Published online Sep 26, 2020. doi: 10.4252/wjsc.v12.i9.1032
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
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.
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.
In this study, we aim to investigate the difference in mechanisms of the immunosuppressive effects of UC-MSCs and BM-MSCs.
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.
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.
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.
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.