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Leukemia. 2018 Dec;32(12):2672-2684. doi: 10.1038/s41375-018-0151-8. Epub 2018 May 22.

Small hypoxia-primed mesenchymal stem cells attenuate graft-versus-host disease.

Kim Y1,2, Jin HJ3, Heo J1,2, Ju H1,2, Lee HY1,2, Kim S1,2, Lee S1,2, Lim J1,2, Jeong SY3, Kwon J3, Kim M3, Choi SJ3, Oh W3, Yang YS3, Hwang HH4, Yu HY1,2, Ryu CM1,2, Jeon HB5, Shin DM6,7.

Author information

1
Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.
2
Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, Korea.
3
Biomedical Research Institute, MEDIPOST Co., Ltd, Seongnam, 13494, Korea.
4
King Abdullah University of Science and Technology (KAUST), Thuwal, Jeddah, 23955-6900, Saudi Arabia.
5
Biomedical Research Institute, MEDIPOST Co., Ltd, Seongnam, 13494, Korea. jhb@medi-post.co.kr.
6
Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea. d0shin03@amc.seoul.kr.
7
Department of Physiology, University of Ulsan College of Medicine, Seoul, 05505, Korea. d0shin03@amc.seoul.kr.

Abstract

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.

PMID:
29789652
PMCID:
PMC6286327
DOI:
10.1038/s41375-018-0151-8
[Indexed for MEDLINE]
Free PMC Article

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