scholarly journals New Mechanism For Mesenchymal Stem Cell Microvesicle To Restore Lung Permeability: Intracellular S1P Signaling Pathway Independent of S1P Receptor-1

2021 ◽  
Author(s):  
Lifang Ye ◽  
Jieqiong Song ◽  
Yijun Zheng ◽  
Ming Zhong ◽  
Jun Liu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Signaling Pathway ◽  
Mrna Levels ◽  
Lung Permeability ◽  
S1p Receptors ◽  
Adhesion Junctions ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
Protein Permeability

Abstract Background: Microvesicles (MV) derived from human bone marrow mesenchymal stem cell (MSC) were demonstrated to restore lung protein permeability and attenuate acute lung injury (ALI). In our previous study, we found that MSC MV increased sphingosine 1 phosphate (S1P) kinase1 mRNA levels in injured human lung microvascular endothelial cells (HLMVEC) significantly. However, the role of S1P signaling in MSC MV to restore lung protein permeability is unknown.Methods: In this study, we hypothesized that MSC MV might restore lung permeability in part through increasing intracellular S1P signaling pathway in injured HLMVEC independent of S1P receptors. We used the transwell co-culture system to study the effect of MSC MV on protein permeability of Lipopolysaccharide (LPS) damaged HLMVEC. Results: Our results showed that LPS significantly increased the permeability of HLMVEC to FITC-dextran (70 kDa) within 24 hours. MSC MV restores this permeability, and to a large extent prevents the cytoskeleton protein F-actin from recombining into "actin stress fibers", and restores the positions of tight junctions and adhesion junctions in the damaged HLMVEC. This therapeutic effect of MSC MV was related to the increase in the S1P level in injured HLMVEC and was not eliminated when adding the antagonist of S1P receptor, suggesting that MSC MV to restore lung permeability was independent of S1P receptors on HLMVEC. Laser confocal further observed that Ca2+ mobilization and Rac1 activiation in LPS injured HLMVEC were increased in parallel with the increase in intracellular S1P level after MSC MV treatment. Conclusions: In short, MSC MV partially restored protein permeability across HLMVEC through the intracellular S1P signaling pathway independent of S1P receptor-1.

scholarly journals Neonatal Mesenchymal Stem Cell Treatment Improves Myelination Impaired by Global Perinatal Asphyxia in Rats

2021 ◽  
Vol 22 (6) ◽  
pp. 3275
Author(s):  
Andrea Tapia-Bustos ◽  
Carolyne Lespay-Rebolledo ◽  
Valentina Vío ◽  
Ronald Pérez-Lobos ◽  
Emmanuel Casanova-Ortiz ◽  
...  
Keyword(s):  
Cell Death ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Perinatal Asphyxia ◽  
Mrna Levels ◽  
Protein Levels ◽  
Delayed Cell Death ◽  
External Capsule ◽  
Stem Cell Treatment ◽  
Main Effects

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.

Adipose mesenchymal stem cell transplantation alleviates spinal cord injury-induced neuroinflammation partly by suppressing the Jagged1/Notch pathway

2019 ◽  
Author(s):  
Zhou Zhilai ◽  
Tian Xiaobo ◽  
Mo Biling ◽  
Xu Huali ◽  
Yao Shun ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Notch Signaling Pathway ◽  
Therapeutic Effects ◽  
Mesenchymal Stem Cell Transplantation ◽  
Cord Injury

Abstract Background The therapeutic effects of adipose-derived mesenchymal stem cell (ADSC) transplantation have been demonstrated in several models of central nervous system (CNS) injury and are thought to involve the modulation of the inflammatory response. However, the exact underlying molecular mechanism is poorly understood. Activation of the Jagged1/Notch signaling pathway is thought to involve inflammatory and gliotic events in the CNS. Here, we elucidated the effect of ADSC transplantation on the inflammatory reaction after spinal cord injury (SCI) and the potential mechanism mediated by Jagged1/Notch signaling pathway suppression.Methods Using a mouse model of compression SCI, ADSCs and Jagged1 small interfering RNA (siRNA) were injected into the spinal cord. Locomotor function, spinal cord tissue morphology and the levels of various proteins and transcripts were compared between groups.Results ADSC treatment resulted in significant downregulation of proinflammatory mediator expression and reduced ionized calcium binding adapter molecule 1 (Iba1) and ED1 staining in the injured spinal cord, promoting the survival of neurons. These changes were accompanied by improved functional recovery. The augmentation of the Jagged1/Notch signaling pathway after SCI was suppressed by ADSC transplantation. The inhibition of the Jagged1/Notch signaling pathway by Jagged1 siRNA resulted in a decrease in SCI-induced proinflammatory cytokines as well as the activation of microglia. Furthermore, Jagged1 knockdown suppressed the phosphorylation of JAK/STAT3 following SCI.Conclusion The results of this study demonstrated that the therapeutic effects of ADSCs in SCI mice were partly due to Jagged1/notch signaling pathway inhibition and a subsequent reduction in JAK/STAT3 phosphorylation.

