Human menstrual blood-derived stem cells alleviate autoimmune hepatitis via JNK/MAPK signaling pathway <i>in vivo</i> and <i>in vitro</i>

doi:10.1007/s11684-022-0953-y

Front. Med.

2023, Vol. 17

Issue (3) : 534-548 https://doi.org/10.1007/s11684-022-0953-y

RESEARCH ARTICLE

Human menstrual blood-derived stem cells alleviate autoimmune hepatitis via JNK/MAPK signaling pathway in vivo and in vitro

Fen Zhang¹, Lanlan Xiao¹, Ya Yang¹, Menghao Zhou¹, Yalei Zhao^1,², Zhongyang Xie¹, Xiaoxi Ouyang¹, Feiyang Ji³, Shima Tang¹, Lanjuan Li¹(

)

¹. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
². Department of Infectious Diseases, First Affiliated Teaching Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an 710049, China
³. Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Zhejiang, Hangzhou 310016, China

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Abstract

Autoimmune hepatitis (AIH) is a severe globally distributed liver disease that could occur at any age. Human menstrual blood-derived stem cells (MenSCs) have shown therapeutic effect in acute lung injury and liver failure. However, their role in the curative effect of AIH remains unclear. Here, a classic AIH mouse model was constructed through intravenous injection with concanavalin A (Con A). MenSCs were intravenously injected while Con A injection in the treatment groups. The results showed that the mortality by Con A injection was significantly decreased by MenSCs treatment and liver function tests and histological analysis were also ameliorated. The results of phosphoproteomic analysis and RNA-seq revealed that MenSCs improved AIH, mainly by apoptosis and c-Jun N-terminal kinase/mitogen-activated protein signaling pathways. Apoptosis analysis demonstrated that the protein expression of cleaved caspase 3 was increased by Con A injection and reduced by MenSCs transplantation, consistent with the TUNEL staining results. An AML12 co-culture system and JNK inhibitor (SP600125) were used to verify the JNK/MAPK and apoptosis signaling pathways. These findings suggested that MenSCs could be a promising strategy for AIH.

Keywords autoimmune hepatitis (AIH) concanavalin A (Con A) human menstrual blood-derived stem cells (MenSCs) apoptosis mitogen-activated protein kinase (MAPK)

Corresponding Author(s): Lanjuan Li

Just Accepted Date: 20 February 2023 Online First Date: 07 April 2023 Issue Date: 28 July 2023

Cite this article:

Fen Zhang,Lanlan Xiao,Ya Yang, et al. Human menstrual blood-derived stem cells alleviate autoimmune hepatitis via JNK/MAPK signaling pathway in vivo and in vitro[J]. Front. Med., 2023, 17(3): 534-548.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-022-0953-y
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I3/534

Fig.1 Established Con A-induced AIH mouse model. (A) H&E staining. (B) Histological activity index (HAI) of 15 mg/kg Con A and 20 mg/kg Con A (n = 3 per group, **P < 0.01). (C and D) Serum ALT and AST levels of NC and Con A groups at different timepoints (n = 7 per NC group, Con A group at 6, 12, and 24 h; n = 4 per Con A group at 48, 72, and 96 h). (E) H&E staining of Con A group at 6, 12, 24, 48, 72, and 96 h (scale bar, 250 μm or 50 μm; the black circle indicated dead hepatocytes; the green arrows indicated immune cells). Data are represented as mean ± SD.

Fig.2 Amelioration of Con A-induced hepatitis by MenSCs transplantation. (A) Survival rate of Con A (20 mg/kg) group compared with that of Con A + MenSCs (20 mg/kg) and NC + MenSCs groups (n = 12 per group, **P < 0.01). (B) Representative images of liver sections stained with H&E. (C) HAI at different timepoints (n = 5 per group; scale bar, 250 μm or 50 μm). (D and E) Serum ALT and AST levels of Con A and Con A + MenSCs groups at three timepoints (n = 7 per group, Con A group vs. Con A + MenSCs group, *P < 0.05 and **P < 0.01). Data are represented as mean ± SD.

