Basic Study
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World J Stem Cells. Aug 26, 2022; 14(8): 599-615
Published online Aug 26, 2022. doi: 10.4252/wjsc.v14.i8.599
Sinomenine promotes differentiation of induced pluripotent stem cells into immature dendritic cells with high induction of immune tolerance
Xiao-Yan Huang, Zhan-Kui Jin, Meng Dou, Bing-Xuan Zheng, Xiang-Rong Zhao, Qing Feng, Yang-Meng Feng, Xiang-Long Duan, Pu-Xun Tian, Cui-Xiang Xu
Xiao-Yan Huang, Xiang-Rong Zhao, Qing Feng, Yang-Meng Feng, Cui-Xiang Xu, Shaanxi Provincial Key Laboratory of Infection and Immune Diseases, Shaanxi Provincial People’s Hospital, Xi'an 710068, Shaanxi Province, China
Zhan-Kui Jin, Department of Orthopedics, Shaanxi Provincial People’s Hospital, Xi'an 710068, Shaanxi Province, China
Meng Dou, Bing-Xuan Zheng, Pu-Xun Tian, Department of Kidney Transplantation, The First Affiliated Hospital of Xi’an Jiaotong University, Xi'an 710061, Shaanxi Province, China
Xiang-Long Duan, Second Department of General Surgery, Shaanxi Provincial People's Hospital, Xi'an 710068, Shaanxi Province, China
Author contributions: Huang XY, Jin ZK, Tian PX and Xu CX conceived and designed the study, and drafted the article; Dou M, Zhao XR, Feng Q, Feng YM and Duan XL performed the experiments; Huang XY and Xu CX analyzed the data; Huang XY, Jin ZK, Dou M and Xu CX performed data analysis; all authors contributed to the collection of literature data, reviewed the manuscript, and approved the version to be published.
Supported by National Natural Science Foundation of China, No. 81900686; Science and Technology Incubation Fund Project of Shaanxi Provincial People’s Hospital, No. 2020YXM-08; Technology Talent Support Program of Shaanxi Provincial People’s Hospital, No. 2021BJ-07; Key Projects of Shaanxi Provincial Department of Education, No. 21JS038; and Medical Research Development Fund of Beijing Kangmeng Charity Foundation, No. 7B202010.
Institutional animal care and use committee statement: All of the procedures and ethics of animal use were reviewed and approved by the Biomedical Ethics Committee of Shaanxi Provicial People’s Hospital, No. 2021-198.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Cui-Xiang Xu, PhD, Chief Doctor, Doctor, Senior Researcher, Shaanxi Provincial Key Laboratory of Infection and Immune Diseases, Shaanxi Provincial People’s Hospital, No. 256 West Road, Beilin District, Xi'an 710068, Shaanxi Province, China. xucuixiang1129@163.com
Received: February 25, 2022
Peer-review started: February 25, 2022
First decision: April 19, 2022
Revised: May 16, 2022
Accepted: July 11, 2022
Article in press: July 11, 2022
Published online: August 26, 2022
Processing time: 182 Days and 2.6 Hours
ARTICLE HIGHLIGHTS
Research background

Immature dendritic cells (imDCs) play a vital role in the induction of donor-specific transplant immune tolerance. However, these cells have limitations, such as rapid maturation and a short lifespan in vivo. The induced pluripotent stem cells (iPSCs) could differentiate to imDCs and sinomenine (SN) could inhibit the maturation of imDCs. Therefore, the iPSCs-derived imDCs treated with SN are expected to become promising seeding cells for inducing immune tolerance in organ transplantation.

Research motivation

The immune chronic rejection after solid organ transplantation is serious and still lacks an effective treatment.

Research objectives

The objective of our study was to evaluate the therapeutic effects of SN-iPSCs-imDC induced immune tolerance in vitro and allogeneic skin graft Mouse model.

Research methods

Mouse iPSCs were induced to differentiate into imDCs in a culture medium with or without SN (iPSCs-imDCs and SN-iPSCs-imDCs). The related surface markers, the effects on T-cell stimulatory function, regulatory T (Treg) cell proliferative function, cytokine expression levels, cell endocytic capacity and cell apoptosis of iPSCs-imDCs and SN-iPSCs-imDCs in vitro and in vivo were analyzed. The induced immunology tolerance of SN-iPSCs-DCs was evaluated by treated the recipients Balb/c skin graft mice. Statistical evaluation of graft survival was performed using Kaplan-Meier curves.

Research results

We successfully obtained iPSCs-imDCs and SN-iPSCs-imDCs. SN-iPSCs-imDCs exhibited higher CD11c levels, lower CD80, CD86 and MHC-II levels, worse T-cell stimulatory function, and higher Treg-cells proliferative function compared with iPSCs-imDCs. Additionally, the levels of interleukin (IL)-2, IL-12, interferon-γ in SN-iPSCs-imDCs were lower than those in iPSCs-imDCs, whereas IL-10 and transforming growth factor-β levels were higher. Moreover, the cell endocytic capacity and apoptosis rate in SN-iPSCs-imDCs was significantly higher. In Balb/c mice recipients immunized with iPSCs-imDCs or SN-iPSCs-imDCs 7 d before skin grafts, Tregs were significantly increased in the spleen after transplantation and the survival span of C57bl/6 skin grafts was significantly prolonged in immunized Balb/c recipients with a donor-specific pattern in SN-iPSCs-imDCs treated group.

Research conclusions

The SN-iPSCs-imDCs have potential applications for the induction of immune tolerance following organ transplantation.

Research perspectives

The SN-iPSCs-imDCs could induce immune immune hyporesponsiveness, even immune tolerance, which may be an effective strategy to treat immune chronic rejection after organ tranplantation.