and metastasis. Zoledronic acid (ZOL), an anti-resorptive and anti-tumor agent, is used for treating osteosarcoma. Delivery of ZOL to the target region is difficult due to its high binding affinity to bone minerals. This study developed a novel treatment for osteosarcoma by delivering ZOL to the target region locally and sustainably. In this study, we fabricated a novel bone substitute by loading ZOL on ß-tricalcium phosphate (ß-TCP). The ZOL-loaded ß-TCP (ZOL/ß-TCP) would be expected to express the inhibitory effects via both bound-ZOL (bound to ß-TCP) and free-ZOL (release from ZOL/ß-TCP). To explore the ability to release ZOL from the ZOL/ß-TCP, the amount of released ZOL was measured. The released profile indicates that a small amount of ZOL was released, and most of it remained on the ß-TCP. Our data showed that ZOL/ß-TCP could successfully express the effects of ZOL via both bound-ZOL and free-ZOL. In addition, we examined the biological effects of bound/free-ZOL using osteosarcoma and osteoclasts (target cells). The results showed that two states of ZOL (bound/free) inhibit target cell activities. As a result, ZOL/ß-TCP is a promising candidate for application as a novel bone substitute.


Asunto(s)
Fosfatos de Calcio/farmacología , Proliferación Celular/efectos de los fármacos , Osteoclastos/metabolismo , Osteosarcoma/metabolismo , Ácido Zoledrónico/farmacología , Animales , Sustitutos de Huesos/química , Sustitutos de Huesos/farmacocinética , Sustitutos de Huesos/farmacología , Fosfatos de Calcio/química , Fosfatos de Calcio/farmacocinética , Diferenciación Celular/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Medios de Cultivo Condicionados/farmacología , Liberación de Fármacos , Humanos , Masculino , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Ratones Endogámicos C57BL , Osteosarcoma/patología , Ácido Zoledrónico/química , Ácido Zoledrónico/farmacocinética
15.
Life Sci ; 274: 119249, 2021 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-33652034

RESUMEN

BACKGROUND: Accumulating evidence has reported the role of microRNA (miR) on atherosclerosis (AS), while it is unclear about the relationship between microRNA-125b-5p (miR-125b-5p) and AS. Thus, the object of this study was to investigate the impact of exosomal miR-125b-5p targeting mitogen-activated protein 4 kinase 4 (Map4k4) on AS plaque formation. METHODS: The AS model was established using a high fat diet in ApoE-/- mice. Mouse bone marrow-derived mesenchymal stem cells (BMSCs) were selected and BMSC-exosomes (BMSC-EXO) were extracted and then identified. The targeted relationship between miR-125b-5p and Map4k4 was tested. BMSC-EXO were modified with miR-125b-5p- and Map4k4-related sequences to interfere with AS mice. MiR-125b-5p and Map4k4 expression in AS tissues were tested. The inflammation-related indices, blood lipid, plaque area, apoptosis index, MMP-9 and α-SMA expression in mice with AS were measured. RESULTS: BMSCs and BMSC-EXO were successfully isolated. MiR-125b-5p was down-regulated and Map4k4 was up-regulated in aorta tissues from ApoE-/- mice after AS modeling, verses those from C57BL/6 mice without modeling. MiR-125b-5p targeted Map4k4. BMSC-EXO increased miR-125b-5p expression and decreased Map4k4 expression. BMSC-EXO/up-regulated miR-125b-5p and down-regulated Map4k4 in exosomes decreased inflammatory reaction, blood lipid, plaque area, MMP-9 expression and increased α-SMA expression, as well as inhibited apoptosis index of AS mice. CONCLUSION: Functional studies revealed that exosomal miR-125b-5p from BMSCs suppresses atherosclerotic plaque formation via inhibiting Map4k4 expression.


Asunto(s)
Médula Ósea/metabolismo , Exosomas/metabolismo , Regulación de la Expresión Génica , Células Madre Mesenquimatosas/metabolismo , MicroARNs/genética , Placa Aterosclerótica/prevención & control , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Exosomas/genética , Masculino , Células Madre Mesenquimatosas/citología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Placa Aterosclerótica/etiología , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patología
16.
Gene ; 782: 145542, 2021 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-33675953

