Mesenchymal stem cells reverse high‑fat diet‑induced non‑alcoholic fatty liver disease through suppression of CD4+ T lymphocytes in mice

  • Authors:
    • Huafeng Wang
    • Huan Zhang
    • Biao Huang
    • Guolin Miao
    • Xiaoyan Yan
    • Gang Gao
    • Yongping Luo
    • Huize Chen
    • Wei Chen
    • Luhong Yang
  • View Affiliations

  • Published online on: December 20, 2017     https://doi.org/10.3892/mmr.2017.8326
  • Pages: 3769-3774
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Abstract

Although the multipotency of mesenchymal stem cells (MSCs) makes them an attractive choice for clinical applications, immune modulation is an important factor affecting MSC transplantation. At present, the effect of treatment with MSCs on non‑alcoholic fatty liver disease (NAFLD) has received little attention. In the present study, a compact bone‑derived method was used to isolate mouse MSCs (mMSCs) and a high‑fat diet was used to establish a mouse model of NAFLD. Immunophenotypic features of mMSCs were analyzed using flow cytometry. Paraffin sections were stained with hematoxylin and eosin to assess inflammation and steatosis, and with picrosirius red to assess fibrosis. Spleen leukocytes were analyzed by flow cytometry. The results demonstrated that compact bone‑derived MSC transplantation decreased high‑fat diet‑induced weight gain, expansion of subcutaneous adipose tissue, steatosis, lobular inflammation and liver fibrogenesis. Flow cytometry analysis of spleen leukocytes demonstrated that compact bone‑derived MSC transplantation suppressed the proliferation of cluster of differentiation (CD) 4+ T lymphocytes in the spleen, which had been induced by the high‑fat diet. In conclusion, compact bone‑derived MSCs may exhibit clinical value in the treatment of NAFLD through their capacity to suppress the activation of CD4+ T cells.

Introduction

Due to the aging population, obesity is common and is frequently associated with non-alcoholic fatty liver disease (NAFLD), which includes non-alcoholic fatty liver and non-alcoholic steatohepatitis (NASH) (1,2). Globally, NAFLD is a widespread disorder which is now considered to be among the most common types of liver disease. Although initially benign, the disease may progress from non-alcoholic steatosis (NAS) to NASH and subsequently to hepatic fibrosis, liver cirrhosis and hepatoma (3). The prevalence of NAFLD in the general population of the western world has been reported to be 20–30% (3). In the general population of Asia, the prevalence of NAFLD has been reported to be 15–30%, and >50% in patients with diabetes and metabolic syndromes (4). In mainland China, ultrasound surveys assessing fatty liver due to any cause have been published since the mid-1990s (5,6). From these surveys, the median prevalence of ultrasonographic steatosis in the Chinese population has been observed to be 10%, with a range of between 1 and 30% (5,7).

A recent study reported that the adiponectin-derived active peptide ADP355 exerts anti-inflammatory and anti-fibrotic activity in thioacetamide-induced liver injury (8). There has been interest in the isolation and characterization of mesenchymal stem cells (MSCs) and in the potential application of these cells to the treatment of liver disease. MSCs are a heterogeneous subset of stromal stem cells, which may be isolated from various adult tissues (9). They are able to differentiate into cells of a mesodermal lineage, including adipocytes, osteocytes and chondrocytes, in addition to cells of other embryonic lineages. The multipotency of mesenchymal stem cells makes them an attractive choice for clinical applications (1012). Immune modulation is an additional important issue in MSC transplantation. It has been demonstrated that MSCs exhibited potent anti-inflammatory and immunomodulatory activity in vitro and in vivo (13). In liver disease, MSC transplantation has been observed to exert therapeutic effects in acute and chronic liver injury (1418). In a recent study, it was demonstrated that bone-derived MSC transplantation was effective in treating experimental liver fibrosis induced by consecutive intraperitoneal injections of CCl4, and molecules secreted by the cells ameliorated fulminant hepatic failure induced by thioacetamide (19). MSCs have been demonstrated to exert a positive effect on the immune micro-environment in animal models of fulminant hepatic failure (FHF) and chronic liver fibrosis (19).

