Mesenchymal Stem Cells-Derived Exosomes as Dexamethasone Delivery Vehicles for Autoimmune Hepatitis Therapy

Exosomes (Exos) are nanosized vesicles (around 100 nm) that recently serve as a promising drug carrier with high biocompatibility and low immunogenicity. Previous studies showed that Exos secreted from mesenchymal stem cells (MSCs) provide protection for concanavalin A (Con A)-induced liver injury. In this study, the protective effect of Exos is confirmed, and dexamethasone (DEX)-incorporated Exos named Exo@DEX are prepared. It is then investigated whether Exo@DEX can function more efficiently compared to free drugs and naive Exos in a Con A-induced autoimmune hepatitis (AIH) mouse model. The results show that Exo@DEX efficiently improves the accumulation of DEX in AIH in the liver. These data suggest that Exo@DEX is a promising drug carrier for AIH and could have applications in other diseases.

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Mesenchymal stem cells alleviate experimental immune-mediated liver injury via chitinase 3-like protein 1-mediated T cell suppression

Cell Death and Disease ◽

10.1038/s41419-021-03524-y ◽

2021 ◽

Vol 12 (3) ◽

Author(s):

Qiuli Liu ◽

Xiaoyong Chen ◽

Chang Liu ◽

Lijie Pan ◽

Xinmei Kang ◽

...

Keyword(s):

Stem Cells ◽

T Cells ◽

Mesenchymal Stem Cells ◽

T Cell ◽

Liver Injury ◽

T Cell Activation ◽

Gene Set Enrichment Analysis ◽

Human Umbilical Cord ◽

Con A ◽

Immune Mediated

AbstractLiver diseases with different pathogenesis share common pathways of immune-mediated injury. Chitinase-3-like protein 1 (CHI3L1) was induced in both acute and chronic liver injuries, and recent studies reported that it possesses an immunosuppressive ability. CHI3L1 was also expressed in mesenchymal stem cells (MSCs), thus we investigates the role of CHI3L1 in MSC-based therapy for immune-mediated liver injury here. We found that CHI3L1 was highly expressed in human umbilical cord MSCs (hUC-MSCs). Downregulating CHI3L1 mitigated the ability of hUC-MSCs to inhibit T cell activation, proliferation and inflammatory cytokine secretion in vitro. Using Concanavalin A (Con A)-induced liver injury mouse model, we found that silencing CHI3L1 significantly abrogated the hUC-MSCs-mediated alleviation of liver injury, accompanying by weakened suppressive effects on infiltration and activation of hepatic T cells, and secretion of pro-inflammatory cytokines. In addition, recombinant CHI3L1 (rCHI3L1) administration inhibited the proliferation and function of activated T cells, and alleviated the Con A-induced liver injury in mice. Mechanistically, gene set enrichment analysis showed that JAK/STAT signalling pathway was one of the most significantly enriched gene pathways in T cells co-cultured with hUC-MSCs with CHI3L1 knockdown, and further study revealed that CHI3L1 secreted by hUC-MSCs inhibited the STAT1/3 signalling in T cells by upregulating peroxisome proliferator-activated receptor δ (PPARδ). Collectively, our data showed that CHI3L1 was a novel MSC-secreted immunosuppressive factor and provided new insights into therapeutic treatment of immune-mediated liver injury.

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The Protective Effect of Sheep Placental Extract on Concanavalin A-induced Liver Injury in Mice

Molecules ◽

10.3390/molecules24010028 ◽

2018 ◽

Vol 24 (1) ◽

pp. 28 ◽

Cited By ~ 3

Author(s):

Jingwen Liu ◽

Suting Luo ◽

Jun Yang ◽

Fazheng Ren ◽

Yu Zhao ◽

...

Keyword(s):

Nitric Oxide ◽

Amino Acids ◽

Liver Injury ◽

Protective Effect ◽

Concanavalin A ◽

B Cell Lymphoma ◽

Therapeutic Effects ◽

Model Group ◽

Con A ◽

Placental Extract

Though the biological effects of human placental extract have been widely studied, it has limited availability and its use poses ethical problems. Thus, domestic animal placental extracts are suggested as alternatives. In this study, the protective effect of sheep placental extract (SPE) on concanavalin A (Con A)-induced liver injury was investigated. BALB/c mice were randomly divided into six groups, including one normal group and five experimental groups, which received different oral doses of SPE (0, 5, 10 and 50 mg/kg) or a mixture of amino acids for 3 days before Con A injection. Compared with Con A-induced model group, the SPE administration significantly decreased serum aminotransaminase activity, alleviated pathological changes, recovered liver antioxidant capacity and prevented the increase of nitric oxide. Secretion of pro-inflammatory cytokines in serum decreased and mRNA expression of hepatic intercellular adhesion molecule-1, interferon-inducible chemokine 10 and inducible nitric oxide synthase were downregulated, while B-cell lymphoma-2 expression increased. The administration of amino acids mixture had no significant effect in most measurements compared with the model group, which indicated proteins and peptides, rather than individual amino acid, were largely responsible for the bioactivity of SPE. The results indicate SPE has potential therapeutic effects against immune-mediated hepatitis.

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Human placental mesenchymal stem cells ameliorate chemotherapy-induced damage in the testis by reducing apoptosis/oxidative stress and promoting autophagy

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02275-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jiafeng Lu ◽

Zhenxing Liu ◽

Mingkai Shu ◽

Liya Zhang ◽

Wenjuan Xia ◽

...

