TGFβ1-Pretreated Exosomes of Wharton Jelly Mesenchymal Stem Cell as a Therapeutic Strategy for Improving Liver Fibrosis

Bavarsad, Samaneh Salehipour; Jalali, Mohammad; Nejad, Darioush Bijan; Alypoor, Behnam; Babaahmadi‐Rezaei, Hossein; Mohammadtaghvaei, Narges

doi:10.5812/hepatmon-123416

Cited by 7 publications

(9 citation statements)

References 53 publications

(65 reference statements)

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“…Treatment with WJ-MSC exosomes resulted in a decline of these markers, suggesting an antifibrotic role of exosomes. This finding is consistent with recent studies, such as Salehipour Bavarsad et al, 2022, which demonstrated the potential of MSC-derived exosomes in mitigating fibrosis (33). The discrepancy in the effects of LPS + Exo treatment on α-SMA and collagen1α may indicate a complex interplay between exosomes and LPS, warranting further investigation.…”

Section: Discussionsupporting

confidence: 91%

The Up-Regulation of miR-146a and miR-29b via Exosomes Protects Against Liver Fibrosis by Inhibiting the TGF-β/Smad3c Signaling Pathway

Jaberian Asl,

Monjezi,

Orak

et al. 2024

Hepat Mon

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Background: Hepatic fibrosis is characterized by the increased proliferation and activation of hepatic stellate cells. Transforming growth factor-beta (TGF-β) stimulates these stellate cells, leading to the development of liver fibrosis. MicroRNA-146a and microRNA-29b have been identified as significant regulatory factors in fibrogenesis. Objectives: In this study, we investigated the ability of exosomes to alleviate liver fibrosis by enhancing the antifibrotic effects of miR-146a and miR-29b. Methods: The LX-2 cells were exposed to TGF-β for 24 hours. Subsequently, the cells were treated with exosomes for an additional 24 hours. Following this treatment, the mRNA expression levels of alpha-smooth muscle actin (α-SMA), collagen1α, miR-146a, and miR-29b, as well as the protein levels of phosphorylated Smad3 (p-Smad3), were evaluated. Results: The findings revealed a significant elevation in the expression of α-SMA (5.37-fold, P < 0.0001) and collagen1α (3.87-fold, P < 0.001) genes, as well as an increase in the levels of p-Smad3 protein (5.87-fold, P < 0.0001) in the presence of TGF-β. Moreover, the expression of miR-146a (0.54-fold, P < 0.05) and miR-29b (0.46-fold, P < 0.01) genes exhibited a notable decrease compared to the control group under the influence of TGF-β. In our investigation, the administration of exosomes effectively mitigated the TGF-β-induced up-regulation of α-SMA (3.26-fold, P < 0.01) and collagen1α (1.76-fold, P < 0.01) genes, as well as the p-Smad3 protein (2.86-fold, P < 0.01), in LX-2 cells. Conclusions: Our results suggest that exosomes effectively impede the continuous activation of hepatic stellate cells (HSCs) by enhancing the antifibrotic effects mediated by miR-146a and miR-29b. Moreover, exosomes demonstrate inhibitory effects on the TGF-β/Smad3 signaling pathway, resulting in decreased extracellular matrix (ECM) accumulation in the context of in vitro liver fibrosis.

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Section: Discussionsupporting

confidence: 91%

The Up-Regulation of miR-146a and miR-29b via Exosomes Protects Against Liver Fibrosis by Inhibiting the TGF-β/Smad3c Signaling Pathway

Jaberian Asl,

Monjezi,

Orak

et al. 2024

Hepat Mon

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“…It was also shown that paracrine activity of MSCs plays a role in tissue damage repair through exosomes ( Salehipour Bavarsad et al, 2022 ). However, the types and concentrations of inflammatory mediators, such as TGF-β1 in the MSCs’ microenvironment may affect their function and therapeutic potential.…”

Section: Wharton’s Jelly Mscs Secretomementioning

confidence: 99%

“…However, the types and concentrations of inflammatory mediators, such as TGF-β1 in the MSCs’ microenvironment may affect their function and therapeutic potential. In this concern, Salehipour Bavarsad et al, (2022) investigated whether WJ-MSCs pretreated with different concentrations of TGF-β1 change the anti-fibrotic properties of their exosomes on activated hepatic stellate cells. Their results demonstrated that exosomes isolated from untreated WJ-MSCs reduced TGFβ-smad2/3 signaling and expression of fibrotic markers.…”

Section: Wharton’s Jelly Mscs Secretomementioning

confidence: 99%

“…Their results demonstrated that exosomes isolated from untreated WJ-MSCs reduced TGFβ-smad2/3 signaling and expression of fibrotic markers. These effects were even more intense upon using exosomes derived from 0.1 ng/ml TGFβ-pretreated WJ-MSCs, suggesting that these pre-treated WJ-MSCs might significantly benefit the liver fibrosis patients ( Salehipour Bavarsad et al, 2022 ).…”

Section: Wharton’s Jelly Mscs Secretomementioning

confidence: 99%

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Wharton’s jelly mesenchymal stem cells: a concise review of their secretome and prospective clinical applications

Drobiova,

Sindhu,

Ahmad

et al. 2023

Front. Cell Dev. Biol.

