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Leukemia, Published: 22 May 2018 | doi:10.1038/s41375-018-0151-8
Small hypoxia-primed mesenchymal stem cells attenuate graft-versus-host disease
YongHwan Kim1,2, Hye Jin Jin3, Jinbeom Heo1,2, Hyein Ju1,2, Hye-Yeon Lee1,2, Sujin Kim1,2, Seungun Lee1,2, Jisun Lim1,2, Sang Young Jeong3, JiHye Kwon3, Miyeon Kim3, Soo Jin Choi3, Wonil Oh3, Yoon Sun Yang3, Hyun Ho Hwang 4, Hwan Yeul Yu1,2, Chae-Min Ryu1,2, Hong Bae Jeon3,*, Dong-Myung Shin 1,2,*
1 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
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
These authors contributed equally: YongHwan Kim, Hye Jin Jin, Jinbeom Heo.
*Correspondence to Hong Bae Jeon or Dong-Myung Shin
These authors contributed equally: YongHwan Kim, Hye Jin Jin, Jinbeom Heo.
*Correspondence to Hong Bae Jeon or Dong-Myung Shin
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 naive 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 naive MSC-infused mice. Collectively, our findings suggest that SHC-MSCs can improve the clinical treatment of allogeneic conflicts, including GVHD.
논문정보
- Research article
- 2018년 05월 (BRIC 등록일 2018-06-01)
- 국내(교신)+국외 연구진
- 의약학 > 분자세포의학
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