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Human endoderm stem cells reverse inflammation-related acute liver failure through cystatin SN-mediated inhibition of interferon signaling

Yilin Xu^1,† , Jinglin Wang^2,3,† , Haozhen Ren^2,3,† , Hao Dai^1,4,† , Ying Zhou¹ , Xiongzhao Ren¹ , Yang Wang⁵ , Sisi Feng¹ , Xiaogang Deng¹ , Jiaying Wu¹ , Tianlong Fu¹ , Tengfei Nie¹ , Haifeng He¹ , Tongkun Wei¹ , Bing Zhu⁶ , Lijian Hui¹ , Bin Li⁵ , Jing Wang⁵ , Hongyan Wang^1,* , Luonan Chen^1,7,* , Xiaolei Shi^2,3,* , Xin Cheng^1,*

¹State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
²Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
³Hepatobiliary Institute Nanjing University, Nanjing, Jiangsu, China
⁴Institute of Brain-Intelligence Technology, Zhangjiang Laboratory, Shanghai, China
⁵5 Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
⁶National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
⁷Key Laboratory of Systems Biology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou, Zhejiang, China
^†These authors contributed equally: Yilin Xu, Jinglin Wang, Haozhen Ren, Hao Dai
* Correspondence: Hongyan Wang(hongyanwang@sibcb.ac.cn)Luonan Chen(lnchen@sibs.ac.cn)Xiaolei Shi(sxl@nju.edu.cn)Xin Cheng(xcheng@sibcb.ac.cn)

Acute liver failure (ALF) is a life-threatening disease that occurs secondary to drug toxicity, infection or a devastating immune response. Orthotopic liver transplantation is an effective treatment but limited by the shortage of donor organs, the requirement for life-long immune suppression and surgical challenges. Stem cell transplantation is a promising alternative therapy for fulminant liver failure owing to the immunomodulatory abilities of stem cells. Here, we report that when transplanted into the liver, human endoderm stem cells (hEnSCs) that are germ layer-specific and nontumorigenic cells derived from pluripotent stem cells are able to effectively ameliorate hepatic injury in multiple rodent and swine drug-induced ALF models. We demonstrate that hEnSCs tune the local immune microenvironment by skewing macrophages/Kupffer cells towards an anti-inflammatory state and by reducing the infiltrating monocytes/macrophages and inflammatory T helper cells. Single-cell transcriptomic analyses of infiltrating and resident monocytes/macrophages isolated from animal livers revealed dramatic changes, including changes in gene expression that correlated with the change of activation states, and dynamic population heterogeneity among these cells after hEnSC transplantation. We further demonstrate that hEnSCs modulate the activation state of macrophages/Kupffer cells via cystatin SN (CST1)-mediated inhibition of interferon signaling and therefore highlight CST1 as a candidate therapeutic agent for diseases that involve over-activation of interferons. We propose that hEnSC transplantation represents a novel and powerful cell therapeutic treatment for ALF.

https://doi.org/10.1038/s41422-022-00760-5

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