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
Abstract
BACKGROUND

Mesenchymal stem cells (MSCs) are an attractive tool to treat graft-versus-host disease because of their unique immunoregulatory properties. Although human bone marrow-derived MSCs (BM-MSCs) were the most widely used MSCs in cell therapy until recently, MSCs derived from human umbilical cords (UC-MSCs) have gained popularity as cell therapy material for their ethical and noninvasive collection.

AIM

To investigate the difference in mechanisms of the immunosuppressive effects of UC-MSCs and BM-MSCs.

METHODS

To analyze soluble factors expressed by MSCs, such as indolamine 2,3-dioxygenase, cyclooxygenase-2, prostaglandin E2 and interleukin (IL)-6, inflammatory environments in vitro were reconstituted with combinations of interferon-gamma (IFN-γ), tumor necrosis factor alpha and IL-1β or with IFN-γ alone. Activated T cells were cocultured with MSCs treated with indomethacin and/or anti-IL-10. To assess the ability of MSCs to inhibit T helper 17 cells and induce regulatory T cells, induced T helper 17 cells were cocultured with MSCs treated with indomethacin or anti-IL-10. Xenogeneic graft-versus-host disease was induced in NOG mice (NOD/Shi-scid/IL-2Rγnull) and UC-MSCs or BM-MSCs were treated as cell therapies.

RESULTS

Our data demonstrated that BM-MSCs and UC-MSCs shared similar phenotypic characteristics and immunomodulation abilities. BM-MSCs expressed more indolamine 2,3-dioxygenase after cytokine stimulation with different combinations of IFN-γ, tumor necrosis factor alpha-α and IL-1β or IFN-γ alone. UC-MSCs expressed more prostaglandin E2, IL-6, programmed death-ligand 1 and 2 in the in vitro inflammatory environment. Cyclooxygenase-2 and IL-10 were key factors in the immunomodulatory mechanisms of both MSCs. In addition, UC-MSCs inhibited more T helper 17 cells and induced more regulatory T cells than BM-MSCs. UC-MSCs and BM-MSCs exhibited similar effects on attenuating graft-versus-host disease.

CONCLUSION

UC-MSCs and BM-MSCs exert similar immunosuppressive effects with different mechanisms involved. These findings suggest that UC-MSCs have distinct immunoregulatory functions and may substitute BM-MBSCs in the field of cell therapy.

Keywords: Mesenchymal stem cells; Graft-versus-host disease; Umbilical cord; Cell therapy; Xenogeneic mouse model; Immunomodulation

Core Tip: Mesenchymal stem cells (MSCs) are a therapeutic approach to treat graft-versus-host disease because of their unique immunomodulatory abilities. Here, we compared and analyzed the differences and similarities between umbilical cord-derived MSCs and bone marrow-derived MSCs due to the growing needs for new sources of MSCs. We suggest that umbilical cord-derived MSCs and bone marrow-derived MSCs exhibit similar immunosuppression by different mechanisms, and umbilical cord-derived MSCs have the potentials to substitute bone marrow-derived MSCs as cell therapy products.