Bone marrow-derived stem cells ameliorate hepatic fibrosis by down-regulating interleukin-17
- Linhua Zheng†1,
- Jindong Chu†1,
- Yongquan Shi†1,
- Xinmin Zhou1,
- Ling Tan2,
- Qiang Li1,
- Lina Cui1,
- Zheyi Han1,
- Ying Han1Email author and
- Daiming Fan1
© Zheng et al.; licensee BioMed Central Ltd. 2013
Received: 3 August 2013
Accepted: 28 October 2013
Published: 6 December 2013
Accumulating evidences have identified the immunoregulatory features of stem cells. In this study, the immunoregulation of bone marrow-derived stem cells (BMSCs) transplanted into patients with HBV-related decompensated cirrhosis and mouse model of liver injury induced by carbon tetrachloride (CCl4) administration was observed.
Compared with healthy controls, patients with HBV-related decompensated cirrhosis showed significantly higher levels of TNF-alpha, IL-12, TGF-beta1, IL-17, and IL-8. However, only IL-17 was markedly decreased after autologous BMSCs transplantation during their follow-up. The same results were found in the CCl4-treated mice. Furthermore, we found that exogenous IL-17 partly abolished the therapeutic effect of BMSCs whereas IL-17-specific antibody promoted improvement of liver injury in CCl4-treated mice, resembling the therapeutic effect of BMSCs transplantation.
These data suggested that BMSCs transplantation induces a decrease of IL-17 level, which at least in part delineates the mechanisms of stem cells-mediated therapeutic benefit on liver disease.
KeywordsBone marrow-derived stem cells Decompensated cirrhosis IL-17 Immunoregulation HBV Carbon tetrachloride
More recently, advances in the understanding of bone marrow-derived stem cells (BMSCs) biology and plasticity have raised hopes that stem cell therapy may offer exciting therapeutic possibilities for patients with liver diseases [1, 2]. However, there is much debate concerning the mechanisms by which BMSCs contribute to hepatic regeneration. Recently, more and more evidence have identified the strong immunoregulatory effect of stem cells [3, 4].
It is well known that inflammation is a critical factor in the initiation and maintenance of liver fibrogenesis. When liver injuries occur, damaged epithelial and/or endothelial cells release inflammatory mediators that recruit peripheral blood inflammatory cells to the damaged liver and release of fibrosis-related mediators including TGF-beta1 and TNF-alpha, triggering activation of hepatic stellate cells and formation of extracellular matrix . Recently, some reports suggest that proinflammatory cytokine IL-17 (also known as IL-17A) plays an important role in many liver diseases, including alcoholic liver disease, hepatocellular carcinoma, autoimmune liver disease, acute and chronic hepatitis B and it is associated with the disease progression [6–9]. Cytokines, signaling proteins produced by different kinds of cell types, are essential for the development and function of both innate and adaptive immune response. However, the regulatory effect of BMSCs on some kinds of cytokines is still obscure.
On the basis of previous studies, we initiated a clinical study analyzing the regulation of BMSCs on several kinds of cytokines after transplanting into HBV-related decompensated cirrhotic patients. And then we verified our clinical results using a well-estimated mouse model of carbon tetrachloride (CCl4)-induced liver injury and we firstly found that the therapeutic effect of BMSCs was, at least in part, due to their down-regulation of IL-17.
Therapeutic effect of autologous BMSCs transplantation on patients with HBV-related decompensated cirrhosis
Improved liver function of patients after bone marrow-derived stem cells (BMSCs) transplantation
Decrease of serum IL-17 after autologous BMSCs transplantation in patients
Dynamic changes of cytokines after bone marrow-derived stem cells (BMSCs) transplantation
Weeks after BMSCs transplantation
Change of IL-17 in mouse model of liver injury induced by CCl4 injection
A causative role of IL-17 in the pathogenesis of liver injury in mice
BMSCs transplantation ameliorates CCl4-induced liver injury and down-regulates IL-17 level in mice
IL-17 is a key for BMSCs-mediated amelioration of liver injury in mice
In an attempt to determine whether decrease of IL-17 levels could be linked to the therapeutic benefits of BMSCs transplantation on CCl4-induced liver injury, the 6-week CCl4-treate mice were randomly divided into several groups as described in the Material and Methods part. As shown in Figure 5, H&E and Sirius red staining showed that the areas of liver fibrosis in BMSCs and anti-IL-17 mAb groups were significant decreased than that in only CCl4-treated group. However, there was no significant difference between BMSCs and Anti-IL-17 mAb groups. Meanwhile, the area of liver fibrosis in rmIL-17 group was markedly increased than that in only CCl4-treated or BMSCs groups. Strikingly, the difference in the area of liver fibrosis between BMSCs and rmIL-17 + BMSCs groups was overt (p < 0.05). These results were confirmed by the hepatic mRNA expressions of alpha-SMA and collagen-1 in liver tissues. Moreover, serum ALB in BMSCs and anti-IL-17 mAb groups was significant higher than that in only CCl4-treated group. And there was no significant difference between BMSCs and Anti-IL-17 mAb groups. Serum ALB in rmIL-17 + BMSCs group displayed significantly lower than that in BMSCs group, indicating exogenous IL-17 could block the therapeutic effect of BMSCs.