Keyword(s):

Oxidative Stress ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Mouse Model ◽

Protective Effect ◽

Sertoli Cells ◽

Male Reproduction ◽

Testosterone Levels ◽

Placental Mesenchymal Stem Cells

Abstract Background The side effects of busulfan on male reproduction are serious, so fertility preservation in children undergoing busulfan treatment is a major worldwide concern. Human placental mesenchymal stem cells (hPMSCs) have advantages such as stable proliferation and lower immunogenicity that make them an ideal material for stimulating tissue repair, especially restoring spermatogenesis. The protective effects of hPMSCs in busulfan-induced Sertoli cells and in busulfan-treated mouse testes have not been determined. Our study aimed to elaborate the protective effect and potential mechanisms of hPMSCs in busulfan-treated testes and Sertoli cells. Methods First, we developed a mouse model of busulfan-induced testicular toxicity in vivo and a mouse Sertoli cell line treated with busulfan in vitro to assess the protective effect and mechanisms of hPMSC treatment on spermatogenesis. Then, the length, width, and weight of the testes were monitored using Vernier calipers. Furthermore, at 1 week and 4 weeks after the transplantation of hPMSCs, histological sections of testes were stained with hematoxylin-eosin, and the seminiferous tubules with fluid-filled cavities were counted. Through ELISA analysis, testosterone levels and MDA, SOD, LDH, and CAT activities, which are associated with ROS, were detected. Markers of ROS, proliferation (Ki67), and apoptosis (Annexin V) were evaluated by FACS. Next, the fluorescence intensity of proliferation markers (BrdU and SCP3), an antioxidant marker (SIRT1), a spermatogenesis marker (PLZF), and autophagy-related genes (P62 and LC3AB) were detected by fluorescence microscopy. The mRNA expression of γ-H2AX, BRCA1, PARP1, PCNA, Ki67, P62, and LC3 was determined by qRT-PCR. Results hPMSCs restored disrupted spermatogenesis, promoted improved semen parameters, and increased testosterone levels, testis size, and autophagy in the testis toxicity mouse model induced by busulfan. hPMSCs suppressed the apoptosis of Sertoli cells and enhanced their rate of proliferation in vitro. Additionally, hPMSCs protected against oxidative stress and decreased oxidative damage in the testis toxicity mouse model induced by busulfan. Furthermore, hPMSCs increased the expression of proliferation genes (PCNA and KI67) and decreased the mRNA levels of apoptotic genes such as γ-H2AX, BRCA1, and PARP1. Conclusions This research showed that hPMSC injection ameliorated busulfan-induced damage in the testis by reducing apoptosis/oxidative stress and promoting autophagy. The present study offers an idea for a new method for clinical treatment of chemotherapy-induced spermatogenesis.

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A Mouse Model of Liver Injury to Evaluate Paracrine and Endocrine Effects of Bone Marrow Mesenchymal Stem Cells

Methods in Molecular Biology - Animal Models for Stem Cell Therapy ◽

10.1007/978-1-4939-1453-1_7 ◽

2014 ◽

pp. 69-79 ◽

Cited By ~ 5

Author(s):

Chiung-Kuei Huang ◽

Soo Ok Lee ◽

Jie Luo ◽

RongHao Wang ◽

Qiang Dang ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Liver Injury ◽

Mouse Model ◽

Endocrine Effects ◽

Marrow Mesenchymal Stem Cells

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Osteoinductive activity of bisdemethoxycurcumin and its synergistic protective effect with human amniotic mesenchymal stem cells against ovariectomy-induced osteoporosis mouse model

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2021.112605 ◽

2022 ◽

Vol 146 ◽

pp. 112605

Author(s):

Jin-Xing Wei ◽

Yi Luo ◽

Yan Xu ◽

Jian-Hui Xiao

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Mouse Model ◽

Protective Effect ◽

Amniotic Mesenchymal Stem Cells

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SHED ameliorated concanavalin A-induced autoimmune hepatitis by protecting hepatocytes from apoptosis

10.21203/rs.3.rs-17847/v1 ◽

2020 ◽

Author(s):

Yikun Zhou ◽

Ruili Yang ◽

Lingsu Zhu ◽

Huaming Huang ◽

Shengjie Cui ◽

...

Keyword(s):

Liver Injury ◽

Autoimmune Hepatitis ◽

Concanavalin A ◽

Acute Liver Injury ◽

Deciduous Teeth ◽

Protective Effects ◽

Hepatocyte Apoptosis ◽

Con A ◽

Tnf Α ◽

Ifn Γ

Abstract Background：Autoimmune hepatitis (AIH) is serious autoimmune liver diseases that threaten people’s health worldwide, emphasizing the need to identify novel treatment. Stem cells from human exfoliated deciduous teeth (SHED), which is easy to obtain and non-invasive, showed pronounced proliferation and immunomodulation capacity. This study aims to investigate the effect of SHED on ConA-induced AIH and the potential underlying mechanisms.Methods: We used a concanavalin A (ConA) induced acute hepatitis mouse model and in vitro co-culture system to study the protective effects of SHED on ConA-induced autoimmune hepatitis and the underlying mechanisms.Results: SHED infusion could prevent aberrant histopathological architecture of liver with infiltration of abundant of CD3+, CD4+, TNF-α+ and IFN-γ+ inflammatory cells induced by ConA. The expression of ALT and AST which indicated the liver function significantly elevated in hepatitis mice. While SHED infusion could block the elevation of ALT and AST induced by ConA. Mechanistically, Con-A upregulated TNF-α and IFN-γ expression activated NF-κB pathways to induced hepatocyte apoptosis, resulting in acute liver injury. SHED administration protected hepatocytes from Con-A-induced apoptosis. Conclusions: These results demonstrated that SHED alleviated ConA-induced acute liver injury via inhibition of hepatocyte apoptosis mediated by the NF-κB pathways. Our findings could provide a potential prevention and therapeutic strategy for hepatitis and acute hepatic injury.

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