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Accumulating evidence indicates that most primary Wharton’s jelly mesenchymal stem cells (WJ-MSCs) therapeutic potential is due to their paracrine activity, i.e., their ability to modulate their microenvironment by releasing bioactive molecules and factors collectively known as secretome. These bioactive molecules and factors can either be released directly into the surrounding microenvironment or can be embedded within the membrane-bound extracellular bioactive nano-sized (usually 30–150 nm) messenger particles or vesicles of endosomal origin with specific route of biogenesis, known as exosomes or carried by relatively larger particles (100 nm–1 μm) formed by outward blebbing of plasma membrane called microvesicles (MVs); exosomes and MVs are collectively known as extracellular vesicles (EVs). The bioactive molecules and factors found in secretome are of various types, including cytokines, chemokines, cytoskeletal proteins, integrins, growth factors, angiogenic mediators, hormones, metabolites, and regulatory nucleic acid molecules. As expected, the secretome performs different biological functions, such as immunomodulation, tissue replenishment, cellular homeostasis, besides possessing anti-inflammatory and anti-fibrotic effects. This review highlights the current advances in research on the WJ-MSCs’ secretome and its prospective clinical applications.

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“…Growth factors, a vital group of biological mediators, were also found to modulate signal transduction involved in cell growth, proliferation, survival, and other regenerative-related capacities (Hu and Li 2018 ). In comparison with unmodified MSCs-EXOs, preconditioning of Wharton’s jelly-MSCs with TGF-β1 produced EXOs with maximum repressive effect on TGF-β1/Smad3 axis and fibrotic markers (α-SMA, type I collagen-alpha 1, E-cadherin) in activated LX-2 cells (Bavarsad et al 2022 ).…”

Section: Strategies To Enhance the Therapeutic Potential Of Msc-evsmentioning

confidence: 99%

Innovative preconditioning strategies for improving the therapeutic efficacy of extracellular vesicles derived from mesenchymal stem cells in gastrointestinal diseases

Didamoony,

Soubh,

Atwa

et al. 2023

Inflammopharmacol

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Gastrointestinal (GI) diseases have become a global health issue and an economic burden due to their wide distribution, late prognosis, and the inefficacy of recent available medications. Therefore, it is crucial to search for new strategies for their management. In the recent decades, mesenchymal stem cells (MSCs) therapy has attracted attention as a viable option for treating a myriad of GI disorders such as hepatic fibrosis (HF), ulcerative colitis (UC), acute liver injury (ALI), and non-alcoholic fatty liver disease (NAFLD) due to their regenerative and paracrine properties. Importantly, recent studies have shown that MSC-derived extracellular vesicles (MSC-EVs) are responsible for most of the therapeutic effects of MSCs. In addition, EVs have revealed several benefits over their parent MSCs, such as being less immunogenic, having a lower risk of tumour formation, being able to cross biological barriers, and being easier to store. MSC-EVs exhibited regenerative, anti-oxidant, anti-inflammatory, anti-apoptotic, and anti-fibrotic effects in different experimental models of GI diseases. However, a key issue with their clinical application is the maintenance of their stability and efficacy following in vivo transplantation. Preconditioning of MSC-EVs or their parent cells is one of the novel methods used to improve their effectiveness and stability. Herein, we discuss the application of MSC-EVs in several GI disorders taking into account their mechanism of action. We also summarise the challenges and restrictions that need to be overcome to promote their clinical application in the treatment of various GI diseases as well as the recent developments to improve their effectiveness. Graphical abstract A representation of the innovative preconditioning techniques that have been suggested for improving the therapeutic efficacy of MSC-EVs in GI diseases. The pathological conditions in various GI disorders (ALI, UC, HF and NAFLD) create a harsh environment for EVs and their parents, increasing the risk of apoptosis and senescence of MSCs and thereby diminishing MSC-EVs yield and restricting their large-scale applications. Preconditioning with pharmacological agents or biological mediators can improve the therapeutic efficacy of MSC-EVs through their adaption to the lethal environment to which they are subjected. This can result in establishment of a more conducive environment and activation of numerous vital trajectories that act to improve the immunomodulatory, reparative and regenerative activities of the derived EVs, as a part of MSCs paracrine system. ALI, acute liver injury; GI diseases, gastrointestinal diseases; HF, hepatic fibrosis; HSP, heat shock protein; miRNA, microRNA; mRNA, messenger RNA; MSC-EVs, mesenchymal stem cell-derived extracellular vesicles; NAFLD, non-alcoholic fatty liver disease; UC, ulcerative colitis.

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TGFβ1-Pretreated Exosomes of Wharton Jelly Mesenchymal Stem Cell as a Therapeutic Strategy for Improving Liver Fibrosis

Cited by 7 publications

References 53 publications

The Up-Regulation of miR-146a and miR-29b via Exosomes Protects Against Liver Fibrosis by Inhibiting the TGF-β/Smad3c Signaling Pathway

The Up-Regulation of miR-146a and miR-29b via Exosomes Protects Against Liver Fibrosis by Inhibiting the TGF-β/Smad3c Signaling Pathway

Wharton’s jelly mesenchymal stem cells: a concise review of their secretome and prospective clinical applications

Innovative preconditioning strategies for improving the therapeutic efficacy of extracellular vesicles derived from mesenchymal stem cells in gastrointestinal diseases

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