More recently, the therapeutic effect of stem cell transplantation on liver diseases have been investigated in mice and human, yet the underlying mechanisms are obscure. The present study demonstrates that transplantation of autologous BMSCs could down-regulate serum IL-17 in patients with HBV-related decompensated cirrhosis and in mouse model of CCl4-induced liver injury, which may at least partly delineate the mechanisms of BMSCs-mediated therapeutic benefit on liver diseases.
The stem cells mostly used to transplant are derived from bone marrow including mesenchymal stem cells (MSCs), hematopoietic stem cells (HSCs) and unsorted mononuclear cells. However, which cell type is more effective in treating liver diseases is largely unknown. Recently, several studies have suggested that MSCs and HSCs function synergistically for the therapy of diabetes and heart failure [10, 11]. The rationale for the synergistic actions of MSCs and HSCs may be that MSCs provide a microenvironment for HSCs in both embryonic and postnatal stage . Thus, the mixture of bone marrow stem cells was used in our study.
Consistent with previous reports [2, 13, 14], we demonstrated that most HBV-related decompensated cirrhotic patients with BMSCs transplantation displayed significantly improved liver function during 48 weeks of follow-up. As shown in Table 1, signs of clinical improvement of liver function, ALB, PTA, CHE, CTP and MELD scores, were observed after transplantation. And the peak of improvement was at 24 weeks after transplantation. Considering the high risk of liver biopsy in end-stage liver disease patients, we did not perform histological analysis. These data suggest that BMSCs transplantation, at least in short term, may be an effective and safe therapeutic approach for HBV-related decompensated cirrhosis.
With accumulating evidences about the implication of inflammation in the pathogenesis of diseases, the immunoregulatory features of stem cells have drawn more attention. It has been reported that MSCs could inhibit the function of T-lymphocytes, natural killer (NK) cells and dendritic cells, and regulate their cytokine spectrums, showing an immunoregulatory capacity in vitro and in vivo[15–17]. Recently, Suh et al. investigated that bone marrow cells have the capacity of anti-inflammation and anti-fibrosis through expression of IL-10. And some studies have reported that MSCs can prevent naive CD4+ T cells from differentiating into Th17 cells and inhibit the production of IL-17 in vitro[19, 20]. However, some other studies indicate that co-culture of splenocytes and MSCs in vitro could increase IL-17 secretion [21, 22]. The opposite regulatory effect of MSCs on the production of IL-17 may be related to the different co-culture systems in vitro. In vivo study, we found that serum IL-17 in patients with HBV-related decompensated cirrhosis statistically decreased at 24 weeks after BMSCs transplantation when compared with baseline. It is noteworthy that there was a highly negative correlation between serum IL-17 and ALB, but a positive correlation between serum IL-17 and MELD score. However, the other cytokines, aforementioned, were not significantly changed after transplantation. And in the mouse model of CCl4-induced liver injury, IL-17 level also markedly declined after transplantation of homologous BMSCs.
IL-17, produced by CD4+ Th17 cells, NKT cells, mast cells, neutrophils and gamma delta T cells [23, 24], plays a major role in host protection against extracellular pathogens and induction of tissue inflammation . It has been found that IL-17 plays a critical role in pulmonary fibrosis  and psoriasis . And some recent clinical studies have been reported that utilization of human anti-IL-17 monoclonal antibody  or human anti-IL-17-receptor monoclonal antibody  could improve clinical symptoms of psoriasis. And emerging evidences have indicated that IL-17 is implicated in the induction of liver injury and liver fibrosis both in human and in mice [30, 31]. Similarly, we found that not only HBV-related decompensated cirrhotic patients, but also mouse model of liver injury induced by CCl4 administration displayed significant higher serum IL-17 levels than that in healthy controls. And in mice, a dynamic change of IL-17 level was observed during the progression of well-established CCl4-induced liver injury in mice. Moreover, the deteriorated effect of exogenous IL-17 and protective effect of neutralizing anti-IL-17 antibody were apparent during the procession of liver injury. Recent study found that IL-17 induces liver injury and fibrosis may through two mechanisms: IL-17 stimulates kupffer cells to express other inflammatory cytokine, such as TNF-alpha, and fibrogenic cytokine TGF-beta1; IL-17 directly stimulates hepatic stellate cells to express collagen and promotes their activation into fibrogenic myofibroblast via Stat3 . These results suggest that IL-17 has a strong profibrogenic effect in the pathogenesis of liver disease and it is positively correlated with the severity of liver injury. However, which cell type is the main producer of IL-17 in the pathogenesis of liver injury, and how IL-17 induces liver injury and fibrosis need to be further pursued.
