scholarly journals The Potential Safe Antifibrotic Effect of Stem Cell Conditioned Medium and Nilotinib Combined Therapy by Selective Elimination of Rat Activated HSCs

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Ahmed Nabil ◽  
Koichiro Uto ◽  
Faten Zahran ◽  
Reham Soliman ◽  
Ayman A. Hassan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Conditioned Medium ◽  
Cell Lines ◽  
Hepatic Stellate Cells ◽  
Normal Cell ◽  
Combined Therapy ◽  
Stellate Cells ◽  
Collagen Deposition ◽  
Anti Inflammatory

Hepatic fibrosis is a progressive disease with serious clinical complications that arise from abnormal propagation and activation of multiple inflammatory pathways. Nilotinib is an oral tyrosine kinase inhibitor with antifibrotic activity. Mesenchymal stem cells (MSCs) are blank cells and can differentiate into specific cell types. They have the potential to repair and regenerate cells. MSCs have a special paracrine fashion where they produce special exosomes, microvesicles, and cytokines like IL-6, transforming growth factor-beta (TGF-β), and HGF as well as hepatic stellate cell suppressors. This paracrine fashion can decrease collagen deposition, enhance antifibrotic, anti-inflammatory, and angiogenic activity in vitro and in vivo. In our study, the rat’s hepatic stellate cells (HSCs) in addition to different normal cell lines were treated with Nilotinib alone and in combination with liver mesenchymal stem cells conditioned medium (LMSCs-CM) for 24 h. Mono and combined therapy antifibrotic and cytotoxicity effects were evaluated using different parameters including α-SMA, cytochrome c, P53 expression, collagen deposition, DNA content, oxidative stress parameters, cell viability, and apoptosis by flow cytometry analysis. Our results showed that Nilotinib and LMSCs-CM in combination had a significantly potent antifibrotic and anti-inflammatory effect on activated hepatic stellate cells than Nilotinib alone; otherwise, this combination showed the best safety with minimal cytotoxicity on different normal cell lines.

scholarly journals Conditioned Medium from Human Amnion-Derived Mesenchymal Stem Cells Regulates Activation of Primary Hepatic Stellate Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Qingjie Fu ◽  
Shunsuke Ohnishi ◽  
Naoya Sakamoto
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Liver Fibrosis ◽  
Conditioned Medium ◽  
Hepatic Stellate Cells ◽  
Collagen Type ◽  
Transforming Growth Factor ◽  
Stellate Cells ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Human Amnion

Mesenchymal stem cells (MSCs), or multipotent mesenchymal stromal cells, are present in almost all organs and tissues, including the amnion. Human amnion-derived mesenchymal stem cell (hAMSC) transplantation has been reported to ameliorate liver fibrosis in animal models. However, the mechanism for the prevention of liver fibrosis is poorly understood. In this study, we investigated the effects, and underlying mechanisms, of a conditioned medium obtained from hAMSC cultures (hAMSC-CM) on a primary culture of rat hepatic stellate cells (HSCs). We observed that in routine culture, hAMSC-CM in HSCs significantly inhibited the expression of alpha-smooth muscle actin (α-SMA), an activation marker of HSCs, and the production of collagen type 1 (COL1), a dominant component of the extracellular matrix (ECM) in the culture medium. In addition, hAMSC-CM upregulated the expression of ECM degradation-related genes, such as metalloproteinase- (Mmp-) 2, Mmp-9, Mmp-13, and tissue inhibitor of metalloproteinase- (Timp-) 1; however, it did not affect the expression of collagen type 1α1 (Col1a1). These regulatory effects on HSCs were concentration-dependent. A cell proliferation assay indicated that hAMSC-CM significantly suppressed HSC proliferation and downregulated the expression of cyclin B (Ccnb), a proliferation-related gene. Transforming growth factor-beta (TGF-β) treatment further activated HSCs and hAMSC-CM significantly inhibited the upregulation of α-Sma and Col1a1 induced by TGF-β. These findings demonstrated that hAMSC-CM can modulate HSC function via secretory factors and provide a plausible explanation for the protective role of hAMSCs in liver fibrosis.

Inhibition of hepatic stellate cells proliferation by mesenchymal stem cells and the possible mechanisms

2009 ◽  
Vol 39 (12) ◽  
pp. 1219-1228 ◽  
Author(s):  
Jing Wang ◽  
Chunjing Bian ◽  
Lianming Liao ◽  
Yashu Zhu ◽  
Jing Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Hepatic Stellate Cells ◽  
Stellate Cells

scholarly journals Human placental mesenchymal stem cells ameliorate liver fibrosis in mice by upregulation of Caveolin1 in hepatic stellate cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yunqi Yao ◽  
Zhemin Xia ◽  
Fuyi Cheng ◽  
Qingyuan Jang ◽  
Jiao He ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Liver Fibrosis ◽  
Therapeutic Effect ◽  
Hepatic Stellate Cells ◽  
Time Window ◽  
Stellate Cells ◽  
Therapeutic Benefits ◽  
Placental Mesenchymal Stem Cells

