title: Diabetes mellitus induces bone marrow microangiopathy.
abstract: OBJECTIVE
  The impact of diabetes on the bone marrow (BM) microenvironment was not adequately explored. We investigated whether diabetes induces microvascular remodeling with negative consequence for BM homeostasis.
  
  
  RESULTS
  We found profound structural alterations in BM from mice with type 1 diabetes with depletion of the hematopoietic component and fatty degeneration. Blood flow (fluorescent microspheres) and microvascular density (immunohistochemistry) were remarkably reduced. Flow cytometry verified the depletion of MECA-32(+) endothelial cells. Cultured endothelial cells from BM of diabetic mice showed higher levels of oxidative stress, increased activity of the senescence marker beta-galactosidase, reduced migratory and network-formation capacities, and increased permeability and adhesiveness to BM mononuclear cells. Flow cytometry analysis of lineage(-) c-Kit(+) Sca-1(+) cell distribution along an in vivo Hoechst-33342 dye perfusion gradient documented that diabetes depletes lineage(-) c-Kit(+) Sca-1(+) cells predominantly in the low-perfused part of the marrow. Cell depletion was associated to increased oxidative stress, DNA damage, and activation of apoptosis. Boosting the antioxidative pentose phosphate pathway by benfotiamine supplementation prevented microangiopathy, hypoperfusion, and lineage(-) c-Kit(+) Sca-1(+) cell depletion.
  
  
  CONCLUSIONS
  We provide novel evidence for the presence of microangiopathy impinging on the integrity of diabetic BM. These discoveries offer the framework for mechanistic solutions of BM dysfunction in diabetes.
authors.affiliation: Chair of Experimental Cardiovascular Medicine, University of Bristol, Bristol BS2 8HW, United Kingdom.
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Oikawa
authors.forename: Mauro
authors.initials: M
authors.lastname: Siragusa
authors.forename: Federico
authors.initials: F
authors.lastname: Quaini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mangialardi
authors.forename: Rajesh G
authors.initials: RG
authors.lastname: Katare
authors.forename: Andrea
authors.initials: A
authors.lastname: Caporali
authors.forename: Jaap D
authors.initials: JD
authors.lastname: van Buul
authors.forename: Floris P J
authors.initials: FP
authors.lastname: van Alphen
authors.forename: Gallia
authors.initials: G
authors.lastname: Graiani
authors.forename: Gaia
authors.initials: G
authors.lastname: Spinetti
authors.forename: Nicolle
authors.initials: N
authors.lastname: Kraenkel
authors.forename: Lucia
authors.initials: L
authors.lastname: Prezioso
authors.forename: Costanza
authors.initials: C
authors.lastname: Emanueli
authors.forename: Paolo
authors.initials: P
authors.lastname: Madeddu
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001853:Bone Marrow / Q000098:blood supply* / Q000378:metabolism / Q000503:physiopathology*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000503:physiopathology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018384:Oxidative Stress / Q000502:physiology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D012039:Regional Blood Flow / Q000502:physiology; D013311:Streptozocin
chemical_list: D000950:Antigens, Ly; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D013311:Streptozocin; D019009:Proto-Oncogene Proteins c-kit