scholarly journals Mesenchymal stem cells versus their extracellular vesicles in treatment of liver fibrosis: Is it possible to compare?

2021 ◽  
Vol 9 (2) ◽  
Author(s):  
Noha Attia ◽  
Yasmine Khalifa ◽  
Dina Rostom ◽  
Mohamed Mashal
Keyword(s):  
Liver Fibrosis ◽  
Extracellular Vesicles ◽  
Therapeutic Strategy ◽  
Secretory Proteins ◽  
Apoptotic Bodies ◽  
Limited Evidence ◽  
In Vivo Models ◽  
Dose Determination

Liver fibrosis (LF) is a worldwide health problem that is associated with a range of complications and high mortality. Due to the scarcity of liver donors, mesenchymal stem cell (MSC) therapy emerged as an alternative therapeutic strategy. However, it is widely accepted that most of the transplanted MSCs exhibit their therapeutic impact mainly via a bystander paracrine (medicinal) capacity. In addition to their secretory proteins, MSCs also produce various types of extracellular vesicles (EVs) that are classified into three main subtypes: microvesicles, exosomes and apoptotic bodies. Thanks to their peculiar cargo composition (e.g., proteins, lipids, and nucleic acids), EVs serve as an advantageous candidate for cell-free therapy. Recently, MSC-derived EVs (MSC-EVs) have gained the podium due to their regenerative and immunomodulatory effect. In mitigation/treatment of LF, a plethora of recent studies have shown the anti-inflammatory, anti-fibrotic and cytoprotective effects of both MSCs and MSC-EVs in various in vitro and in vivo models of LF. However, despite the limited evidence, we sought in this mini review to sort out the established data and formulate several challenging questions that must be answered to pave the way for further clinical applications. One of the major questions to ask is “Which is the best therapeutic approach, MSCs or MSC-EVs?” We tried to highlight how difficult it might be to compare the two approaches while our understanding of both candidates is still deficient. Among the major obstacles against such comparison is the inaccurate equivalent dose determination, the unknown in vivo behavior, and the undetermined lifespan/fate of each. Currently, the fields of MSCs and MSC-EVs seem to be rich in ideas but lacking in appropriate technologies to test these ideas. Nevertheless, continuous efforts are likely to help resolve some of the challenges listed here.

scholarly journals Evaluation of NV556, a Novel Cyclophilin Inhibitor, as a Potential Antifibrotic Compound for Liver Fibrosis

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1409 ◽  
Author(s):  
Sonia Simón Serrano ◽  
Alvar Grönberg ◽  
Lisa Longato ◽  
Krista Rombouts ◽  
Joseph Kuo ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Stellate Cell ◽  
Unmet Need ◽  
Potential Candidate ◽  
In Vivo Models ◽  
Fibrotic Process ◽  
Increased Risk ◽  
Cyclophilin Inhibitor

Hepatic fibrosis can result as a pathological response to nonalcoholic steatohepatitis (NASH). Cirrhosis, the late stage of fibrosis, has been linked to poor survival and an increased risk of developing hepatocellular carcinoma, with limited treatment options available. Therefore, there is an unmet need for novel effective antifibrotic compounds. Cyclophilins are peptidyl-prolyl cis-trans isomerases that facilitate protein folding and conformational changes affecting the function of the targeted proteins. Due to their activity, cyclophilins have been presented as key factors in several stages of the fibrotic process. In this study, we investigated the antifibrotic effects of NV556, a novel potent sanglifehrin-based cyclophilin inhibitor, in vitro and in vivo. NV556 potential antifibrotic effect was evaluated in two well-established animal models of NASH, STAM, and methionine-choline-deficient (MCD) mice, as well as in an in vitro 3D human liver ECM culture of LX2 cells, a human hepatic stellate cell line. We demonstrate that NV556 decreased liver fibrosis in both STAM and MCD in vivo models and decreased collagen production in TGFβ1-activated hepatic stellate cells in vitro. Taken together, these results present NV556 as a potential candidate for the treatment of liver fibrosis.

