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Cited by 184Mesenchymal stem cell researchLiver physiology and pathologyLiver Disease and Transplantation

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Mesenchymal stem cells and their secreted molecules predominantly ameliorate fulminant hepatic failure and chronic liver fibrosis in mice respectively

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Huang, Biao, Cheng, Xixi, Wang, Huafeng, Huang, Wenjing, la Ga hu, Zha, Wang, Dan, Zhang, Kai, Zhang, Huan, Xue, Zhenyi, Da, Yurong, Zhang, Ning, Hu, Yongcheng, Yao, Zhi, Qiao, Liang, Gao, Fei, Zhang, Rongxin·2016·Journal of Translational Medicine
DOI 10.1186/s12967-016-0792-1PMC PMC4746907
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Abstract

BACKGROUND: Orthotopic liver transplantation is the only effective treatment for liver failure but limited with shortage of available donor organs. Recent studies show promising results of mesenchymal stem cells (MSCs)-based therapies. METHODS: We systematically investigate the therapeutic effects of MSCs or MSC-conditioned medium (MSC-CM) in ameliorating fulminant hepatic failure (FHF) and chronic liver fibrosis in mice. In addition, extensive flow cytometry analysis of spleens from vehicle and MSC- and MSC-CM-treated mice was applied to reveal the alteration of inflammatory state. RESULTS: In FHF model, MSCs treatment reduced remarkably the death incidents; the analysis of gross histopathology showed that control livers were soft and shrunken with extensive extravasated blood, which was gradually reduced at later time points, while MSC-treated livers showed gross pathological changes, even 24 h after MSC infusion, and hematoxylin and eosin staining revealed dramatical hepatocellular death with cytoplasmic vacuolization suppressed by MSCs treatment; flow cytometry analysis of total lymphocytes showed that macrophages (F4/80) infiltrated into control livers more than MSC-treated livers; by contrast, MSC-CM partially ameliorates FHF. In chronic liver injury model, MSC and MSC-CM both suppressed fibrogenesis and necroinflammatory, and the later was better; activation of hepatic stellate cells (α-SMA) was inhibited; glycogen synthesis and storage (indicated by periodic acid-Schiff -staining) was improved; liver regeneration (Ki67) was promoted while liver apoptosis (TUNEL) was reduced. In the in vitro, MSCs promote macrophage line RAW264.7 apoptosis and MSC-CM promotes apoptosis and inhibits proliferation of HSC line LX-2. We also found that MSCs and MSC-CM could improve spleen; MSC-CM increased levels of Th2 and Treg cells, and reduced levels of Th17 cells, whereas levels of Th1 cells were unchanged; comparatively, MSC treatment did not affect Th17 and Treg cells and only slightly alters inflammatory state; MSC and MSC-CM treatment both substantially down-regulated macrophages in the spleens. CONCLUSION: Both MSCs and MSC-CM exert therapeutic effects by acting on various key cells during the pathogenesis of FHF and chronic fibrosis, stimulating hepatocyte proliferation and suppressing apoptosis, down-regulating infiltrating macrophages, converting CD4(+) T lymphocyte system into an anti-inflammatory state, and facilitating hepatic stellate cell death.