However, the question in our results is that we cannot distinguish cause and effect. Was the down-regulation of serum IL-17 a cause of the therapeutic effect of BMSCs on patients/mice with liver diseases, or was merely a satellite phenomenon? In the mouse model of CCl4-induced liver injury, we found that blockage of endogenous IL-17 with anti-IL-17-specific antibody could promote improvement of liver injury, resembling the therapeutic effect of BMSCs transplantation. It suggests that amelioration of liver injury may be due to the down-regulation of IL-17 either by neutralizing anti-IL-17 antibody or by BMSCs transplantation. Furthermore, injection of exogenous rmIL-17 significantly exacerbated liver injury, and even abolished the therapeutic effect of BMSCs transplantation on CCl4-induced mouse liver injury, indicating down-regulating IL-17 is a key for BMSCs-mediated amelioration of hepatic injury in mice. However, how BMSCs regulates IL-17 will be our next studies.
It should admit the shortcomings in our study that the mouse model of CCl4-induced liver injury, which has long been used as a valuable model to investigate the pathophysiological mechanism of liver injury and fibrosis, is different from patients with HBV-related decompensated cirrhosis. Therefore, it will be helpful in the future to utilize two or more animal models to clarify the role of IL-17 in the process of BMSCs-mediated amelioration of liver diseases.
Here, we have shown that IL-17 increases significantly in HBV-related decompensated cirrhotic patients and CCl4-treated mice compare with controls. And a highly negative correlation between IL-17 and liver function indeed exists. Moreover, the deteriorated effect of exogenous IL-17 and protective effect of neutralizing anti-IL-17 antibody are apparent during the procession of CCl4-induced liver injury in mice.
A marked decrease of IL-17 after BMSCs transplantation in patients and CCl4-treated mice has been found. In animal study, it is demonstrated that exogenous IL-17 partly abolishes the therapeutic effect of BMSCs whereas IL-17-specific antibody promotes improvement of liver injury in CCl4-treated mice, resembling the therapeutic effect of BMSCs transplantation.
Overall, we reveal a previously unrecognized finding that BMSCs transplantation exerts their beneficial action on liver diseases, at least partly, through down-regulating IL-17.
Material and methods
Baseline clinical characteristics of the enrolled patients
Total bilirubin(3.4-20.5 umol/L)
All patients were followed up for more than 1 year during this study. Clinical manifestation and physical examination were performed at 3-month intervals during the follow-up. At each visit, the concentrations of serum ALB, PTA, and CHE were measured to monitor the liver function of patients. CTP and MELD scores were calculated to assess the kinetics of the liver function of patients. During our follow-up, enrolled patients received regular anti-viral treatment and the virus load should be under the limit of detection. If virologic breakthrough or resistance occurred, “add on” or “switch to” another effective anti-viral drug would be adopted in according to guideline-recommend rescue measure. Venous blood samples were collected from all enrolled patients at each visit for the text of serum cytokines. The end of follow-up was December 2011. Endpoint was defined as the end of follow-up.
Enzyme-linked immunosorbent assay (ELISA)
Serum levels of TNF-alpha, IFN-gamma, IL-12, IL-13, IL-4, TGF-beta1, IL-17, and IL-8 in enrolled populations were measured by ELISA kits (R&D Systems, Abingdon, UK) according to the manufacturer’s instruction. All the samples were assessed in duplicate. Plates were read using the Thermofisher (Massachusetts, America) microplate reader and cytokine concentration was calculated from the standard curve by the plate-reader software.