RESUMEN

Squamous cell carcinoma (SCC) is a relatively common cancer with a low survival rate, poor prognosis and no effective treatment strategy. The use of cell-free conditioned media derived from mesenchymal stem cells (CM-MSCs) has shown promising results in treating various diseases. This study aimed to evaluate the effects of CM-MSCs on proliferation and apoptosis of CAL-27 and FaDu SCC cell lines. CM derived from human bone marrow and human amniotic membrane MSCs (BM-MSCs and AM-MSCs) was used in this investigation. MTT assay demonstrated that CM-BMMSC decreased the viability of CAL-27 and FaDu cell lines, 24, 48, and 72 h after treatment. Quantitative real-time PCR indicated that mRNA expression of PCNA as a proliferative marker, and BCL-2 as an anti-apoptotic protein, decreased in both cell lines treated with CM-BMMSC. Based on the flow cytometry results, the number of positive proliferative Ki67 cells and apoptotic Annexin-V cells decreased and increased in both cell lines treated with CM-BMMSC, respectively. However, CM-AMMSC treatment had both pro-and anti-neoplastic effects in our samples and showed considerable differences between the two cell lines. Taken together, our findings demonstrated that CM-BMMSC and, to a lesser degree, CM-AMMSC decrease cell viability and proliferation and increase cell apoptosis in SCC cell lines in a time-dependent manner. However, further studies are needed, especially to evaluate the anti-tumor potential of CM-BMMSC in vivo.


Asunto(s)
Apoptosis/efectos de los fármacos , Carcinoma de Células Escamosas/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Medios de Cultivo Condicionados/farmacología , Células Madre Mesenquimatosas/metabolismo , Amnios/metabolismo , Células de la Médula Ósea , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Citometría de Flujo , Humanos , Neoplasias Hepáticas
17.
Carbohydr Polym ; 260: 117780, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33712136

RESUMEN

In this study, we prepared a biomimetic hyaluronic acid oligosaccharides (oHAs)-based composite scaffold to develop a bone tissue-engineered scaffold for stimulating osteogenesis and endothelialization. The functional oHAs products were firstly synthesized, namely collagen/hyaluronic acid oligosaccharides/hydroxyapatite (Col/oHAs/HAP), chitosan/hyaluronic acid oligosaccharides (CTS/oHAs), and then uniformly distributed in poly (lactic-co-glycolic acid) (PLGA) solution followed by freeze-drying to obtain three-dimensional interconnected scaffolds as temporary templates for bone regeneration. The morphology, physicochemical properties, compressive strength, and degradation behavior of the fabricated scaffolds, as well as in vitro cell responses seeded on these scaffolds and in vivo biocompatibility, were investigated to evaluate the potential for bone tissue engineering. The results indicated that the oHAs-based scaffolds can promote the attachment of endothelial cells, facilitate the osteogenic differentiation of MC3T3-E1 and BMSCs, and have ideal biocompatibility and tissue regenerative capacity, suggesting their potential to serve as alternative candidates for bone tissue engineering applications.


Asunto(s)
Materiales Biocompatibles/química , Quitosano/química , Colágeno/química , Ingeniería de Tejidos , Animales , Materiales Biocompatibles/farmacología , Diferenciación Celular/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Durapatita/química , Ácido Hialurónico/química , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Ratones , Oligosacáridos/química , Osteoblastos/citología , Osteoblastos/metabolismo , Osteogénesis/efectos de los fármacos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Andamios del Tejido/química
18.
Int J Mol Sci ; 22(4)2021 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-33669239

RESUMEN

Irregular inflammatory responses are a major contributor to tissue dysfunction and inefficient repair. Skin has proven to be a powerful model to study mechanisms that regulate inflammation. In particular, skin wound healing is dependent on a rapid, robust immune response and subsequent dampening of inflammatory signaling. While injury-induced inflammation has historically been attributed to keratinocytes and immune cells, a vast body of evidence supports the ability of non-immune cells to coordinate inflammation in numerous tissues and diseases. In this review, we concentrate on the active participation of tissue-resident adipocytes and fibroblasts in pro-inflammatory signaling after injury, and how altered cellular communication from these cells can contribute to irregular inflammation associated with aberrant wound healing. Furthering our understanding of how tissue-resident mesenchymal cells contribute to inflammation will likely reveal new targets that can be manipulated to regulate inflammation and repair.