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Fig. 1 MSC infusion promotes survival, improves gross and microscopic histopathology in TAA-induced FHF. a MSC treatment substantially improved the gross histopathological appearance of TAA-stimulated livers with reduction of extravasated blood. Asterisk marks the changes occurred to liver 24 h after MSC infusion. b Kaplan–Meier survival analysis of mice with TAA-induced FHF. c Flow cytometry analysis of macrophages. d HE staining e F4/80 immunohistochemistry f CD45+ immunofluorescence staining of livers sections from control and MSC-treated mice demonstrated a massive reduction of leukocyte and macrophage infiltration. Data are shown as mean ± standard error of the mean of 10 random high-power fields per mouse. *P < 0.05; **P < 0.01; ***P < 0.001
Fig. 1 MSC infusion promotes survival, improves gross and microscopic histopathology in TAA-induced FHF. a MSC treatment substantially improved the gross histopathological appearance of TAA-stimulated livers with reduction of extravasated blood. Asterisk marks the changes occurred to liver 24 h after MSC infusion. b Kaplan–Meier survival analysis of mice with TAA-induced FHF. c Flow cytometry analysis of macrophages. d HE staining e F4/80 immunohistochemistry f CD45+ immunofluorescence staining of livers sections from control and MSC-treated mice demonstrated a massive reduction of leukocyte and macrophage infiltration. Data are shown as mean ± standard error of the mean of 10 random high-power fields per mouse. *P < 0.05; **P < 0.01; ***P < 0.001CC BY · PubMed Central
Fig. 2 MSC treatment suppresses inflammatory infiltration and down-regulates activated HSCs, inhibiting fiber deposition in CCl4-induced chronic liver fibrosis. a Sirius Red, b HE, and c PAS staining of liver sections from control and MSC-treated mice. d α-SMA immunofluorescence staining of liver sections shows a down-regulation of activated HSCs. e F4/80 immunofluorescence staining of liver sections from normal, control and MSCs-treated mice. f, g Fibrosis and necroinflammatory scores determined using the scoring system of Ishak [31]. h, i, j Quantification of PAS-positivity, α-SMA-positivity and F4/80-positivety. Data are shown as mean ± standard error of the mean of 10 random high-power fields per mouse. *P < 0.05; **P < 0.01; ***P < 0.001
Fig. 2 MSC treatment suppresses inflammatory infiltration and down-regulates activated HSCs, inhibiting fiber deposition in CCl4-induced chronic liver fibrosis. a Sirius Red, b HE, and c PAS staining of liver sections from control and MSC-treated mice. d α-SMA immunofluorescence staining of liver sections shows a down-regulation of activated HSCs. e F4/80 immunofluorescence staining of liver sections from normal, control and MSCs-treated mice. f, g Fibrosis and necroinflammatory scores determined using the scoring system of Ishak [31]. h, i, j Quantification of PAS-positivity, α-SMA-positivity and F4/80-positivety. Data are shown as mean ± standard error of the mean of 10 random high-power fields per mouse. *P < 0.05; **P < 0.01; ***P < 0.001CC BY · PubMed Central
Fig. 3 MSC delivery decreases apoptosis and enhances hepatocellular proliferation in mice with liver failure. Liver sections from a TAA-stimulated and b CCl4-stimulated mice were stained by TUNEL (dark brown nuclei, large for hepatocytes) and counterstained with methyl green (light blue). Ki67 immunofluorescence staining of liver sections from c TAA-stimulated and d CCl4-stimulated mice.Quantification of TUNEL-positivity in e TAA-stimulated and f CCl4-stimulated livers. Quantification of Ki67-positivity in g TAA-stimulated and h CCl4-stimulated livers. Data are shown as mean ± standard error of the mean of 10 random high-power fields per mouse. *P < 0.05; **P < 0.01; ***P < 0.001
Fig. 3 MSC delivery decreases apoptosis and enhances hepatocellular proliferation in mice with liver failure. Liver sections from a TAA-stimulated and b CCl4-stimulated mice were stained by TUNEL (dark brown nuclei, large for hepatocytes) and counterstained with methyl green (light blue). Ki67 immunofluorescence staining of liver sections from c TAA-stimulated and d CCl4-stimulated mice.Quantification of TUNEL-positivity in e TAA-stimulated and f CCl4-stimulated livers. Quantification of Ki67-positivity in g TAA-stimulated and h CCl4-stimulated livers. Data are shown as mean ± standard error of the mean of 10 random high-power fields per mouse. *P < 0.05; **P < 0.01; ***P < 0.001CC BY · PubMed Central