Abstract Background Liver fibrosis (LF) is a common pathological process characterized by the activation of hepatic stellate cells (HSCs) and accumulation of extracellular matrix. Severe LF causes cirrhosis and even liver failure, a major cause of morbidity and mortality worldwide. Transplantation of human placental mesenchymal stem cells (hPMSCs) has been considered as an alternative therapy. However, the underlying mechanisms and the appropriate time window for hPMSC transplantation are not well understood. Methods We established mouse models of CCl4-injured LF and administered hPMSCs at different stages of LF once a week for 2 weeks. The therapeutic effect of hPMSCs on LF was investigated, according to histopathological and blood biochemical analyses. In vitro, the effect of hPMSCs and the secretomes of hPMSCs on the inhibition of activated HSCs was assessed. RNA sequencing (RNA-seq) analysis, real-time PCR array, and western blot were performed to explore possible signaling pathways involved in treatment of LF with hPMSCs. Results hPMSC treatment notably alleviates experimental hepatic fibrosis, restores liver function, and inhibits inflammation. Furthermore, the therapeutic effect of hPMSCs against mild-to-moderate LF was significantly greater than against severe LF. In vitro, we observed that the hPMSCs as well as the secretomes of hPMSCs were able to decrease the activation of HSCs. Mechanistic dissection studies showed that hPMSC treatment downregulated the expression of fibrosis-related genes, and this was accompanied by the upregulation of Caveolin-1 (Cav1) (p < 0.001). This suggested that the amelioration of LF occurred partly due to the restoration of Cav1 expression in activated HSCs. Upregulation of Cav1 can inhibit the TGF-β/Smad signaling pathway, mainly by reducing Smad2 phosphorylation, resulting in the inhibition of activated HSCs, whereas this effect could be abated if Cav1 was silenced in advance by siRNAs. Conclusions Our findings suggest that hPMSCs could provide multifaceted therapeutic benefits for the treatment of LF, and the TGF-β/Cav1 pathway might act as a therapeutic target for hPMSCs in the treatment of LF.

scholarly journals Immunomodulation of activated hepatic stellate cells by mesenchymal stem cells

2007 ◽  
Vol 363 (2) ◽  
pp. 247-252 ◽  
Author(s):  
Biju Parekkadan ◽  
Daan van Poll ◽  
Zaki Megeed ◽  
Naoya Kobayashi ◽  
Arno W. Tilles ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Activated Hepatic Stellate Cells

Human bone marrow mesenchymal stem cells suppress the proliferation of hepatic stellate cells by inhibiting the ubiquitination of p27

2017 ◽  
Vol 95 (6) ◽  
pp. 628-633 ◽  
Author(s):  
Liang Wang ◽  
Guang Bai ◽  
Fei Chen
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Bone Marrow ◽  
Cell Proliferation ◽  
Mesenchymal Stem Cells ◽  
Cell Cycle Arrest ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Cycle Arrest ◽  
Marrow Mesenchymal Stem Cells

Bone marrow mesenchymal stem cells (BMSCs) have considerable therapeutic potential for the treatment of end-stage liver disease. Previous studies have demonstrated that BMSCs secrete growth factors and cytokines that inactivate hepatic stellate cells (HSCs), which inhibited the progression of hepatic fibrosis. The aim of this study was to determine the mechanism by which BMSCs suppress the function of HSCs in fibrosis. Our results showed that co-culture of BMSCs and HSCs induced cell cycle arrest at the G10/G1 phase and cell apoptosis of HSCs, which finally inhibited the cell proliferation of HSCs. Consistent with the cell cycle arrest, co-culture of BMSCs and HSCs increased the abundance of the cell cycle protein p27. Mechanistically, we further uncovered that following the co-culture with BMSCs, the expression level of the E3 ligase S-phase kinase-associated protein 2 (SKP2) that is responsible for the ubiquitination of p27 was decreased, which attenuated the ubiquitination of p27 and increased the stability of p27 in HSCs. Collectively, our results indicated the potential involvement of the SKP2–p27 axis for the inhibitory effect of BSMCs on the cell proliferation of HSCs.

scholarly journals Tumor Microenvironment Changing through Application of MicroRNA-34a Related Mesenchymal Stem Cells Conditioned Medium: Modulation of Breast Cancer Cells toward Non-aggressive Behavior

2021 ◽  
Author(s):  
Katayoun Bahman Soufiani ◽  
Ali Akbar Pourfathollah ◽  
Mahin Nikougoftar Zarifi ◽  
Ehsan Arefian
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cancer Cells ◽  
Cell Line ◽  
Conditioned Medium ◽  
Cell Lines ◽  
Test Group ◽  
Bioactive Molecules ◽  
Simultaneous Application