In the present study, the potential beneficial effects of MSCs were investigated in a high fat diet (HFD)-induced NAFLD model, including further examination of whether MSCs induced immunosuppression. A mouse model of NAFLD was established through treatment with a TROPHIC (T)/HFD (20). Isolation and culture of murine MSCs from compact bone were acquired using modified previously-described procedures (19,21). The results of the present study demonstrated that NASH induced by a HFD was ameliorated by treatment with MSCs, as indicated by a decrease in obesity, the expansion of subcutaneous adipose tissue, hepatic lipid accumulation, liver inflammation and fibrosis. MSC-mediated immunomodulation resulted from a decrease in cluster of differentiation (CD)4+ T lymphocytes in the spleen.

Materials and methods

Animals and diet

A total of 18 of male C57BL/6 mice, aged 6–8 weeks, weighing 16–18 g, were purchased from the Academy of Military Medical Science (Beijing, China) and were housed in a pathogen-free room, with a 12 h light/dark cycle at 20–25°C. They were maintained on a normal diet or HFD obtained from TROPHIC Animal Feed High-Tech Co., Ltd. (Nantong, Jiangsu, China). The food compositions of the two dietary groups are presented in Table I. The total energy and cholesterol content in the two dietary groups are presented in Table II. The total protein, carbohydrate and total fat content within the total energy in the two dietary groups are presented in Table III. The mice were randomized into two groups: i) Normal mice; and ii) T/HFD mice. A total of 21 weeks subsequently, the T/HFD mice were randomized into two groups: i) T/HFD mice; and ii) T/HFD+MSC mice, which were intravenously injected twice with 1×106 MSCs/mouse, at 21 and 23 weeks. A total of 21 weeks subsequently, the diets of the T/HFD and T/HFD+MSC mice were replaced with a normal diet. A total of 28 weeks subsequently, all of the animals were sacrificed and tissues were harvested. Mice were weighed weekly. The present study was approved by the Animal Ethics Committee of Tianjin Medical University (Tianjin, China).

Table I.

Food composition in the two dietary groups.

Table I.

Food composition in the two dietary groups.

Mass, g

ComponentNormal dietHigh-fat diet
Casein193.000262.000
Corn starch296.5000.000
Maltodextrin33.000161.000
Sucrose332.00089.000
Soybean oil24.00032.000
Lard19.000317.000
Cellulose47.00065.000
Mineral mix43.00058.000
Vitamin mix9.50013.000
L-cysteine3.0004.000
Choline bitartrate3.0003.000
TBHQ0.0080.069
Total1,000.0001,000.000

[i] TBHQ, tertiary butylhydroquinone.

Table II.

Total energy and cholesterol content in the two dietary groups.

Table II.

Total energy and cholesterol content in the two dietary groups.

Diet

ComponentNormal dietHigh-fat diet
Total energy, kcal/g   3.8   5.2
Total cholesterol, mg/kg40.8228.0

Table III.

Total Protein, carbohydrate and fat content within the total energy in the two dietary groups.

Table III.

Total Protein, carbohydrate and fat content within the total energy in the two dietary groups.

Diet

ComponentNormal dietHigh fat diet
Total protein, %1818
Total carbohydrate, %7222
Total fat, %1060
Isolation and culture of bone-derived MSCs

MSCs obtained from murine compact bone were isolated and culture-expanded as described previously (19,21). Femurs and tibiae were collected from a total of 3 2–3-week-old female C57BL/6 mice (weighing 6–10 g) and were purchased from the Academy of Military Medical Science, Beijing, China. They were housed in a pathogen-free room, with a 12 h light/dark cycle at 20–25°C. Bone marrow was flushed with PBS or α-modified minimal essential medium (α-MEM) (Gibco; Thermo Fisher Scientific, Inc., Waltham, MA, USA) using a syringe. The compact bones were excised into chips of ~1 mm into plastic culture dishes, and washed with PBS or α-MEM until the released cells were removed. The cells were incubated in α-MEM containing 10% select fetal bovine serum (Gibco; Thermo Fisher Scientific, Inc.) at 37°C, in an atmosphere containing 5% CO2. The medium was replaced every 4–5 days. Adherent cells (passage 0) were confluent following 1–2 weeks of incubation and were harvested using a cell scraper. The cells were passaged by digestion with 0.25% trypsin-EDTA (Gibco; Thermo Fisher Scientific, Inc.). Subsequent to 5–8 passages, the cells were used for further experiments.

