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Perivascular Cells and NADPH Oxidase Inhibition Partially Restore Hyperglycemia-Induced Alterations in Hematopoietic Stem Cell and Myeloid-Derived Suppressor Cell Populations in the Bone Marrow
International Journal of Stem Cells
Published online December 31, 2018;  
© 2018 Korean Society for Stem Cell Research.

Ji-Young Kim1, Ji Yoon Lee2, Kwon-Soo Ha3, Eun-Taek Han4, Won Sun Park5, Chang-Ki Min6,7, Seok-Ho Hong1

1Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, Korea
2Department of Biomedical Sciences, Stem Cell Institute, CHA University, Seongnam, Korea
3Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Korea
4Department of Medical Environmental Biology and Tropical Medicine, School of Medicine, Kangwon National University, Chuncheon, Korea
5Department of Physiology, School of Medicine, Kangwon National University, Chuncheon, Korea
6Department of Hematology, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea
7Leukemia Research Institute, The Catholic University of Korea, Seoul, Korea
Correspondence to: Seok-Ho Hong
Department of Internal Medicine, School of Medicine, Kangwon National University, 1 Kangwondaehak-gil, Chuncheon 24341, Korea
Tel: +82-33-250-7819, Fax: +82-33-244-2367, E-mail: shhong@kangwon.ac.kr
Chang-Ki Min
Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea
Tel: +82-2-2258-6053, Fax: +82-2-599-3589, E-mail: ckmin@catholic.ac.kr
Received October 19, 2018; Revised October 19, 2018; Accepted November 25, 2018.
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background and Objectives: Patients suffer from long-term diabetes can result in severe complications in multiple organs through induction of vascular dysfunctions. However, the effects of chronic hyperglycemic conditions on hematopoiesis and the microenvironment in the bone marrow (BM) are not yet well understood.
Methods: BM cells were harvested from femurs of mice and analyzed using flow cytometry. Human PVCs were cultured in serum-free α-MEM. After 24hrs, PVC-CM was collected and filtered through a 0.22 μm filter.
Results: In this study, we showed that hyperglycemia alters hematopoietic composition in the BM, which can partially be restored via paracrine mechanisms, including perivascular cells (PVCs) and NADPH oxidase (NOX) inhibition in mice with streptozotocin-induced diabetes. Prolonged hyperglycemic conditions resulted in an increase in the frequency and number of long-term hematopoietic stem cells as well as the number of total BM cells. The altered hematopoiesis in the BM was partially recovered by treatment with PVC-derived conditioned medium (CM). Long-term diabetes also increased the number of myeloid-derived suppressor cells in the BM, which was partially restored by the administration of PVC-CM and diphenyleneiodonium (DPI), a NOX inhibitor. We further showed the downregulation of ERK and p38 phosphorylation in BM cells of diabetic mice treated with PVC-CM and DPI. This may be associated with dysfunction of hematopoietic cells and promotion of subsequent diabetic complications.
Conclusions: Our data suggested that alterations in BM hematopoietic composition due to prolonged hyperglycemic conditions might be restored by improvement of the hematopoietic microenvironment and modulation of NOX activity.
Keywords : Hyperglycemia, Hematopoiesis, Perivascular niche, NOX, MDSCs


October 2018, 11 (2)