Adipose-derived mesenchymal stem cells alleviate TNBS-induced colitis in rats by influencing intestinal epithelial cell regeneration, Wnt signaling, and T cell immunity

Jian-Guo Gao; Mo-Sang Yu; Meng-Meng Zhang; Xue-Wei Gu; Yue Ren; Xin-Xin Zhou; Dong Chen; Tian-Lian Yan; You-Ming Li; Xi Jin

doi:10.3748/wjg.v26.i26.3750

Adipose-derived mesenchymal stem cells alleviate TNBS-induced colitis in rats by influencing intestinal epithelial cell regeneration, Wnt signaling, and T cell immunity

World J Gastroenterol. 2020 Jul 14;26(26):3750-3766. doi: 10.3748/wjg.v26.i26.3750.

Authors

Affiliations

¹ Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China.
² Department of Colorectal Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China.
³ Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China. [email protected].

Abstract

Background: Conventional Crohn's disease (CD) treatments are supportive rather than curative and have serious side effects. Adipose-derived mesenchymal stem cells (ADSCs) have been gradually applied to treat various diseases. The therapeutic effect and underlying mechanism of ADSCs on CD are still not clear.

Aim: To investigate the effect of ADSC administration on CD and explore the potential mechanisms.

Methods: Wistar rats were administered with 2,4,6-trinitrobenzene sulfonic acid (TNBS) to establish a rat model of CD, followed by tail injections of green fluorescent protein (GFP)-modified ADSCs. Flow cytometry, qRT-PCR, and Western blot were used to detect changes in the Wnt signaling pathway, T cell subtypes, and their related cytokines.

Results: The isolated cells showed the characteristics of ADSCs, including spindle-shaped morphology, high expression of CD29, CD44, and CD90, low expression of CD34 and CD45, and osteogenic/adipogenic ability. ADSC therapy markedly reduced disease activity index and ameliorated colitis severity in the TNBS-induced rat model of CD. Furthermore, serum anti-sacchromyces cerevisiae antibody and p-anti-neutrophil cytoplasmic antibody levels were significantly reduced in ADSC-treated rats. Mechanistically, the GFP-ADSCs were colocalized with intestinal epithelial cells (IECs) in the CD rat model. GFP-ADSC delivery significantly antagonized TNBS-induced increased canonical Wnt pathway expression, decreased noncanonical Wnt signaling pathway expression, and increased apoptosis rates and protein level of cleaved caspase-3 in rats. In addition, ADSCs attenuated TNBS-induced abnormal inflammatory cytokine production, disturbed T cell subtypes, and their related markers in rats.

Conclusion: Successfully isolated ADSCs show therapeutic effects in CD by regulating IEC proliferation, the Wnt signaling pathway, and T cell immunity.

Keywords: Adipose-derived mesenchymal stem cell; Crohn’s disease; Inflammation; Intestinal epithelial cell; T cell; Wnt pathway.

MeSH terms

Adipose Tissue*
Animals
Colitis* / chemically induced
Colitis* / therapy
Epithelial Cells
Mesenchymal Stem Cell Transplantation
Mesenchymal Stem Cells*
Rats
Rats, Wistar
Regeneration
T-Lymphocytes
Trinitrobenzenesulfonic Acid / toxicity
Wnt Signaling Pathway

Substances

Trinitrobenzenesulfonic Acid