scholarly journals FGF21 Mediates Mesenchymal Stem Cell Senescence via Regulation of Mitochondrial Dynamics

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Xin Li ◽  
Yimei Hong ◽  
Haiwei He ◽  
Guojun Jiang ◽  
Wei You ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Signaling Pathway ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Mitochondrial Fusion ◽  
Fibroblast Growth Factor 21 ◽  
Early Passage ◽  
Ampk Signaling ◽  
Novel Strategy

Mesenchymal stem cell- (MSC-) based therapy is a novel strategy in regenerative medicine. The functional and regenerative capacities of MSCs decline with senescence. Nonetheless, the potential mechanisms that underlie their senescence are not fully understood. This study was aimed at exploring the potential mechanisms of fibroblast growth factor 21 (FGF21) in the regulation of MSC senescence. The senescence of MSCs was determined by senescence-associated β-galactosidase (SA-β-gal) staining. The morphology and the level of mitochondrial reactive oxygen species (ROS) of MSCs were assessed by MitoTracker and Mito-Sox staining, respectively. The expression of FGF21 and mitochondrial dynamics-related proteins was detected by Western blotting. As MSCs were expanded in vitro, the expression of FGF21 decreased. Depletion of FGF21 enhanced production of mitochondrial reactive oxidative species (ROS) and increased the senescence of early-passage MSCs whereas inhibition of ROS abolished these effects. The senescent MSCs exhibited increased mitochondrial fusion and decreased mitochondrial fission. Treatment of early-passage MSCs with FGF21 siRNA enhanced mitochondrial fusion and reduced mitochondrial fission. Moreover, treatment of mitofusin2- (Mfn2-) siRNA inhibited depletion of FGF21-induced MSC senescence. Furthermore, we demonstrated that depletion of FGF21-induced mitochondrial fusion was regulated by the AMPK signaling pathway. Treatment with an AMPK activator, AICAR, abrogated the depletion of FGF21-induced senescence of MSCs by inhibiting mitochondrial fusion. Compared with MSCs isolated from young donors, those derived from aged donors showed a lower level of FGF21 and a higher level of senescent activity. Furthermore, overexpression of FGF21 in aged MSCs inhibited senescence. Our study shows that FGF21, via the AMPK signaling pathway, regulates the senescence of MSCs by mediating mitochondrial dynamics. Targeting FGF21 might represent a novel strategy to improve the quality and quantity of MSCs.

Sphingosine 1-phosphate signalling in cancer

2012 ◽  
Vol 40 (1) ◽  
pp. 94-100 ◽  
Author(s):  
Nigel J. Pyne ◽  
Francesca Tonelli ◽  
Keng Gat Lim ◽  
Jaclyn S. Long ◽  
Joanne Edwards ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Sphingosine Kinase ◽  
Receptor Expression ◽  
Sphingosine Kinase 1 ◽  
Histone Deacetylase 1 ◽  
S1p Receptors ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor

There is an increasing body of evidence demonstrating a critical role for the bioactive lipid S1P (sphingosine 1-phosphate) in cancer. S1P is synthesized and metabolized by a number of enzymes, including sphingosine kinase, S1P lyase and S1P phosphatases. S1P binds to cell-surface G-protein-coupled receptors (S1P1–S1P5) to elicit cell responses and can also regulate, by direct binding, a number of intracellular targets such as HDAC (histone deacetylase) 1/2 to induce epigenetic regulation. S1P is involved in cancer progression including cell transformation/oncogenesis, cell survival/apoptosis, cell migration/metastasis and tumour microenvironment neovascularization. In the present paper, we describe our research findings regarding the correlation of sphingosine kinase 1 and S1P receptor expression in tumours with clinical outcome and we define some of the molecular mechanisms underlying the involvement of sphingosine kinase 1 and S1P receptors in the formation of a cancer cell migratory phenotype. The role of sphingosine kinase 1 in the acquisition of chemotherapeutic resistance and the interaction of S1P receptors with oncogenes such as HER2 is also reviewed. We also discuss novel aspects of the use of small-molecule inhibitors of sphingosine kinase 1 in terms of allosterism, ubiquitin–proteasomal degradation of sphingosine kinase 1 and anticancer activity. Finally, we describe how S1P receptor-modulating agents abrogate S1P receptor–receptor tyrosine kinase interactions, with potential to inhibit growth-factor-dependent cancer progression.

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