Asunto(s)
Adipocitos Blancos/inmunología , Dermis/citología , Dermis/lesiones , Fibroblastos/inmunología , Cicatrización de Heridas/inmunología , Envejecimiento/inmunología , Envejecimiento/metabolismo , Animales , Comunicación Celular/inmunología , Polaridad Celular/inmunología , Citocinas/metabolismo , Diabetes Mellitus/inmunología , Diabetes Mellitus/metabolismo , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Células Madre Mesenquimatosas/metabolismo , Transducción de Señal/inmunología
19.
Int J Mol Sci ; 22(4)2021 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-33670243

RESUMEN

Fibrosis is a leading cause of death in occidental states. The increasing number of patients with fibrosis requires innovative approaches. Despite the proven beneficial effects of mesenchymal stem cell (MSC) therapy on fibrosis, there is little evidence of their anti-fibrotic effects in colorectal fibrosis. The ability of MSCs to reduce radiation-induced colorectal fibrosis has been studied in vivo in Sprague-Dawley rats. After local radiation exposure, rats were injected with MSCs before an initiation of fibrosis. MSCs mediated a downregulation of fibrogenesis by a control of extra cellular matrix (ECM) turnover. For a better understanding of the mechanisms, we used an in vitro model of irradiated cocultured colorectal fibrosis in the presence of human MSCs. Pro-fibrotic cells in the colon are mainly intestinal fibroblasts and smooth muscle cells. Intestinal fibroblasts and smooth muscle cells were irradiated and cocultured in the presence of unirradiated MSCs. MSCs mediated a decrease in profibrotic gene expression and proteins secretion. Silencing hepatocyte growth factor (HGF) and tumor necrosis factor-stimulated gene 6 (TSG-6) in MSCs confirmed the complementary effects of these two genes. HGF and TSG-6 limited the progression of fibrosis by reducing activation of the smooth muscle cells and myofibroblast. To settle in vivo the contribution of HGF and TSG-6 in MSC-antifibrotic effects, rats were treated with MSCs silenced for HGF or TSG-6. HGF and TSG-6 silencing in transplanted MSCs resulted in a significant increase in ECM deposition in colon. These results emphasize the potential of MSCs to influence the pathophysiology of fibrosis-related diseases, which represent a challenging area for innovative treatments.


Asunto(s)
Moléculas de Adhesión Celular/metabolismo , Enfermedades del Colon/metabolismo , Factor de Crecimiento de Hepatocito/metabolismo , Células Madre Mesenquimatosas/metabolismo , Traumatismos Experimentales por Radiación/metabolismo , Animales , Enfermedades del Colon/patología , Enfermedades del Colon/terapia , Fibrosis , Humanos , Células Madre Mesenquimatosas/patología , Traumatismos Experimentales por Radiación/patología , Traumatismos Experimentales por Radiación/terapia , Ratas , Ratas Sprague-Dawley , Ratas Transgénicas
20.
Int J Mol Sci ; 22(4)2021 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-33672524

RESUMEN

Human bone marrow stem cells (HBMSCs) are isolated from the bone marrow. Stem cells can self-renew and differentiate into various types of cells. They are able to regenerate kinds of tissue that are potentially used for tissue engineering. To maintain and expand these cells under culture conditions is difficult-they are easily triggered for differentiation or death. In this study, we describe a new culture formula to culture isolated HBMSCs. This new formula was modified from NCDB 153, a medium with low calcium, supplied with 5% FBS, extra growth factor added to it, and supplemented with N-acetyl-L-cysteine and L-ascorbic acid-2-phosphate to maintain the cells in a steady stage. The cells retain these characteristics as primarily isolated HBMSCs. Moreover, our new formula keeps HBMSCs with high proliferation rate and multiple linage differentiation ability, such as osteoblastogenesis, chondrogenesis, and adipogenesis. It also retains HBMSCs with stable chromosome, DNA, telomere length, and telomerase activity, even after long-term culture. Senescence can be minimized under this new formulation and carcinogenesis of stem cells can also be prevented. These modifications greatly enhance the survival rate, growth rate, and basal characteristics of isolated HBMSCs, which will be very helpful in stem cell research.


Asunto(s)
Antioxidantes/farmacología , Calcio/farmacología , Senescencia Celular , Medios de Cultivo/química , Células Madre Mesenquimatosas/citología , Antígenos CD/metabolismo , Biomarcadores/metabolismo , Diferenciación Celular/efectos de los fármacos , Linaje de la Célula/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Separación Celular , Forma de la Célula/efectos de los fármacos , Células Cultivadas , Senescencia Celular/efectos de los fármacos , Daño del ADN , Humanos , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Osteoblastos/citología , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Telomerasa/metabolismo , Homeostasis del Telómero , Proteína 1 de Unión al Supresor Tumoral P53/metabolismo
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