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Table 1 Role of MSCs, MSC gene modifications, and exosomes in experimental autoimmune hepatitis studies

From: Stem cell therapies for autoimmune hepatitis

  Disease modeling  Groups MSCs Sacrifice  Animal strain Efficacy outcome Mechanism Ref.
SC source   Number of cells/dose of exosome Route of inj Time of inj of stem/exosome
MSC IP injection of the S100/adjuvant for EAH model induction. 1, Control group BM-MSCs   IV   On day 42 C57BL/6 mice BMSCs could reduce EAH in a dose-dependent way.
The therapeutic efficacy of MSCs given three times was superior to that of MSCs provided once.
MSCs stimulate PD-L1 and by turn inhibit the pro-inflammatory interleukin 17. [46]
2. Model group
3. Drug-treated group (prednisolone and azathioprine)
4. Once MSC-treated group   1 × 105 On day 21
5. Double MSC-treated group   1 × 105 On days 21 and 28
6. Triple MSC-treated group   1 × 105 On days 21, 28, and 35
MSC gene modifications IV injection with Con A (15 mg/Kg body weight) 1, IL-35-MSCs
2, MSCs
3, PBS
AD-MSC   IV Stem cells injected 2 h before Con A inj   C57BL/6J mice Both IL-35-MSCs and MSCs have a protective effect in the Con A-induced fulminant hepatitis, but IL-35-MSCs exerted stronger therapeutic effects than MSCs. - MSCs could alleviate the hepatic injury by reducing the IL-17 secretion of liver MNCs, but not IFN-γ.
- IL-35-MSCs could exert stronger protection through regulating the secretion of both IL-17 and IFN-γ, which might be the results of combined action.
- IL-35-MSCs prevented the hepatocytes apoptosis by decreasing the FasL expression by MNC and decreased the IFN-γ expression level through the JAK1-STAT1/STAT4 signal pathway.
Exosome IP injection of the S100/adjuvant for EAH model induction 1. Control group
2. Model group
3. BMSC-exo-treated group
4. BMSC-exomiR-223(+)-treated group
5. BMSC-exomiR-223(-)
BM-MSCs exosomes - - On days 21, 28, and 35 On day 21, 28, and 35 C57BL/6 mice In mice and hepatocytes, both groups 3 and 4 effectively reversed S100 or LPS/ATP-induced damage meaning that BMSC-derived exosomes can protect the liver in EAH. The exosomal miR-223 suppressed the NLRP3 activation by binding to its 3′-UTR, resulting in NLRP3 mRNA degradation hence a reduction in liver inflammation and cell death. [48]
AML12 (mouse hepatocytes) is a cell line derived from hepatocytes from a male mouse. LPS/ATP-treated AML12 cells were incubated with the following:
1. Control medium
2. BMSC-exo (20 μg/ml)
3. BMSC-exomiR-223(+) (20 μg/ml)
4. BMSC-exomiR-223(-) (20 μg/ml)
- In vivo
A model of EAH was established by IP injection of the S100/adjuvant.
- In vitro
Macrophage RAW264.7 cells
1. Model
2. Prednisolone and azathioprin
3. MSC-exosomes
4. MSC-exosomesmiR-223-3p
5. MSC-exosomesmiR-223-3p(i)
BM-MSCs exosome 2 μg/g body weight in 200 μl of PBS per animal IV On days 21 and 35 On day 42 C57BL/6 mice Liver of EAH as well as macrophage show reduction in cytokine production in response to exosomes or exosomesmiR-223-3p, beside reduction in hepatic inflammation of EAH miR-223-3p downregulate the expression of the inflammatory gene STAT3 which is considered to be a major upstream activator of interleukin 1β and 6. Also, miR-223-3p causes elevation of the Treg/Th17 ratio. Furthermore, in macrophages, miR-223-3p inhibits the production of IL-6 and IL-1 produced by LPS. [49]
  1. EAH experimental autoimmune hepatitis, inj injection, IV intravenous, IP intraperitoneal, BM-MSCs bone marrow mesenchymal stem cells, PD-L1 the ligand of PD-1 “Programmed death-1”, PBS phosphate buffer saline, AD-MSCs adipose-derived mesenchymal stem cells, MNC mononuclear cells, Con A concanavalin A, FASL Fas ligand, IFN-γ interferon-gamma, IL interleukin, JAK Janus kinase, STAT signal transducer and activator of transcription), LPS (Lipopolsaccharide), 3′-UTR (untranslated region ), MSC-exosomesmiR-223-3p(i) (MSC-exosomes with miR-223-3p knockdown), Treg (Regulatory T cells), Th17(T helper 17 cells).