Conditioned medium (CM) derived from mesenchymal stem cells (MSCs) contains bioactive molecules including microRNAs (miRs) that could be a potential tool for controlling cancer cells' behavior. Due to the properties of CM, this study assesses the effects of miR-34a related MSCCM on tumor behavior through the evaluation of migration, invasion, apoptosis, and PDL1 expression in breast cancer cell lines. The miR-34a overexpression vector or scramble control was produced using lentiviral vectors, DNA cloning, and the transfection of the HEK-293 T cell line. It was then transduced into human adipose-derived mesenchymal stem cells (hAD-MSCs). MSC-CMs were collected and added onto MDA-MB-231 cell lines. The functional evaluations were performed by transwell, wound healing, and Annexin V/PI methods on the treated MDA-MB-231 cell lines. The PDL1 expression was also assessed by Real-time PCR and western blot. The findings of this study showed that ectopic miR-34a expression was significantly upregulated in manipulated hASC with miR-34a (p<0.0001). Treatment of MDA-MB-231 cell line with miR-34a-hAD-MSC-CM, scramble-hAD-MSC-CM, or hAD-MSC-CM displayed not only a reduction in the number of migrated or invaded cells (p=0.01) but also an increase in the apoptotic cells in the test group (p=0.02) when compared to the control groups. It also showed down-regulation in the gene (p=0.05) and protein expression levels of PDL1 in the test group. The results of the present study showed that simultaneous application of miR-34a and MSCCM can be considered as a new method for changing the cancerous microenvironment; and therefore, as a potential strategy in breast cancer therapy.

scholarly journals Combinatory Effects of Bone Marrow-Derived Mesenchymal Stem Cells and Indomethacin on Adjuvant-Induced Arthritis in Wistar Rats: Roles of IL-1β, IL-4, Nrf-2, and Oxidative Stress

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Eman A. Ahmed ◽  
Osama M. Ahmed ◽  
Hanaa I. Fahim ◽  
Emad A. Mahdi ◽  
Tarek M. Ali ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Body Weight ◽  
Combined Therapy ◽  
Antioxidant Defense System ◽  
Serum Levels ◽  
Human Beings ◽  
Anti Inflammatory

Rheumatoid arthritis (RA) is a disorder triggered by autoimmune reactions and related with chronic inflammation and severe disability. Bone Marrow-derived Mesenchymal Stem Cells (BM-MSCs) have shown a hopeful immunomodulatory effect towards repairing cartilage and restoring joint function. Additionally, indomethacin (IMC), a nonsteroidal compound, has been considered as a potent therapeutic agent that exhibits significant antipyretic properties and analgesic effects. The target of the current research is to assess the antiarthritic efficacy of BM-MSCs (106 cells/rat at 1, 6, 12 and 18 days) and IMC (2 mg/kg body weight/day for 3 weeks) either alone or concurrently administered against complete Freund’s adjuvant-induced arthritic rats. Changes in paw volume, body weight, gross lesions, and antioxidant defense system, as well as oxidative stress, were assessed. The Th1 cytokine (IL-1β) serum level and Th2 cytokine (IL-4) and Nrf-2 ankle joint expression were detected. In comparison to normal rats, it was found that the CFA-induced arthritic rats exhibited significant leukocytosis and increase in paw volume, LPO level, RF, and IL-1β serum levels. In parallel, arthritic rats that received BM-MSCs and/or IMC efficiently exhibited decrease in paw edema, leukocytosis, and enhancement in the antioxidant enzymatic levels of SOD, GPx, GST, and GSH in serum besides upregulation of Nrf-2 and anti-inflammatory IL-4 expression levels in the ankle articular joint. Likewise, these analyses were more evidenced by the histopathological sections and histological score. The data also revealed that the combined administration of BM-MSC and IMC was more potent in suppressing inflammation and enhancing the anti-inflammatory pathway than each agent alone. Thus, it can be concluded that the combined therapy with BM-MSC and IMC may be used as a promising therapeutic choice after assessing their efficacy and safety in human beings with RA, and the antiarthritic effects may be mediated via modulatory effects on Th1/Th2 cytokines, ozidative stress, and Nrf-2.

scholarly journals The Hepatic Stellate Cells (HSTCs) and Adipose-derived Mesenchymal Stem Cells (ASCs) Axis as a Potential Major Driver of Metabolic Syndrome – Novel Concept and Therapeutic Implications

2021 ◽  
Author(s):  
Krzysztof Marycz ◽  
Katarzyna Kornicka-Garbowska ◽  
Larry Galuppo ◽  
Lynda Bourebaba
Keyword(s):  
Metabolic Syndrome ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Hepatic Stellate Cells ◽  
Metabolic Diseases ◽  
Stellate Cells ◽  
Therapeutic Implications ◽  
Prevention And Treatment ◽  
Novel Concept ◽  
Molecular Crosstalk

Abstract Herein, we would like to introduce a novel concept for the prevention and treatment of metabolic syndrome, which is based on molecular relationship between liver and adipose tissue. Particularly, we believe, that unravelling the molecular crosstalk between hepatokines and adipokines will allow to better understand the pathophysiology of metabolic diseases and allow to develop novel, effective therapeutic solutions against obesity and metabolic syndrome. Graphical Abstract Inter-organ communication on the level of stem progenitor cells-hepatic stellate cells (HSTCs) and adipose-derived progenitors (ASCs) could represents a key mechanism involved in controlling glucose tolerance as well as insulin sensitivity.

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