Examination of immunophenotypic features of MSCs

The prepared MSCs, as described above, were harvested by digestion with trypsin, and stained for 30 min at 4°C with fluorescein isothiocyanate-conjugated anti-mouse CD11b, CD45, CD105 and ataxin-1 (Sca-1) antibodies, or phycoerythrin-conjugated anti-mouse CD29, CD44 and CD135 antibodies (all eBioscience, Inc.; Thermo Fisher Scientific, Inc.). Cells were analyzed using a FACSCalibur instrument using a laser at a wavelength of 488 nm (BD Biosciences, Franklin Lakes, NJ, USA). Flow cytometric data were analyzed using Flow Jo software (version 7.6; Tree Star, Inc., Ashland, OR, USA).

Histological analysis of livers

Livers were perfused with PBS, removed, weighed and sliced into 0.5×0.5 cm sections. The sections were embedded in paraffin subsequent to being fixed in 4% (w/v) paraformaldehyde and were cut into 6-µm-thick sections. The paraffin sections were stained with 0.5 % w/v hematoxylin for 5 min and 1% w/v eosin for 10 sec (HE) at room temperature to assess inflammation and steatosis, and picrosirius red to assess fibrosis. Evaluation of the extent of resultant NASH (3) was performed using the following scaling scores.

Steatosis

Hepatocytes containing fat vacuoles were subjectively visualized and graded according to the following scale: 0, Normal, no hepatocytes affected; 1, minor, <5% of hepatocytes affected; 2, mild, 5–33% of hepatocytes affected; 3, moderate, 34–66% of hepatocytes affected; and 4, severe, >66% of hepatocytes affected.

Lobular inflammation

Grading of lobular inflammation was performed as follows: 0, None; 1, 1–2 foci/x20 field; 2, 2–4 foci/x20 field; and 3, >4 foci/x20 field.

Stages of NASH

Staging of NASH was performed as follows: 0, None; 1, extensive zone 3 perisinusoidal fibrosis; 2, zone 3 perisinusoidal, and portal or periportal fibrosis; 3, bridging fibrosis; and 4, cirrhosis.

Analysis of spleen leukocytes

Single-cell suspensions derived from spleens were prepared by mechanical disruption and filtered through a 40-µm cell strainer (BD Biosciences). The cells were placed in H2O 30–50s, soon later added with 1/10 volume 10× PBS, and red blood cells were removed with cytolysis. The cells were stimulated with 50 ng/ml phorbol 12-myristate 13-acetate, 1 µg/ml ionomycin (Enzo Life Sciences, Inc., Farmingdale, NY, USA) and 3 µg/ml brefeldin A (eBioscience, Inc.; Thermo Fisher Scientific, Inc.) for 5 h. The cells were subsequently stained for surface markers using rat anti-mouse CD4-allophycocyanin (catalog no. 17-0042-81, eBioscience, Inc., San Diego, CA, USA) for 30 min at 4°C. The cells were analyzed using the 488 nm laser of a FACSCalibur instrument and the data generated were analyzed using FlowJo software version 7.6.1 (Tree Star Inc., Ashland, OR, USA).

Statistical analysis

GraphPad PRISM software (version 5.0; GraphPad Software, Inc., La Jolla, CA, USA) was used to perform a Student's t test Results are presented as the mean ± standard deviation. P<0.05 was considered to indicate a statistically significant difference.

Results

Cells isolated from compact bone were characterized as MSCs

According to modified previously-described procedures (19), mMSCs were isolated from compact bone (from 2–3-week-old female C57BL/6 mice) and cultured. The MSCs appeared to be vortex-shaped and fibroblast-like, although not polygon-shaped (osteocytes) (Fig. 1A). In order to further identify the adherent cells, immunophenotypic features were analyzed. As presented in Fig. 1B, negative surface markers of MSCs, including CD11b, CD45 and CD135, were not expressed; however, the cells expressed surface markers characteristic of MSCs, including CD29, CD44, CD105 and Sca-1. The results of the present study indicated that these cells were MSCs.

