Growth differentiation factor 11 mitigates liver fibrosis via expansion of liver progenitor cells

2020 ◽  
Author(s):  
Z Dai ◽  
G Song ◽  
A Balakrishnan ◽  
Q Yuan ◽  
T Yang ◽  
...  
Gut ◽  
2019 ◽  
Vol 69 (6) ◽  
pp. 1104-1115 ◽  
Author(s):  
Zhen Dai ◽  
Guangqi Song ◽  
Asha Balakrishnan ◽  
Taihua Yang ◽  
Qinggong Yuan ◽  
...  

ObjectiveLiver fibrosis and cirrhosis resulting from chronic liver injury represent a major healthcare burden worldwide. Growth differentiation factor (GDF) 11 has been recently investigated for its role in rejuvenation of ageing organs, but its role in chronic liver diseases has remained unknown. Here, we investigated the expression and function of GDF11 in liver fibrosis, a common feature of most chronic liver diseases.DesignWe analysed the expression of GDF11 in patients with liver fibrosis, in a mouse model of liver fibrosis and in hepatic stellate cells (HSCs) as well as in other liver cell types. The functional relevance of GDF11 in toxin-induced and cholestasis-induced mouse models of liver fibrosis was examined by in vivo modulation of Gdf11 expression using adeno-associated virus (AAV) vectors. The effect of GDF11 on leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5)+ liver progenitor cells was studied in mouse and human liver organoid culture. Furthermore, in vivo depletion of LGR5+ cells was induced by injecting AAV vectors expressing diptheria toxin A under the transcriptional control of Lgr5 promoter.ResultsWe showed that the expression of GDF11 is upregulated in patients with liver fibrosis and in experimentally induced murine liver fibrosis models. Furthermore, we found that therapeutic application of GDF11 mounts a protective response against fibrosis by increasing the number of LGR5+ progenitor cells in the liver.ConclusionCollectively, our findings uncover a protective role of GDF11 during liver fibrosis and suggest a potential application of GDF11 for the treatment of chronic liver disease.


2020 ◽  
Vol 73 ◽  
pp. S512
Author(s):  
Zhen Dai ◽  
Guangqi Song ◽  
Asha Balakrishnan ◽  
Taihua Yang ◽  
Qinggong Yuan ◽  
...  

2018 ◽  
Vol 5 (7) ◽  
pp. 2480-2492
Author(s):  
Alexander E. Berezin ◽  
Alexander A. Kremzer ◽  
Daniel Petrovich ◽  
Ioana Mozos ◽  
Alexander A. Berezin

The objective: to investigate the relationship between levels of growth differentiation factor-15 (GDF-15) and circulating number of endothelial progenitor cells (EPCs) with angiopoietin phenotypes: CD34+CD14+CD309+, and CD34+CD14+CD309+Tie2+ in patients with type 2 DM. Methods: The study was retrospectively involved 76 patients with type 2 DM aged 38 to 55 years and 30 healthy volunteers. Data collection included demographic and anthropometric information, hemodynamic performances and biomarkers of the diseases. Flow cytometry was used to determine EPCs' populations. Results: The levels of GDF-15 in peripheral blood of diabetics associated with age (r = 0.31, P = 0.044), high-sensitive C-reactive protein [hs-CRP] (r = 0.40, P = 0.001), smoking (r = 0.38, P = 0.001), body mass index [BMI] (r = 0.34, P = 0.001), LDL cholesterol (r = 0.28, P = 0.001), glycated hemoglobin [HbA1c] (r = -0.28, P = 0.001), number of CV risk factors (r = 0.26, P = 0.001). In univariate logistic regression analysis we found that level of GDF-15 ≥ 618 pg/mL, hs-CRP ≥7.12 mg/L, HbA1c ≥6.4%, fasting glucose ≥6.7 mmol/L, and BMI ≥27.3 kg/m2 predicted deficiency of both angiopoetic phenotypes of EPCs. In multivariate logistic regression model GDF-15 ≥618 pg/mL demonstrated the best odds ratio values for declining of EPCs in diabetics in comparison with other predictors including BMI, HbA1c and hs-CRP. Conclusion: GDF-15 was remarkably evaluated in type 2 DM population to healthy volunteers, and it was an independent factor that contributes to mobilization and probably proliferation of endothelial precursors with high angiopoetic activity.


QJM ◽  
2020 ◽  
Vol 113 (Supplement_1) ◽  
Author(s):  
D Sabry ◽  
W A Khalifa ◽  
M M Abdelgwad ◽  
M Alhelf ◽  
Z M Altaib

Abstract Background Bone marrow mesenchymal stem cells (BM-MSCs) and human umbilical cord endothelial progenitor cells (UC-EPCs) have several benefits for liver regeneration. We speculate huge impacts of rat BM-MSCs and UC-EPCs on reversal of hepatic injury and improvement of liver function in liver fibrosis induced by carbon tetrachloride (CCl4). Methods Forty adult rats were divided into 4 groups; control group, CCl4 group, CCl4/BM-MSCs group and CCl4/UCEPCs group. Blood samples were driven from rats at 1, 2 and 3months to measure serum concentration of albumin and alanine aminotransferase (ALT). Quantitative expression of HGF,TGF-β, MMP-2, and VEGF were assessed by polymerase chain reaction. Histological examination of the liver tissue was performed. α-SMA immunohistochemistry to identify the myoepithelial cells (MECs) and Ki-67 to identify cell prolifration immunohistochemistry are detected in groups injected with cells to confirm cells regeneration. Results Regarding liver function, there was elevating albumin (P < 0.05) and reducing ALT (P < 0.05) concentrations in groups treated with BM-MSCs and UC-EPCs effect compared to untreated CCL4 group. Concerning gene expression, UC-EPCs treated group have significantly higher MMP-2 and VEGF (P < 0.01) genes expression than BM-MSCs treated group. Furthermore, UC-EPCs were more valuable than BM-MSCs in increasing gene expression of HGF (P < 0.05) and immunohistochemistry of α-SMA and Ki-67 (P < 0.01). BM-MSCs have significantly lower TGF- β (P < 0.00) compared to UC-EPCs. Conclusion This study highlighted on liver regeneration role of both human UC-EPCs and BM-MSCs in liver fibrosis by different signaling mechanistic.


2017 ◽  
Vol 70 (1) ◽  
pp. 129-140 ◽  
Author(s):  
Kunfu Wang ◽  
Hao Liu ◽  
Jinjuan Yang ◽  
Caiyun Ma ◽  
Zebiao Zhang ◽  
...  

Sign in / Sign up

Export Citation Format

Share Document