Fig.3 Quantitative profiling of phosphoproteomic among NC, Con A, and Con A + MenSCs groups at 12 h. (A) Principal component analysis of phosphoproteome. (B) Number of sites and proteins identified in phosphoproteome. (C) Interaction network of 57 proteins. (D–G) Bubble diagram representing the top 10 enriched KEGG, BP, MF, and CC pathways in the phosphoproteome among the three groups, respectively. (H) Number of differentially expressed proteins and sites in different groups. (I) Venn diagram of phosphorylation sites and seven overlap sites (n = 3 per NC and Con A + MenSCs groups; n = 4 per Con A group).

Fig.4 Functional analysis of RNA-seq among NC, Con A, and Con A + MenSCs groups at 12 h. (A and B) Volcano plot and KEGG analysis between Con A and NC groups at 12 h. (C and D) Volcano plot and KEGG analysis between Con A and Con A + MenSCs groups at 12 h (n = 3 per group).

Fig.5 Reduction in Con A-induced hepatitis by MenSCs transplantation through apoptosis signaling pathway. (A and B) TUNEL staining of NC, Con A, and Con A + MenSCs groups at 12 h (n = 5 per group, ** P < 0.01). (C–H) Western blot analysis of caspase 3, cleaved-caspase 3, Bad, Bcl-xL, caspase 8, cleaved-caspase 8, PARP, cleaved PARP, and GAPDH protein expression levels in the NC, Con A, and Con A + MenSCs groups at 12 h (n = 4 per group; *P < 0.05 and **P < 0.01). Data are represented as mean ± SD.

Fig.6 Improvement in Con A-induced apoptosis by MenSCs transplantation through inhibiting the JNK/MAPK pathway. (A–F) Western blot analysis of AKT, p-AKT, JNK, p-JNK, p-c-Jun ser73, p-c-Jun ser63, Fas, and GAPDH protein expression levels in the NC, Con A, and Con A + MenSCs groups at 12 h (n = 4 per group; *P < 0.05 and **P < 0.01). Data are represented as mean ± SD.

Fig.7 AML12 cell coculture system validation of MenSCs’ curative effect in Con A model. (A) Flowchart of coculture system. (B–E) Apoptosis of AML12 cells in the NC, Con A, and Con A + MenSCs groups as detected by flow cytometry (early apoptosis, Annexin V positive; end-stage apoptosis and death, Annexin V and PI positive, n = 4 per group). (F and G) Cellular supernatant ALT and AST levels of AML12 cells in the NC group, Con A, and Con A + MenSCs groups (n = 4 per group). (H–L) Western blot analysis of JNK, p-JNK, caspase 3, cleaved caspase 3, p-c-Jun ser73, p-c-Jun ser63, and GAPDH. G and H, Relative protein levels of p-JNK and cleaved caspase 3 (n = 3 per group). *P < 0.05 and **P < 0.01. Data are represented as mean ± SD.

Fig.8 SP600125 inhibition of Con A-activated JNK/MAPK signaling pathway. (A) Representative images of liver sections stained with H&E. (B) HAI in the NC, Con A and Con A + SP groups (scale bars, 250 or 50 μm). (C and D) Serum ALT and AST levels of AML12 cells in the NC, Con A, and Con A + MenSCs groups. (E–I) Western blot analysis of JNK, p-JNK, p-c-Jun ser63, p-c-Jun ser73, caspase 3, cleaved caspase 3, and GAPDH protein expression levels in the NC, Con A, and Con A + SP groups. (J–L) FasL, IL-6, and TNF-α mRNA levels in the NC, Con A, and Con A + SP groups. (M and N) Serum IL-6 and TNF-α concentrations in the NC, Con A, and Con A + SP groups (n = 3 per group, *P < 0.05 and **P < 0.01). Data are represented as mean ± SD.

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