Small hypoxia-primed mesenchymal stem cells attenuate graft-versus-host disease
Type
ArticleAuthors
Kim, YongHwanJin, Hye Jin
Heo, Jinbeom
Ju, Hyein
Lee, Hye-Yeon
Kim, Sujin
Lee, Seungun
Lim, Jisun
Jeong, Sang Young
Kwon, JiHye
Kim, Miyeon
Choi, Soo Jin
Oh, Wonil
Yang, Yoon Sun
Hwang, Hyun Ho

Yu, Hwan Yeul
Ryu, Chae-Min
Jeon, Hong Bae
Shin, Dong-Myung

KAUST Department
Publication Srvcs and Researcher SupportDate
2018-05-22Online Publication Date
2018-05-22Print Publication Date
2018-12Permanent link to this record
http://hdl.handle.net/10754/627984
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Mesenchymal 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.Citation
Kim 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.Sponsors
This 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).Publisher
Springer NatureJournal
LeukemiaAdditional Links
https://www.nature.com/articles/s41375-018-0151-8ae974a485f413a2113503eed53cd6c53
10.1038/s41375-018-0151-8
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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