Human umbilical cord-derived mesenchymal stem cells improve the function of liver in rats with acute-on-chronic liver failure via downregulating Notch and Stat1/Stat3 signaling

Yulin He, Xingrong Guo, Tingyu Lan, Jianbo Xia, Jinsong Wang, Bei Li, Chunyan Peng, Yue Chen, Xiang Hu, Zhongji Meng, Yulin He, Xingrong Guo, Tingyu Lan, Jianbo Xia, Jinsong Wang, Bei Li, Chunyan Peng, Yue Chen, Xiang Hu, Zhongji Meng

Abstract

Background: Effective treatments for acute-on-chronic liver failure (ACLF) are lacking. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have been applied in tissue regeneration and repair, acting through paracrine effects, cell fusion, and actual transdifferentiation. The present study was designed to investigate the therapeutic potential of hUC-MSCs in acute-on-chronic liver injury (ACLI) and ACLF rat models.

Methods: Wistar rats aged 6 weeks were intraperitoneally administered porcine serum (PS) at a dose of 0.5 mL twice per week for 11 weeks to generate an immune liver fibrosis model. After 11 weeks, rats with immune liver fibrosis were injected intravenously with lipopolysaccharide (LPS) to induce an ACLI model or combined LPS and D-galactosamine (D-GalN) to induce an ACLF model. The rats with ACLI or ACLF were injected intravenously with 2×106 hUC-MSCs, 4×106 hUC-MSCs, or 0.9% sodium chloride as a control. The rats were sacrificed at 1, 2, 4, and 6 weeks (ACLI rats) or 4, 12, and 24 h (ACLF rats). The blood and liver tissues were collected for biochemical and histological investigation.

Results: The application of hUC-MSCs in rats with ACLI and ACLF led to a significant decrease in the serum levels of ALT, AST, TBil, DBil, ALP, ammonia, and PT, with ALB gradually returned to normal levels. Inflammatory cell infiltration and collagen fiber deposition in liver tissues were significantly attenuated in ACLI rats that received hUC-MSCs. Inflammatory cell infiltration and apoptosis in liver tissues of ACLF rats that received hUC-MSCs were significantly attenuated. Compared with those in the rats that received 0.9% sodium chloride, a significant reduction in proinflammatory cytokine levels and elevated serum levels of hepatocyte growth factor (HGF) were found in ACLF rats that received hUC-MSCs. Furthermore, Notch, IFN-γ/Stat1, and IL-6/Stat3 signaling were inhibited in ACLI/ACLF rats that received hUC-MSCs.

Conclusions: hUC-MSC transplantation can improve liver function, the degree of fibrosis, and liver damage and promote liver repair in rats with ACLI or ACLF, mediated most likely by inhibiting Notch signaling and reversing the imbalance of the Stat1/Stat3 pathway.