scholarly journals IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells

Blood ◽  
2015 ◽  
Vol 125 (20) ◽  
pp. 3144-3152 ◽  
Author(s):  
Carolina Schinke ◽  
Orsolya Giricz ◽  
Weijuan Li ◽  
Aditi Shastri ◽  
Shanisha Gordon ◽  
...  
Keyword(s):  
Stem Cells ◽  
Therapeutic Strategy ◽  
In Vivo Models ◽  
Cxcr2 Expression ◽  
Key Points ◽  
Pathway Inhibition ◽  
Worse Prognosis

Key Points IL8-CXCR2 is overexpressed in purified stem cells from AML and MDS, and CXCR2 expression is associated with worse prognosis. Inhibition of CXCR2 by genetic and pharmacologic means leads to decreased viability in AML/MDS stem cells and in vitro and in vivo models.

scholarly journals Extracellular Vesicles: Intercellular Communication Mediators in Antiphospholipid Syndrome

2021 ◽  
Author(s):  
Ula Štok ◽  
Saša Čučnik ◽  
Snežna Sodin-Šemrl ◽  
Polona Žigon
Keyword(s):  
Extracellular Vesicles ◽  
Antiphospholipid Syndrome ◽  
Intercellular Communication ◽  
Systemic Autoimmune Disease ◽  
In Vivo Models ◽  
Isolation And Characterization ◽  
Increased Risk ◽  
Insight Into

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombosis, obstetric complications and the presence of antiphospholipid antibodies (aPL) that cause endothelial injury and thrombophilia. Extracellular vesicles are involved in endothelial and thrombotic pathologies and may therefore have an influence on the prothrombotic status of APS patients. Intercellular communication and connectivity are important mechanisms of interaction between healthy and pathologically altered cells. Despite well-characterized in vitro and in vivo models of APS pathology, the field of extracellular vesicles is still largely unexplored and could therefore provide an insight into the APS mechanism and possibly serve as a biomarker to identify patients at increased risk. The analysis of EVs poses a challenge due to the lack of standardized technology for their isolation and characterization. Recent findings in the field of EVs offer promising aspects that may explain their role in the pathogenesis of various diseases, including APS.

Extracellular vesicles derived from Malassezia furfur stimulate IL-6 production in keratinocytes as demonstrated in in vitro and in vivo models

2019 ◽  
Vol 93 (3) ◽  
pp. 168-175 ◽  
Author(s):  
Yu-Jing Zhang ◽  
Yang Han ◽  
Yu-Zhe Sun ◽  
Hang-Hang Jiang ◽  
Min Liu ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Malassezia Furfur ◽  
In Vivo Models

Microvesiculation and Disease

2013 ◽  
Vol 41 (1) ◽  
pp. 237-240 ◽  
Author(s):  
Jameel M. Inal ◽  
Una Fairbrother ◽  
Sheelagh Heugh
Keyword(s):  
Infectious Disease ◽  
Extracellular Vesicles ◽  
Immune Cell ◽  
In Vivo Models ◽  
Cell Functions ◽  
Models Of Disease ◽  
New Treatments ◽  
Acute Myeloid

The important roles of extracellular vesicles in the pathogenesis of various diseases are rapidly being elucidated. As important vehicles of intercellular communication, extracellular vesicles, which comprise microvesicles and exosomes, are revealing important roles in cancer tumorigenesis and metastases and in the spread of infectious disease. The September 2012 Focused Meeting ‘Microvesiculation and Disease’ brought together researchers working on extracellular vesicles. The papers in this issue of Biochemical Society Transactions review work in areas including HIV infection, kidney disease, hypoxia-mediated tumorigenesis and down-regulation of immune cell functions in acute myeloid leukaemia by tumour-derived exosomes. In all cases, microvesicles and exosomes have been demonstrated to be important factors leading to the pathophysiology of disease or indeed as therapeutic vehicles in possible new treatments. The aim was, having enhanced our molecular understanding of the contribution of microvesicles and exosomes to disease in vitro, to begin to apply this knowledge to in vivo models of disease.