Treatment with MSCs reverses HFD-induced weight gain and expansion of subcutaneous adipose tissue

In order to investigate the beneficial effects of MSCs on NAFLD, a mouse model of NAFLD was established using HFD, and the mice were intravenously-injected twice with 1×106 MSCs/mouse at weeks 21 and 23 (Fig. 2A). A marked difference was observed between T/HFD and T/HFD+MSC mice at 28 weeks post-treatment (Fig. 2B). Compared with normal control mice, the T/HFD-fed mice exhibited an accelerated elevation of body weight between 1 and 21 weeks (Fig. 2C). Following the two intravenous injections of MSCs, the weight of the T/HFD-fed mice decreased markedly at 21–28 weeks (Fig. 2C).

Weight gain is often accompanied by the expansion of subcutaneous adipose tissue. The results of the present study demonstrated that the mass of subcutaneous abdominal adipose tissue increased in the T/HFD-fed mice, an effect which was reversed by the MSC treatment (Fig. 3).

Treatment with MSCs decreases HFD-induced steatosis and lobular inflammation

NFLD may progress via hepatic lipid accumulation to NAS, and via lobular inflammation to NASH (3). Hepatocytes containing fat vacuoles may be visualized as clear bubbles following liver section HE staining. As presented in Fig. 4, hepatic lipid accumulation indicated by clear bubbles occurred in T/HFD-fed mice (Fig. 4A), while it was decreased in T/HFD+MSC mice (Fig. 4B). It was additionally observed that HFD-induced lobular inflammation was present within the THFD-fed mouse livers (Fig. 4A), which was suppressed in the T/HFD+MSC mice (Fig. 4B). As indicated by scores obtained from the methods described above, increases in steatosis (Fig. 4C) and lobular inflammation (Fig. 4D) induced by HFD were significantly decreased in response to MSC treatment.

Treatment with MSCs suppresses HFD-induced liver fibrogenesis

NAFLD frequently progresses to fibrosis (3). Therefore, the stages of fibrosis in the liver samples were assessed by staining with picrosirius red. Fibrogenesis was observed within the T/HFD-fed mouse livers (Fig. 5A), and a reduction of hepatic fibrogenesis occurred in the T/HFD+MSC mice (Fig. 5B). Significant differences in fibrosis stage scores were observed between the T/HFD and T/HFD+MSC mice (Fig. 5C).

The number of CD4+ T lymphocytes in the spleen is decreased by treatment with MSCs

MSCs are able to interact with innate and adaptive immune system cells, leading to the modulation of numerous effector functions (9). Analysis of splenic leukocytes was performed in order to explore the effect of MSCs on immunological responses. It was observed that, compared with T/HFD-fed mice, the number of CD4+ T lymphocytes in the spleen was decreased by treatment with MSCs in the T/HFD+MSC mice (Fig. 6).

Discussion

MSCs were originally isolated from bone marrow by Friedenstein et al (22) in 1976, and have subsequently been observed to exist in other organs and tissues (21). However, the bone marrow-derived method based on plastic adherence has proved unsuccessful for mMSCs, due to the low frequency of mMSCs and the contamination of hematopoietic cells in culture (23). In the present study, the compact bone-derived method established originally by Zhu et al (21) was used. MSCs that appeared vortex-shaped and fibroblast-like were successfully isolated, and were demonstrated to express putative surface markers of MSCs, including CD29, CD44, CD105 and Sca-1, which was consistent with a previous report (21).

