Table 1 Role of MSCs, MSC gene modifications, and exosomes in experimental autoimmune hepatitis studies
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. | [47] | ||
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] | |