scholarly journals Crosstalk between tongue carcinoma cells, extracellular vesicles, and immune cells in in vitro and in vivo models

Oncotarget ◽  
2017 ◽  
Vol 8 (36) ◽  
pp. 60123-60134 ◽  
Author(s):  
Ahmed Al-Samadi ◽  
Shady Adnan Awad ◽  
Katja Tuomainen ◽  
Yue Zhao ◽  
Abdelhakim Salem ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Immune Cells ◽  
Carcinoma Cells ◽  
Tongue Carcinoma ◽  
In Vivo Models

scholarly journals Enhancement of therapeutic potential of mesenchymal stem cell-derived extracellular vesicles

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Kyong-Su Park ◽  
Elga Bandeira ◽  
Ganesh V. Shelke ◽  
Cecilia Lässer ◽  
Jan Lötvall
Keyword(s):  
Cell Therapy ◽  
Extracellular Vesicles ◽  
Therapeutic Potential ◽  
Biological Activities ◽  
Therapeutic Effects ◽  
In Vivo Models ◽  
Secreted Factors ◽  
Associated Proteins

Abstract After the initial investigations into applications of mesenchymal stem cells (MSCs) for cell therapy, there was increased interest in their secreted soluble factors. Following studies of MSCs and their secreted factors, extracellular vesicles (EVs) released from MSCs have emerged as a new mode of intercellular crosstalk. MSC-derived EVs have been identified as essential signaling mediators under both physiological and pathological conditions, and they appear to be responsible for many of the therapeutic effects of MSCs. In several in vitro and in vivo models, EVs have been observed to have supportive functions in modulating the immune system, mainly mediated by EV-associated proteins and nucleic acids. Moreover, stimulation of MSCs with biophysical or biochemical cues, including EVs from other cells, has been shown to influence the contents and biological activities of subsequent MSC-derived EVs. This review provides on overview of the contents of MSC-derived EVs in terms of their supportive effects, and it provides different perspectives on the manipulation of MSCs to improve the secretion of EVs and subsequent EV-mediated activities. In this review, we discuss the possibilities for manipulating MSCs for EV-based cell therapy and for using EVs to affect the expression of elements of interest in MSCs. In this way, we provide a clear perspective on the state of the art of EVs in cell therapy focusing on MSCs, and we raise pertinent questions and suggestions for knowledge gaps to be filled.

scholarly journals Antifibrotic Effect of Combination of Nilotinib and Stem Cell-Conditioned Media on CCl4-Induced Liver Fibrosis

2020 ◽  
Vol 2020 ◽  
pp. 1-10 ◽  
Author(s):  
Gamal Shiha ◽  
Ahmed Nabil ◽  
Ahmed Lotfy ◽  
Reham Soliman ◽  
Ayman A. Hassan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Liver Fibrosis ◽  
Kinase Inhibitor ◽  
Histopathological Examination ◽  
Conditioned Media ◽  
Secretory Proteins ◽  
Antifibrotic Effect

