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

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 allogenei...

Full description

Saved in:
Bibliographic Details
Published in:Leukemia 2018-12, Vol.32 (12), p.2672-2684
Main Authors: Kim, YongHwan, Jin, 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
Format: Article
Language:English
Subjects:
Angiogenesis
Animals
Calcium
Calcium ions
Care and treatment
Cell adhesion
Cell adhesion & migration
Cell Adhesion - immunology
Cell cycle
Cell Cycle - immunology
Cell Line
Cell proliferation
Cell Proliferation - physiology
Cord blood
Cytokines
Demethylation
Deoxyribonucleic acid
Development and progression
DNA
Embryo cells
Gene expression
Genes
Genetic aspects
Genomes
Genomics
Graft versus host disease
Graft vs Host Disease - immunology
Graft vs. host disease
Graft-versus-host reaction
GTP-binding protein
Health aspects
Humans
Hypoxia
Hypoxia - immunology
Immunomodulation
Injury prevention
Kinases
Leukocytes, Mononuclear
Lymphocytes T
Male
Medical schools
Medical treatment
Mesenchymal Stem Cell Transplantation - methods
Mesenchymal stem cells
Mesenchymal Stem Cells - immunology
Mesenchyme
Mice
Mice, Inbred NOD
Monocyte chemoattractant protein
Monocyte chemoattractant protein 1
Monocytes
Organs
p53 Protein
Polo
Polo-like kinase
Proteins
Senescence
Stem cell transplantation
Stem cells
T cells
T-Lymphocytes - immunology
Umbilical cord
Up-Regulation - immunology
Weight loss
Weight reduction
Zinc
Zinc finger proteins
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0887-6924
1476-5551
DOI:10.1038/s41375-018-0151-8