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

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

Hepatology Research ◽

10.1111/j.1872-034x.2009.00564.x ◽

2009 ◽

Vol 39 (12) ◽

pp. 1219-1228 ◽

Cited By ~ 25

Author(s):

Jing Wang ◽

Chunjing Bian ◽

Lianming Liao ◽

Yashu Zhu ◽

Jing Li ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Hepatic Stellate Cells ◽

Stellate Cells

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

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02358-x ◽

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.

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Immunomodulation of activated hepatic stellate cells by mesenchymal stem cells

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2007.05.150 ◽

2007 ◽

Vol 363 (2) ◽

pp. 247-252 ◽

Cited By ~ 165

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

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

Biochemistry and Cell Biology ◽

10.1139/bcb-2017-0127 ◽

2017 ◽

Vol 95 (6) ◽

pp. 628-633 ◽

Cited By ~ 2

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.

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