MSCs exhibit potential clinical value in the treatment of liver disease. In a previous study, it was demonstrated that compact bone-derived MSCs improved gross and microscopic liver histopathology and prolonged the survival of mice with thioacetamide-induced FHF, in addition to suppressing CCl4-induced chronic liver fibrosis (19). In addition, it was demonstrated that treatment with MSCs partially ameliorated FHF, and markedly improved chronic liver fibrosis (19). In the present study, a model of NAFLD was established using T/HFD (20), in order to explore whether MSCs exhibit potential clinical value in NAFLD. It was observed that HFD-fed mice with MSC intervention exhibited a decrease in weight gain. Obesity is often accompanied by the expansion of subcutaneous adipose tissue (4), which was demonstrated to be reversed by treatment with MSCs in the present study. In addition, the steatosis and liver fibrosis in the present model of NAFLD were ameliorated by treatment with MSCs. The results of the present study suggested that MSCs may exhibit clinical value in NAFLD.

The immunomodulatory and immunosuppressive functions of MSCs are potentially involved in the beneficial effect of MSC transplantation, in chronic and acute liver disease (24). Recently, it was demonstrated that MSC therapy suppressed liver fibrosis by downregulating immune cell infiltration (19). In the present study, MSC intervention suppressed lobular inflammatory cell infiltration, indicated by HE staining, in the livers of T/HFD mice. The results of the present study demonstrated that the immunomodulatory and immunosuppressive functions of MSCs may serve a role in the beneficial effect of MSC transplantation observed in the present model of NAFLD.

The immunosuppressive effect of treatment with MSCs, inducing an anti-inflammatory state, has been demonstrated to be associated with an altered distribution of CD4+ T lymphocytes (19). Autologous and allogeneic bone marrow-derived MSCs have been demonstrated to dose-dependently and contact-independently reduce CD4+ T cell proliferation, induced by cellular or nonspecific mitogenic stimuli (25). The suppressive capacities of MSCs were further confirmed in preclinical studies, demonstrating that treatment with MSC is able to modulate pathogenic T cell responses (2628). In the present study, it was demonstrated that transplantation of compact bone-derived MSCs led to a suppression of CD4+ T cell proliferation in the spleens of T/HFD mice. It is hypothesized that the suppression of CD4+ T cells is one mechanism by which MSCs exert immunomodulatory and immunosuppressive functions.

In summary, compact bone-derived MSCs exhibit potential clinical value in a mouse model of NAFLD. MSC transplantation decreased weight gain and the expansion of subcutaneous adipose tissue, decreased HFD-induced steatosis and lobular inflammation, and suppressed liver fibrogenesis. MSCs exert beneficial effects in the mouse model of NAFLD via immunomodulation and immunosuppression, including the suppression of CD4+ T cells.

Acknowledgements

The present study was supported by the One College One Policy Project, Modern College of Arts and Science, Shanxi Normal University and the Scientific Research Foundation for Doctors, Shanxi Normal University (grant no. 0505/02070293).

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Wang H, Zhang H, Huang B, Miao G, Yan X, Gao G, Luo Y, Chen H, Chen W, Yang L, Yang L, et al: Mesenchymal stem cells reverse high‑fat diet‑induced non‑alcoholic fatty liver disease through suppression of CD4+ T lymphocytes in mice. Mol Med Rep 17: 3769-3774, 2018
APA
Wang, H., Zhang, H., Huang, B., Miao, G., Yan, X., Gao, G. ... Yang, L. (2018). Mesenchymal stem cells reverse high‑fat diet‑induced non‑alcoholic fatty liver disease through suppression of CD4+ T lymphocytes in mice. Molecular Medicine Reports, 17, 3769-3774. https://doi.org/10.3892/mmr.2017.8326
MLA
Wang, H., Zhang, H., Huang, B., Miao, G., Yan, X., Gao, G., Luo, Y., Chen, H., Chen, W., Yang, L."Mesenchymal stem cells reverse high‑fat diet‑induced non‑alcoholic fatty liver disease through suppression of CD4+ T lymphocytes in mice". Molecular Medicine Reports 17.3 (2018): 3769-3774.
Chicago
Wang, H., Zhang, H., Huang, B., Miao, G., Yan, X., Gao, G., Luo, Y., Chen, H., Chen, W., Yang, L."Mesenchymal stem cells reverse high‑fat diet‑induced non‑alcoholic fatty liver disease through suppression of CD4+ T lymphocytes in mice". Molecular Medicine Reports 17, no. 3 (2018): 3769-3774. https://doi.org/10.3892/mmr.2017.8326