Liver fibrosis is the excessive extracellular matrix accumulation of proteins, such as collagen, which follows the chronic liver diseases. Advanced liver fibrosis leads to cirrhosis and liver failure. Nilotinib is a second-generation tyrosine kinase inhibitor, which showed antifibrotic efficacy. Stem cell therapy still has some limitations such as oncogenesis, unexpected differentiation, and ethical consideration. Stem cells secrete cytokines and growth factors that showed paracrine-mediated antifibrotic and anti-inflammatory effects in vivo and in vitro. Thus, stem cell-conditioned medium (SC-CM), which contains the secretory proteins of stem cells, may have an antifibrotic role. This study was carried out to examine the antifibrotic effect of Nilotinib and stem cell exosomes on CCl4-induced liver fibrosis in rats. Male Wistar rats were injected intraperitoneally with CCl4 twice a week for 9 weeks and given daily treatments of Nilotinib (20 mg/kg), stem cell exosomes (0.5 ml/rat), and the combination treatment of Nilotinib and stem cell exosomes during the last 5 weeks of CCl4 intoxication. Liver fibrosis and also antifibrotic efficacy of the treatments were estimated with liver function tests, oxidative stress parameters, apoptotic parameters, histopathological examination, and hydroxyproline contents. Results showed that the combination of Nilotinib and stem cell-conditioned media had more antifibrotic effects than each one alone (P value < 0.001).

scholarly journals Extracellular Vesicles: A Therapeutic Option for Liver Fibrosis

2020 ◽  
Vol 21 (12) ◽  
pp. 4255
Author(s):  
Stefania Bruno ◽  
Giulia Chiabotto ◽  
Giovanni Camussi
Keyword(s):  
Liver Fibrosis ◽  
Extracellular Vesicles ◽  
Therapeutic Option ◽  
Membrane Vesicles ◽  
Hepatocyte Proliferation ◽  
Target Cells ◽  
In Vivo Models ◽  
Pathological Conditions ◽  
Different Types

Extracellular vesicles (EVs) are a heterogeneous population of small membrane vesicles released by all types of cells in both physiological and pathological conditions. EVs shuttle different types of molecules and are able to modify the behavior of target cells by various mechanisms of action. In this review, we have summarized the papers present in the literature, to our acknowledge, that reported the EV effects on liver diseases. EVs purified from serum, stem cells, and hepatocytes were investigated in different experimental in vivo models of liver injury and in particular of liver fibrosis. Despite the different EV origin and the different types of injury (toxic, ischemic, diet induced, and so on), EVs showed an anti-fibrotic effect. In particular, EVs had the capacities to inhibit activation of hepatic stellate cells, one of the major players of liver fibrosis development; to reduce inflammation and apoptosis; to counteract the oxidative stress; and to increase hepatocyte proliferation, contributing to reducing fibrosis and ameliorating liver function and morphology.

scholarly journals Renal Regenerative Potential of Extracellular Vesicles Derived from miRNA-Engineered Mesenchymal Stromal Cells

2019 ◽  
Vol 20 (10) ◽  
pp. 2381 ◽  
Author(s):  
Marta Tapparo ◽  
Stefania Bruno ◽  
Federica Collino ◽  
Gabriele Togliatto ◽  
Maria Chiara Deregibus ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Therapeutic Interventions ◽  
In Vivo Models ◽  
Regenerative Effect ◽  
In Vivo Experiments ◽  
Renal Regeneration

Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) possess pro-regenerative potential in different animal models with renal injury. EVs contain different molecules, including proteins, lipids and nucleic acids. Among the shuttled molecules, miRNAs have a relevant role in the pro-regenerative effects of EVs and are a promising target for therapeutic interventions. The aim of this study was to increase the content of specific miRNAs in EVs that are known to be involved in the pro-regenerative effect of EVs, and to assess the capacity of modified EVs to contribute to renal regeneration in in vivo models with acute kidney injuries. To this purpose, MSCs were transiently transfected with specific miRNA mimics by electroporation. Molecular analyses showed that, after transfection, MSCs and derived EVs were efficiently enriched in the selected miRNAs. In vitro and in vivo experiments indicated that EVs engineered with miRNAs maintained their pro-regenerative effects. Of relevance, engineered EVs were more effective than EVs derived from naïve MSCs when used at suboptimal doses. This suggests the potential use of a low amount of EVs (82.5 × 106) to obtain the renal regenerative effect.

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