Fig. 4 MSC-CM delivery ameliorates TAA-stimulated FHF and CCl4-stimulated liver fibrosis. a Schema depicting MSC-CM treatment for FHF. b Schema depicting MSC-CM treatment for chronic liver fibrosis. c Kaplan–Meier survival analysis of mice with TAA-induced FHF. d MSC-CM treatment substantially improved the gross histopathological appearance of TAA-stimulated livers. e, f Fibrosis and necroinflammatory scores were determined using the scoring system of Ishak for CCl4-stimulated livers. Quantification of (g) α-SMA-, (h) Ki67-, and (i) TUNEL-positivity. j HE staining of liver sections from control and MSC-CM-treated TAA-stimulated livers. k Necroinflammatory scores determined by Necroinflammatory score system of Ishak in TAA-stimulated livers. l Sirius red, m HE, n α-SMA immunofluorescence, o Ki67 immunofluorecence, p TUNEL staining of liver sections from CCl4-stimulated all group. Data are shown as mean ± standard error of the mean of 10 random high-power fields per mouse.*P < 0.05; **P < 0.01; ***P < 0.001
Fig. 4 MSC-CM delivery ameliorates TAA-stimulated FHF and CCl4-stimulated liver fibrosis. a Schema depicting MSC-CM treatment for FHF. b Schema depicting MSC-CM treatment for chronic liver fibrosis. c Kaplan–Meier survival analysis of mice with TAA-induced FHF. d MSC-CM treatment substantially improved the gross histopathological appearance of TAA-stimulated livers. e, f Fibrosis and necroinflammatory scores were determined using the scoring system of Ishak for CCl4-stimulated livers. Quantification of (g) α-SMA-, (h) Ki67-, and (i) TUNEL-positivity. j HE staining of liver sections from control and MSC-CM-treated TAA-stimulated livers. k Necroinflammatory scores determined by Necroinflammatory score system of Ishak in TAA-stimulated livers. l Sirius red, m HE, n α-SMA immunofluorescence, o Ki67 immunofluorecence, p TUNEL staining of liver sections from CCl4-stimulated all group. Data are shown as mean ± standard error of the mean of 10 random high-power fields per mouse.*P < 0.05; **P < 0.01; ***P < 0.001CC BY · PubMed Central
Fig. 5 MSCs promote RAW264.7 apoptosis, and low concentration of MSC-CM facilitates LX-2 apoptosis and inhibition of proliferation. a Co-culture of RAW264.7 and MSCs induced massive apoptosis of RAW264.7 48 h later, shown using a fluorescent live/dead assay. b A low concentration of MSC-CM suppressed LX-2 proliferation 48 h later. c A low concentration of MSC-CM increased LX-2 apoptosis 48 h later, shown using a fluorescent live/dead assay. d Percentage of apoptosis for co-culture and RAW264.7-alone conditions. e Percentage of apoptosis for co-culture and LX-2-alone conditions. f Division index analysis of co-culture and LX-2-alone conditions. Experiments were performed in triplicate. Data are shown as mean ± standard deviation. *P < 0.05; **P < 0.01; ***P < 0.001
Fig. 5 MSCs promote RAW264.7 apoptosis, and low concentration of MSC-CM facilitates LX-2 apoptosis and inhibition of proliferation. a Co-culture of RAW264.7 and MSCs induced massive apoptosis of RAW264.7 48 h later, shown using a fluorescent live/dead assay. b A low concentration of MSC-CM suppressed LX-2 proliferation 48 h later. c A low concentration of MSC-CM increased LX-2 apoptosis 48 h later, shown using a fluorescent live/dead assay. d Percentage of apoptosis for co-culture and RAW264.7-alone conditions. e Percentage of apoptosis for co-culture and LX-2-alone conditions. f Division index analysis of co-culture and LX-2-alone conditions. Experiments were performed in triplicate. Data are shown as mean ± standard deviation. *P < 0.05; **P < 0.01; ***P < 0.001CC BY · PubMed Central
Fig. 6 MSC and MSC-CM down-regulate macrophages and converts the CD4+ T lymphocyte system into an anti-inflammatory state in TAA-stimulated spleens. a Spleens from control and MSC-treated TAA-stimulated mice 72 h after MSC treatment. b Spleen weight in MSC-treated mice with FHF. Quantification of (c) Th1, (d) Th17, (e) Th2, (f) Treg and (g) macrophages in spleen
Fig. 6 MSC and MSC-CM down-regulate macrophages and converts the CD4+ T lymphocyte system into an anti-inflammatory state in TAA-stimulated spleens. a Spleens from control and MSC-treated TAA-stimulated mice 72 h after MSC treatment. b Spleen weight in MSC-treated mice with FHF. Quantification of (c) Th1, (d) Th17, (e) Th2, (f) Treg and (g) macrophages in spleenCC BY · PubMed Central