Animals and treatments
Male C57BL/6 mice (10 to 12 weeks old, 20 to 28 g) were obtained from the animal center of the Fourth Military Medical University (Xi’an, China). They were provided food and water ad libitum and maintained on a 12-h light/dark cycle. All animal experiments were performed in accordance with guidelines from the Fourth Military Medical University Institutional Animal Care and Use Committee. Animals were assigned to groups randomly and we adopted a new procedure for inducing liver injury  with slight modification. In brief, liver injury was induced by intraperitoneal injection of 0.2 ml of a mixture of CCl4 and olive oil twice weekly for 6 weeks. The percentage of CCl4 in the olive oil (v/v) was increased gradually over time as follows: week 1, 13%; week 2, 16%; week 3, 20%; and weeks 4 to 6, 25%. Control mice received olive oil only.
Bone marrow stem cells preparation
C57BL/6 mice were killed by CO2 asphyxia and their limbs were removed for bone marrow isolation. The bone marrow was flushed from the femurs and tibias with serum-free RPMI-1640 (Gibco BRL, Carlsbad, CA) medium using 25 G needle, filtrated and centrifuged at 400 g for 5 min. For elimination of red blood cells, the cells were incubated in an RBC lysis solution (Gibco BRL) for 3 min.
Examination of liver injury
Liver injury was determined by measuring serum ALB, as well as H&E and Sirius red staining. The liver fibrosis area was quantified with Sirius red staining as described previously . Briefly, the red areas with Sirius red staining were assessed at 100 × magnification with a quantitative image analyzer. The mean value of five randomly selected areas per sample was used as the percentage of fibrotic areas.
Measurement of IL-17 levels
The serum IL-17 levels were measured by ELISA using a Ready-SET-GO! Mouse IL-17A kit from eBioscience (San Diego, CA) according to the manufacturer’s instructions.
Total RNA was extracted from 50 mg fresh or frozen liver tissues using RNA extraction kits from Takara Bio (Otsu, Japan) according to the manufacturer’s instructions. RNA (1 μg) was reverse-transcribed to cDNA at 37°C for 15 minutes and 85°C for 15 seconds using Superscript I kit (Takara Bio). Primers for alpha-SMA, collagen-1 and beta-actin were predesigned and validated by Takara. Primers were as follows: forward, 5′-AAGAGCATCCGACACTGCTGAC-3′, reward, 5′-AGCACAGCCTGAATAGCCACATAC-3′ (alpha-SMA); forward, 5′-GACATGTTCAGCTTTGTGGACCTA-3′, reward, 5′-GGGACCCTTAGGCCATTGTGTA-3′ (collagen-1); forward, 5′-CATCCGTAAAGACCTCTATGCCAAC-3′, reward, 5′-ATGGAGCCACCGATCCACA-3′ (beta-actin). beta-actin primer was used for internal control. RT-PCR was performed using Express SYBR Green (Takara). All reactions were performed in triplicate. Levels are expressed relative to matched control samples from the same time points. The specificity of the amplification products was confirmed by ethidium bromide-stained 1.5% agarose gels.
The effect of IL-17 on the pathogenesis of liver injury induced by CCl4 administration in mice
Monoclonal rat anti-mouse IL-17 antibody (anti-IL-17 mAb), rat IgG2a isotype and rmIL-17 were purchased from R&D Systems (Abingdon, UK). On days −1, +1, +3, +5 and +7 after 6-week CCl4 administration, mice were injected anti-IL-17 mAb intraperitoneally (100 μg of anti-IL-17 mAb in 0.2 ml of sterile phosphate buffer solution (PBS)) (five total injections) in non-fasting condition. As a control, rat IgG2a was administered. RmIL-17 was intraperitoneally injected (1 μg of rmIL-17 in 0.2 ml of sterile PBS containing 0.5% BSA) on day −1 after 6-week CCl4 administration in nonfasting condition. As a control, vehicle was administered. Mice were sacrificed after 6 weeks of CCl4 administration.
The role of IL-17 in the therapeutic effect of homogeneous BMSCs transplantation on CCl4-treated mice
Comparison between groups was analyzed by the Student’s t test or ANOVA. The Spearman rank correlation test was used for correlation analysis. Data are reported as means ± standard deviation (SD). A p value lower than 0.05 was considered to be statistically significant. Statistical analysis was performed by GraphPad Prism 5.0 (GraphPad Software, Inc., La Jolla, CA) on a personal computer with Windows 7 operating system.
Bone marrow-derived stem cells
Model for End-Stage liver disease
Enzyme-linked immunosorbent assay
Real time-polymerase chain reaction
Mesenchymal stem cells
Smooth muscle actin
Hematoxylin and eosin.
The authors are grateful to the volunteers who allowed us to carry out this study. We are also grateful to prof. Yongzhan Nie and Dr. Zheng Chen ay State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Disease for their technical help during the experiment.
This work was supported by grants from the “863 Project” of China (No.2011AA020111).
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