Int J Stem Cells.  2019 Mar;12(1):63-72. 10.15283/ijsc18097.

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

Affiliations
  • 1Department of Internal Medicine, School of Medicine, Kangwon National University, Chuncheon, Korea. shhong@kangwon.ac.kr
  • 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. ckmin@catholic.ac.kr
  • 7Leukemia Research Institute, The Catholic University of Korea, Seoul, Korea.

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.

Keyword

Hyperglycemia; Hematopoiesis; Perivascular niche; NOX; MDSCs

MeSH Terms

Animals
Bone Marrow*
Culture Media, Conditioned
Diabetes Complications
Down-Regulation
Femur
Flow Cytometry
Hematopoiesis
Hematopoietic Stem Cells*
Humans
Hyperglycemia
Mice
NADP*
NADPH Oxidase*
Phosphorylation
Culture Media, Conditioned
NADP
NADPH Oxidase
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