title: Differentiation of bone marrow-derived endothelial progenitor cells is shifted into a proinflammatory phenotype by hyperglycemia.
abstract: Bone marrow (BM)-derived endothelial progenitor cells (EPC) contribute to vascular maintenance by participating in angiogenesis, re-endothelialization, and remodeling. Myeloid progenitor cells in the BM are functionally and quantitatively an important precursor pool for cells that contribute to these processes. However, these precursor pools in the BM also give rise to important effector cells of the innate immune system, such as macrophages and dendritic cells. We hypothesized that the disturbed repair responses that are being observed in diabetes mellitus are also related to an effect on functional and differentiation characteristics at the level of this bone marrow precursor pool. Indeed, we observed that bone marrow differentiation cultures for EPC, macrophages (Mph), or dendritic cells (DC) from hyperglycemic BM yielded 40% fewer EPC and 50% more Mph compared with control BM. These changes were directly related to the hemoglobin A(1C) levels of the donor mice. BM-derived DC numbers were not affected by hyperglycemia. The composition of the BM was not altered; in particular, the numbers of CD31+/Ly6C+ cells, which serve as common progenitors for EPC, Mph, and DC, were unaffected. In addition, BM-derived EPC from hyperglycemic mice were less angiogenic and more proinflammatory in regards to endocytosis, T-cell activation, and interleukin 12 production. HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibition by statin supplementation of the culture medium counteracted these hyperglycemia-induced changes. Our study results show that hyperglycemia alters the differentiation fate of BM precursor cells, reducing the potential to generate vascular regenerative cells and favoring the development of proinflammatory cells.
authors.affiliation: Department of Nephrology and the Einthoven Laboratory for Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Cindy Jm
authors.initials: CJ
authors.lastname: Loomans
authors.forename: Rien
authors.initials: R
authors.lastname: van Haperen
authors.forename: Jacques M
authors.initials: JM
authors.lastname: Duijs
authors.forename: Caroline
authors.initials: C
authors.lastname: Verseyden
authors.forename: Rini
authors.initials: R
authors.lastname: de Crom
authors.forename: Pieter Jm
authors.initials: PJ
authors.lastname: Leenen
authors.forename: Hemmo A
authors.initials: HA
authors.lastname: Drexhage
authors.forename: Hetty C
authors.initials: HC
authors.lastname: de Boer
authors.forename: Eelco Jp
authors.initials: EJ
authors.lastname: de Koning
authors.forename: Ton J
authors.initials: TJ
authors.lastname: Rabelink
authors.forename: Frank Jt
authors.initials: FJ
authors.lastname: Staal
authors.forename: Anton Jan
authors.initials: AJ
authors.lastname: van Zonneveld
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology; D005434:Flow Cytometry; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D006943:Hyperglycemia / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D013311:Streptozocin / Q000494:pharmacology; D014470:Umbilical Cord / Q000166:cytology
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013311:Streptozocin