Activation of Notch1 signaling by marrow-derived mesenchymal stem cells through cell–cell contact inhibits proliferation of hepatic stellate cells

Chen, Si; Xu, Liang; Lin, Nan; Pan, Weidong; Hu, Kunpeng; Xu, Rui‐hua

doi:10.1016/j.lfs.2011.10.012

Cited by 53 publications

(31 citation statements)

References 33 publications

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“…TGFβ and other fibrogenic cytokines/factors are known inducers of myofibroblast differentiation from these diverse precursors [38-40]. Recent evidence further indicates that the Notch signaling pathway is also involved in the regulation of myofibroblast differentiation in chronic fibrosis including in the lung [7, 15, 18, 41], kidney [42-46], liver [47-51], heart [12, 14] and skin [16, 52]. …”

Section: Notch and Myofibroblast Differentiationmentioning

confidence: 99%

“…In HSC-T6 cells, an immortalized rat liver stellate cell line, Notch1 inhibits but Hes1 stimulates the promoter activities of α-SMA, COL1α1 and COL1α2 [9]. Co-culture of bone marrow-derived mesenchymal stem cells with HSCs inhibits HSC proliferation that requires cell-cell contact and is partially mediated by Notch pathway activation [51]. Notch signaling stimulates Sox9b expression, which is required to maintain Notch signaling in intrahepatic biliary cells [122].…”

Section: Notch and Liver Fibrosismentioning

confidence: 99%

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Notch in fibrosis and as a target of anti-fibrotic therapy

Phan

2016

Pharmacological Research

111

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The Notch pathway represents a highly conserved signaling network with essential roles in regulation of key cellular processes and functions, many of which are critical for development. Accumulating evidence indicates that it is also essential for fibrosis and thus the pathogenesis of chronic fibroproliferative diseases in diverse organs and tissues. Different effects of Notch activation are observed depending on cellular and tissue context as well as in both physiologic and pathologic states. Close interactions of Notch signaling pathway with other signaling pathways have been identified. In this review, current knowledge on the role of the Notch signaling with special focus on fibrosis and its potential as a therapeutic target is summarized.

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Section: Notch and Myofibroblast Differentiationmentioning

confidence: 99%

Section: Notch and Liver Fibrosismentioning

confidence: 99%

Notch in fibrosis and as a target of anti-fibrotic therapy

Phan

2016

Pharmacological Research

111

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“…All of them except for Notch4 are capable of regulating myofibroblast differentiation [10,55–58]. Notch1 and Notch3 are known to stimulate α- SMA gene expression in lung fibroblasts [10] and hepatic stellate cells [55], whereas Notch2 inhibits TGFβ-induced α- SMA and collagen I gene expression through downregulation of Notch3 in myoblasts [57]. However, in 10T1/2 fibroblasts, Notch3 represses expression of smooth muscle target genes including α- SMA by inhibition of the activation of Smad3 and p38 mitogen-activated protein kinase [58].…”

Section: Regulation Of Myofibroblast Differentiationmentioning

confidence: 99%

Myofibroblasts

Phan

2013

Current Opinion in Rheumatology

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Purpose of review Interest in the myofibroblast as a key player in propagation of chronic progressive fibrosis continues to elicit many publications, with focus on its cellular origins and the mechanisms underpinning their differentiation and/or transition. The objective of the review is to highlight this recent progress. Recent findings The epithelial origin of the myofibroblast in fibrosis has been challenged by recent studies, with the pericyte suggested as a possible precursor instead. Additional signaling pathways, including Notch, Wnt, and hedgehog, are implicated in myofibroblast differentiation. The importance of NADPH oxidase 4 was highlighted recently to suggest a potential link between cellular/oxidative stress and the genesis of the myofibroblast. Recent observations on the importance of lysophosphatidic acid in fibrosis suggest that this may be due, in part, to its ability to regulate myofibroblast differentiation. Finally, there is increasing evidence for the role of epigenetic mechanisms in regulating myofibroblast differentiation, including DNA methylation and miRNA regulation of gene expression. Summary These recent discoveries open up a whole new array of potential targets for novel antifibrotic therapies. This is of special importance given the current bleak outlook for chronic progressive fibrotic diseases, such as scleroderma, due to lack of effective therapies.

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“…Our result suggested higher proportion of inactive HSCs in 3D co-culture BMSCs and HSCs compare to monoculture HSCs. Previous study using direct 2D co-culture HSCs and BM MSCs showed lower expression of activated HSCs (11). Increased HSCs apoptosis and decreased proliferation may cause lower proportion of activated HSCs (10, 11, 22).…”

Section: Discussionmentioning

confidence: 89%

“…In vitro studies showed BMSCs effect on hepatic stellate cell’s activity via paracrine factors (indirect co-culture using transwell) or direct co-culture 2D for juxtacrine effect (10, 11). Tenascin-C is one of the extracellular matrix protein that increases during liver fibrosis (12–14).…”

Section: Introductionmentioning

confidence: 99%

Bone Marrow Stem Cells Anti-liver Fibrosis Potency: Inhibition of Hepatic Stellate Cells Activity and Extracellular Matrix Deposition

Sitanggang

Antarianto

Jusman

et al. 2017

IJSC

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Transplantation of bone marrow derived stem cells (BMSCs) has been reported inhibits liver fibrosis. Several in vitro studies by co-culturing BMSCs and hepatic stellate cells (HSCs) indirectly or directly in 2D models showed inhibition of HSC as the key player in liver fibrosis. In this study, we investigated direct effect of BMSCs on HSCs by co-culturing BMSCs and HSCs in 3D model as it represents the liver microenvironment with intricate cell-cell and cell-matrix interactions. Primary isolated rat HSCs and BMSCs were directly co-cultured at 1:1 ratio with hanging drop method. The monoculture of rat HSCs served as positive control. Mono-culture and co-culture samples were harvested on day 3, 5 and 7 for histological analysis. The samples were analyzed for extracellular matrix deposition by Masson’s Trichrome staining, tenascin-C immunocytochemistry, resting HSC’s state as shown by positive Oil Red O stained cells. Our results indicated CD90+CD34− BMSCs anti-liver fibrosis potency as evidenced by higher proportion of Oil Red O-positive cells in the co-culture group compared to the monoculture group and the significant decrease in extracellular matrix deposition as well as the decrease in tenascin-C expression in the co-culture group (p<0.05) compared to the monoculture group. These findings demonstrate that BMSCs have a potential therapeutic effect against liver fibrotic process through their capacity to inhibit HSCs activation and their effect in minimizing extracellular matrix deposition.

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Activation of Notch1 signaling by marrow-derived mesenchymal stem cells through cell–cell contact inhibits proliferation of hepatic stellate cells

Cited by 53 publications

References 33 publications

Notch in fibrosis and as a target of anti-fibrotic therapy

Notch in fibrosis and as a target of anti-fibrotic therapy

Myofibroblasts

Bone Marrow Stem Cells Anti-liver Fibrosis Potency: Inhibition of Hepatic Stellate Cells Activity and Extracellular Matrix Deposition

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