Keywords: ACLF; Liver fibrosis; Liver injury; Notch; Paracrine; Stat1; Stat3; hUC-MSCs.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Schedules of the experiments in rats. a Schematic design of hUC-MSC treatment for rats with ACLI. b Schematic design of hUC-MSC treatment for rats with ACLF. c–e Liver fibrosis/cirrhosis was verified by ELISA for serum HA and PIIINP (c), HE staining (d), and Masson staining (e) of liver specimens from rats that received PS treatment. PS injection. Sacrifice. LPS infusion. D-GalN injection. hUC-MSCs infusion
Fig. 2
Fig. 2
The effect of hUC-MSC transplantation in improving liver function in rats with ACLI. ACLI rats were transplanted with hUC-MSCs or 0.9% sodium chloride as controls, and serum levels of ALT (a), AST (b), TBil (c), DBil (d), ALP (e), and ALB (f) were detected with an automatic biochemical analyzer (n = 3/group). Data are presented as the mean ± SD. *P < 0.05
Fig. 3
Fig. 3
The effects of hUC-MSC transplantation on improving liver function and coagulation function in ACLF rats. ACLF rats were transplanted with hUC-MSCs or 0.9% sodium chloride as a control. Serum levels of ALT (a) and AST (b), plasma levels of ammonia (c), and serum levels of ALB (d), TBil (e), and DBil (f) were detected with an automatic biochemical analyzer, and plasma PT (g) and INR (h) were detected with a coagulation analyzer (4h, n = 3/group; 12h and 24h, n = 4/group). Data are presented as the mean ± SD. *P < 0.05, **P < 0.01
Fig. 4
Fig. 4
Histopathological recovery of liver tissues from rats with ACLI transplanted with hUC-MSCs. ACLI rats were transplanted with hUC-MSCs or 0.9% sodium chloride as a control, and liver sections were used for histological investigation with HE staining (a) or Masson staining (b) and microscopic examination (n = 3/group). Representative photographs are shown for the liver histological presentations of rats with ACLI transplanted with hUC-MSCs or 0.9% sodium chloride as a control at weeks 0, 1, 2, 4, and 6
Fig. 5
Fig. 5
Histopathological recovery of liver tissues from ACLF rats transplanted with hUC-MSCs. ACLF rats were transplanted with hUC-MSCs or 0.9% sodium chloride as a control, and liver sections were used for histological investigation with HE staining and microscopic examination (4h, n = 3/group; 12h and 24h, n = 4/group). Representative photographs are shown for the liver histological presentations of ACLF rats transplanted with hUC-MSCs or 0.9% sodium chloride as a control at hours 4, 12, and 24
Fig. 6
Fig. 6
The effects of hUC-MSC transplantation on liver fibrosis in rats with ACLI. ACLI rats were transplanted with hUC-MSCs or 0.9% sodium chloride as a control, and liver sections from ACLI rats 6 weeks post-hUC-MSC transplantation were used for immunohistochemical staining of α-SMA, desmin, MMP9, and TIMP1 and microscopic examination (n = 3/group). Representative photographs are shown (a). Positive staining was quantified and is presented as the mean ± SD (b). *P < 0.05, **P < 0.01
Fig. 7
Fig. 7
The effects of hUC-MSC transplantation on hepatocyte regeneration in ACLF rats. Liver sections from ACLF rats 12 and 24 h post-hUC-MSC transplantation or 0.9% sodium chloride injection as a control were used for immunohistochemical staining of AFP, CK18, HGF, and PCNA and microscopic examination (n = 4/group). Representative photographs are shown (a). Positive staining was quantified and is presented as the mean ± SD (b, c). d Serum levels of HGF were detected by ELISA (4h, n = 3/group; 12h and 24h, n = 4/group). Data are presented as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001
Fig. 8
Fig. 8
The effects of hUC-MSC transplantation on the production of proinflammatory cytokines and antiinflammatory cytokines in rats with ACLI. ACLI rats were transplanted with hUC-MSCs or 0.9% sodium chloride as a control. The serum levels of the cytokines TNF-α (a), IFN-γ (b), IL-6 (c), IL-1β (d), TGF-β1 (e), IL-4 (f), and IL-10 (g) were detected by ELISA at weeks 1, 2, 4, and 6 (n = 3/group). Data are presented as the mean ± SD. *P < 0.05
Fig. 9
Fig. 9
The effects of hUC-MSC transplantation on the production of proinflammatory cytokines in ACLF rats. ACLF rats were transplanted with hUC-MSCs or 0.9% sodium chloride as a control. The serum levels of the cytokines TNF-α (a), IFN-γ (b), IL-6 (c), and IL-1β (d) were detected by ELISA at hours 4, 12, and 24 (4h, n = 3/group; 12h and 24h, n = 4/group). Data are presented as the mean ± SD. *P < 0.05, **P < 0.01
Fig. 10
Fig. 10
The effects of hUC-MSC transplantation on Notch signaling pathway-related genes and Stat1/Stat3 signaling molecules in ACLF rats. Total RNA and protein were extracted from the liver tissues from rats with ACLF transplanted with hUC-MSCs or 0.9% sodium chloride as a control(n = 4/group). The mRNA expression levels of Notch1, Hes1, and P21 were detected by quantitative PCR (a). Total protein was subjected to western blotting analysis. Relative protein expression of Stat1, pStat1, Stat3, pStat3, c-Myc, Bcl2, and CyclinD1 were quantitated (b, c). The mRNA expression levels of c-Myc, Bcl2, and CyclinD1 were detected by quantitative PCR (d). Liver sections were used for immunohistochemically staining of pStat1 and pStat3. Representative photographs and the quantitative analysis were shown (e). Data were presented as the mean ± SD. *P < 0.05

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