Small hypoxia-primed mesenchymal stem cells attenuate graft-versus-host disease
Jin, Hye Jin
Jeong, Sang Young
Choi, Soo Jin
Yang, Yoon Sun
Hwang, Hyun Ho
Yu, Hwan Yeul
Jeon, Hong Bae
KAUST DepartmentKing Abdullah University of Science and Technology (KAUST), Thuwal, Jeddah, 23955-6900, Saudi Arabia.
MetadataShow full item record
AbstractMesenchymal stem cells (MSCs) are of particular interest for the treatment of immune-related diseases due to their immunosuppressive capacity. Here, we show that Small MSCs primed with Hypoxia and Calcium ions (SHC-MSCs) exhibit enhanced stemness and immunomodulatory functions for treating allogeneic conflicts. Compared with naïve cultured human umbilical cord blood-derived MSCs, SHC-MSCs were resistant to passage-dependent senescence mediated via the monocyte chemoattractant protein-1 and p53/p21 cascade and secreted large amounts of pro-angiogenic and immunomodulatory factors, resulting in suppression of T-cell proliferation. SHC-MSCs showed DNA demethylation in pluripotency, germline, and imprinted genes similarly to very small embryonic-like stem cells, suggesting a potential mutual relationship. Genome-wide DNA methylome and transcriptome analyses indicated that genes related to immune modulation, cell adhesion, and the cell cycle were up-regulated in SHC-MSCs. Particularly, polo-like kinase-1 (PLK1), zinc-finger protein-143, dehydrogenase/reductase-3, and friend-of-GATA2 play a key role in the beneficial effects of SHC-MSCs. Administration of SHC-MSCs or PLK1-overexpressing MSCs significantly ameliorated symptoms of graft-versus-host disease (GVHD) in a humanized mouse model, resulting in significantly improved survival, less weight loss, and reduced histopathologic injuries in GVHD target organs compared with naïve MSC-infused mice. Collectively, our findings suggest that SHC-MSCs can improve the clinical treatment of allogeneic conflicts, including GVHD.
CitationKim Y, Jin HJ, Heo J, Ju H, Lee H-Y, et al. (2018) Small hypoxia-primed mesenchymal stem cells attenuate graft-versus-host disease. Leukemia. Available: http://dx.doi.org/10.1038/s41375-018-0151-8.
SponsorsThis research was supported by the Global High-Tech Biomedicine Technology Development Program of the National Research Foundation (NRF) and the Korea Health Industry Development Institute (KHIDI) funded by the Korean government (MSIP&MOHW) (NRF-2015M3D6A1065114 and NRF-2015M3D6A1065364), by the National Research Foundation of Korea (NRF-2018R1A2B2001392 and NRF-2017M3A9B4061890), and by the Ministry of Education (grant number: 2017R1D1A1B03031379).
Except where otherwise noted, this item's license is described as The final publication is available at Springer via http://dx.doi.org/10.1038/s41375-018-0151-8