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

Xinmei Kang,Shuai Dong,Yanli Li,Andy Peng Xiang,Qi Zhang,Lijie Pan,Xiaoyong Chen,Cong Du,Chang Liu,Yan Xu,Qiuli Liu

doi:10.1038/s41419-021-03524-y

Abstract

Liver 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.

Highlights

Abnormal immune responses and immune cell infiltration, elicited by various liver injuries, can destroy the immune privileged state of the liver and result in liver inflammation[1]
We examined our RNA sequencing data and found that peroxisome proliferator-activated receptor δ (PPARδ) was upregulated in T cells cultured alone (T cells) co-cultured with MSCshNTC compared to activated T cells but was decreased in T cells cocultured with MSCshCHI3L1 (Fig. 6G), which is in contrast to the phosphorylated STAT1/3 levels
We identified Chitinase-3-like protein 1 (CHI3L1) as a novel mediator of the immunosuppressive effects of hUCMSCs and the therapeutic effect of hUC-mesenchymal stem cells (MSCs) on Con Ainduced liver injury in mice

Summary

Introduction

Abnormal immune responses and immune cell infiltration, elicited by various liver injuries (such as viral or parasite infection, drug toxicity, alcohol abuse and metabolic diseases), can destroy the immune privileged state of the liver and result in liver inflammation[1]. Decreasing CHI3L1 expression attenuated the ability of hUC-MSCs to inhibit CD3+ T cell activation and proliferation and suppress the production of tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) in vitro and in vivo. Administration of recombinant CHI3L1 (rCHI3L1) was sufficient to inhibit T cell proliferation and function in vitro and alleviate Con Ainduced liver injury in vivo. The immunosuppressive effect of hUC-MSC-derived CHI3L1 was dependent on the upregulation of PPARδ and subsequent inhibition of STAT1/3 phosphorylation in T cells. We demonstrated that CHI3L1 is a novel secreted factor that mediates the immunosuppressive effects of hUCMSCs and provided new insights into promising therapeutics for refractory liver diseases

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Results

Conclusion