Fig. 7 MSC and MSC-CM down-regulate macrophages and converts the CD4+ T lymphocyte system into an anti-inflammatory state in CCl4-stimulated spleens. Both MSC and MSC-CM treatment had no significant effect on (a) Th1. A significant reduction of (b) Th17 was observed 3 weeks after MSC-CM but not MSC treatment. However, (c) an increase in Th2 and (e) a reduction in macrophages was observed after both MSC and MSC-CM treatment. MSC-CM but not MSC treatment up-regulated (d) Treg. Quantification of (f) Th1, (g) Th17, (h) Th2, (i) Treg, and (j) macrophages in the spleen. k Spleen weight in MSC-CM-treated mice with chronic liver fibrosis. l Spleens from control and MSC-CM-treated CCl4-stimulated mice
Fig. 7 MSC and MSC-CM down-regulate macrophages and converts the CD4+ T lymphocyte system into an anti-inflammatory state in CCl4-stimulated spleens. Both MSC and MSC-CM treatment had no significant effect on (a) Th1. A significant reduction of (b) Th17 was observed 3 weeks after MSC-CM but not MSC treatment. However, (c) an increase in Th2 and (e) a reduction in macrophages was observed after both MSC and MSC-CM treatment. MSC-CM but not MSC treatment up-regulated (d) Treg. Quantification of (f) Th1, (g) Th17, (h) Th2, (i) Treg, and (j) macrophages in the spleen. k Spleen weight in MSC-CM-treated mice with chronic liver fibrosis. l Spleens from control and MSC-CM-treated CCl4-stimulated miceCC BY · PubMed Central
Fig. 8 Schema depicting mechanisms of MSC and MSC-CM therapy. MSCs and MSC-CM containing MSC-secreted soluble factors ameliorate TAA-induced acute liver injury and CCl4-induced chronic liver fibrosis by acting on hepatocytes, macrophages, CD4 + helper T lymphocytes, and HSCs, which have important roles during the pathogenesis of liver injury. muMSC: murine mesenchymal stem cell; M0: undifferentiated macrophage; M1: M1 macrophage; M2: M2 macrophage
Fig. 8 Schema depicting mechanisms of MSC and MSC-CM therapy. MSCs and MSC-CM containing MSC-secreted soluble factors ameliorate TAA-induced acute liver injury and CCl4-induced chronic liver fibrosis by acting on hepatocytes, macrophages, CD4 + helper T lymphocytes, and HSCs, which have important roles during the pathogenesis of liver injury. muMSC: murine mesenchymal stem cell; M0: undifferentiated macrophage; M1: M1 macrophage; M2: M2 macrophageCC BY · PubMed Central

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Authors
Huang, B., Cheng, X., Wang, H., Huang, W., la Ga hu, Z., Wang, D., Zhang, K., Zhang, H., Xue, Z., Da, Y., Zhang, N., Hu, Y., Yao, Z., Qiao, L., Gao, F., & Zhang, R.
Affiliations
  • Tianjin Medical University (CN)
  • Tianjin Hospital (CN)
  • The University of Sydney (AU)
  • Chinese Academy of Sciences (CN)
Corresponding author
  • Gao, Fei
  • Zhang, Rongxin
ORCID
Venue
Journal of Translational Medicine
Publisher
Springer Science and Business Media LLC
Published
2016-02-09
Volume
14
Issue
1
Pages
45-45
ISSN
1479-5876 (ISSN-L)
DOI
10.1186/s12967-016-0792-1
PMC
PMC4746907
OpenAlex
W2254654454
Cited by
183
References
31
Citations by year
2026: 3 · 2025: 14 · 2024: 22 · 2023: 21 · 2022: 20 · 2021: 35 · 2020: 21 · 2019: 22 · 2018: 9 · 2017: 10 · 2016: 6
FWCI
11.37
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Journal of Translational Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Ministry of Science and Technology of China (2012CB932503)
  • Ministry of Science and Technology of the People's Republic of China (CN) (2011CB933100)
  • National Natural Science Foundation of China (CN) (91029705, 81172864, 81272317)
  • Scientific Innovation Project of the Chinese Academy of Science (XDA 01040106)
  • Ministry of Education (Tianjin) (TD12-5025)
  • Natural Science Foundation of Tianjin City (CN) (14JCTPJC00487)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
Keywords
mesenchymal stem cells, MSC-conditioned medium, acute liver failure, chronic liver fibrosis, hepatic stellate cells, macrophage infiltration, Th17/Treg balance, hepatocyte apoptosis, liver regeneration, hepatocyte proliferation, liver fibrosis, MSC-based therapy
MeSH terms
RAW 264.7 Cells, Animals, Carbon Tetrachloride, Chronic Disease, Female, Inflammation, Liver, Liver Cirrhosis, Macrophages, Mice, Inbred C57BL, Mice, Inbred ICR, Regeneration, Down-Regulation, Survival Analysis, Culture Media, Conditioned, Liver Failure, Acute, Apoptosis, Mesenchymal Stem Cell Transplantation, Cell Proliferation, Mice, Hepatic Stellate Cells, Mesenchymal Stem Cells

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