Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Sep 26, 2020; 12(9): 1032-1049
Published online Sep 26, 2020. doi: 10.4252/wjsc.v12.i9.1032
Human mesenchymal stem cells derived from umbilical cord and bone marrow exert immunomodulatory effects in different mechanisms
Yunejin Song, Jung-Yeon Lim, Taekyu Lim, Keon-Il Im, Nayoun Kim, Young-Sun Nam, Young-Woo Jeon, Jong Chul Shin, Hyun Sun Ko, In Yang Park, Seok-Goo Cho
Yunejin Song, Jung-Yeon Lim, Keon-Il Im, Nayoun Kim, Young-Sun Nam, Young-Woo Jeon, Seok-Goo Cho, Institute for Translational Research and Molecular Imaging, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
Yunejin Song, Jung-Yeon Lim, Keon-Il Im, Nayoun Kim, Young-Sun Nam, Young-Woo Jeon, Seok-Goo Cho, Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
Yunejin Song, Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
Jung-Yeon Lim, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Taekyu Lim, Division of Hematology Oncology, Department of Internal Medicine, Veterans Health Service Medical Center, Seoul 05368, South Korea
Young-Woo Jeon, Seok-Goo Cho, Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
Jong Chul Shin, Department of Obstetrics and Gynecology, CHA Bundang Medical Center, CHA University, Seongnam 13496, South Korea
Hyun Sun Ko, In Yang Park, Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
Seok-Goo Cho, Division of Hematology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
Author contributions: Song Y and Lim JY conceptualized the original idea, designed the experiments and wrote the manuscript; Song Y, Lim JY, Lim T, Im KI, Kim N, Nam YS and Jeon YW isolated the stem cells, performed the experiments and analyzed the data; Shin JC, Ko HS and Park IY provided human resources; All authors approved the final version of the article.
Supported by Korean Health Technology R&D Project, No. HI16C2178.
Institutional review board statement: This study was reviewed and approved by the Catholic University of Korea Catholic Medical Center Institutional Review Board.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by Institutional Animal care and Use Committee in School of Medicine, The Catholic University of Korea; approval number: CUMC-2018-0270-01.
Conflict-of-interest statement: The authors have nothing to disclose.
Data sharing statement: The dataset supporting the conclusions of this article are included within in the article.
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: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Seok-Goo Cho, MD, PhD, Professor, Division of Hematology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Banpodaero 222, Seocho-Gu, Seoul 06591, South Korea. chosg@catholic.ac.kr
Received: March 20, 2020
Peer-review started: March 20, 2020
First decision: April 25, 2020
Revised: June 20, 2020
Accepted: July 19, 2020
Article in press: July 19, 2020
Published online: September 26, 2020
Processing time: 185 Days and 21.1 Hours
ARTICLE HIGHLIGHTS
Research background

Mesenchymal stem cells (MSCs) are a promising therapeutic approach to treat graft-versus-host disease (GVHD) because of their immunoregulatory properties. Until recently, human bone marrow-derived MSCs (BM-MSCs) were used widely as cell therapy sources. However, the needs for new source of MSCs are growing due to the invasive collection method and decrease in donors. Among many other adult and fetal tissues, human umbilical cord has emerged as a promising source of MSCs because of their ethical and noninvasive collection.

Research motivation

Although several studies have pointed out the potential of human umbilical cord-derived MSCs (UC-MSCs), the difference in immunomodulatory effects and mechanisms of BM-MSCs and UC-MSCs should be examined in greater detail.

Research objectives

In this study, we aim to investigate the difference in mechanisms of the immunosuppressive effects of UC-MSCs and BM-MSCs.

Research methods

Western blot, quantitative real-time polymerase chain reaction and luminex multiplex cytokine assay were employed to examine the expression of soluble factors after MSCs were primed with different combinations of interferon-gamma, tumor necrosis factor alpha and interleukin (IL)-1β, or interferon-gamma alone. Human peripheral blood mononuclear cells stimulated with phytohemagglutinin were cocultured with MSCs to examine the immunosuppressive effects of the MSCs in vitro. Several inhibitors of soluble factors were used to identify which soluble factors played critical roles in the immunomodulation of MSCs. Lastly, xenogeneic GVHD was induced in NOG mice (NOD/Shi-scid/IL-2Rγnull) and UC-MSCs or BM-MSCs were used as cell therapies.

Research results

BM-MSCs and UC-MSCs shared similar phenotypic characteristics and immunosuppressive effects. COX2 and IL-10 were key factors in the immunomodulatory mechanisms of both MSCs. However, upon in vitro cytokine stimulation, BM-MSCs expressed more indolamine 2,3-dioxygenase, and UC-MSCs expressed more prostaglandin E2, IL-6, PD-L1 and PD-L2. UC-MSCs and BM-MSCs established different T cell subpopulations when cultured with stimulated T cells. UC-MSCs inhibited more T helper 17 cells and induced more regulatory T cells than BM-MSCs. In a humanized GVHD mouse model, UC-MSCs and BM-MSCs showed comparable effects in attenuating GVHD.

Research conclusions

Our data provides a deeper understanding in similarities and differences between UC-MSCs and BM-MSCs. This study demonstrated that UC-MSCs and BM-MSCs exhibited similar immunosuppression in different mechanisms. Also, this study introduced that UC-MSCs have the potential to substitute for BM-MSCs as cell therapy products.

Research perspectives

In summary, we have demonstrated that UC-MSCs and BM-MSCs exhibit different tendencies toward expression of proteins known to contribute to immunosuppression although they share similar phenotypic characteristics and immunomodulation abilities. Our data also suggest that UC-MSCs and BM-MSCs induced immunosuppression through different pathways underscoring the need for future studies to identify detailed mechanisms of MSCs derived from different sources.