title: Impaired endothelial progenitor cell mobilization and dysfunctional bone marrow stroma in diabetes mellitus.
abstract: BACKGROUND
  Circulating Endothelial Progenitor Cell (EPC) levels are reduced in diabetes mellitus. This may be a consequence of impaired mobilization of EPC from the bone marrow. We hypothesized that under diabetic conditions, mobilization of EPC from the bone marrow to the circulation is impaired -at least partly- due to dysfunction of the bone marrow stromal compartment.
  
  
  METHODS
  Diabetes was induced in mice by streptozotocin injection. Circulating Sca-1(+)Flk-1(+) EPC were characterized and quantified by flow cytometry at baseline and after mobilization with G-CSF/SCF injections. In vivo hemangiogenic recovery was tested by 5-FU challenge. Interaction within the bone marrow environment between CD34(+) hematopoietic progenitor cells (HPC) and supporting stroma was assessed by co-cultures. To study progenitor cell-endothelial cell interaction under normoglycemic and hyperglycemic conditions, a co-culture model using E4Orf1-transfected human endothelial cells was employed.
  
  
  RESULTS
  In diabetic mice, bone marrow EPC levels were unaffected. However, circulating EPC levels in blood were lower at baseline and mobilization was attenuated. Diabetic mice failed to recover and repopulate from 5-FU injection. In vitro, primary cultured bone marrow stroma from diabetic mice was impaired in its capacity to support human CFU-forming HPC. Finally, hyperglycemia hampered the HPC supportive function of endothelial cells in vitro.
  
  
  CONCLUSIONS
  EPC mobilization is impaired under experimental diabetic conditions and our data suggest that diabetes induces alterations in the progenitor cell supportive capacity of the bone marrow stroma, which could be partially responsible for the attenuated EPC mobilization and reduced EPC levels observed in diabetic patients.
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Westerweel
authors.forename: Martin
authors.initials: M
authors.lastname: Teraa
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
authors.forename: Janneke E
authors.initials: JE
authors.lastname: Jaspers
authors.forename: Ian A
authors.initials: IA
authors.lastname: White
authors.forename: Andrea T
authors.initials: AT
authors.lastname: Hooper
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Doevendans
authors.forename: Marianne C
authors.initials: MC
authors.lastname: Verhaar
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D001853:Bone Marrow / Q000503:physiopathology*; D002452:Cell Count; D002465:Cell Movement; D002470:Cell Survival; D002478:Cells, Cultured; D018920:Coculture Techniques; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D042783:Endothelial Cells / Q000473:pathology*; D005472:Fluorouracil / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D013234:Stem Cells / Q000473:pathology*
chemical_list: D018952:Antigens, CD34; D005472:Fluorouracil
references.citation: Nat Med. 2003 Nov;9(11):1370-6
references.pmid: 14556003
references.citation: Trends Biochem Sci. 2006 Oct;31(10):589-95
references.pmid: 16911868
references.citation: N Engl J Med. 2005 Sep 8;353(10):999-1007
references.pmid: 16148285
references.citation: Fetal Diagn Ther. 2004 Jan-Feb;19(1):2-8
references.pmid: 14646410
references.citation: Diabetes. 2010 Aug;59(8):1974-83
references.pmid: 20484135
references.citation: Lancet. 2006 Jul 1;368(9529):29-36
references.pmid: 16815377
references.citation: N Engl J Med. 2003 Feb 13;348(7):593-600
references.pmid: 12584367
references.citation: Cardiovasc Res. 2001 Feb 16;49(3):554-60
references.pmid: 11166268
references.citation: Circulation. 2001 Aug 28;104(9):1046-52
references.pmid: 11524400
references.citation: Nat Rev Immunol. 2012 May 25;12(6):403-16
references.pmid: 22627859
references.citation: Diabetes. 2007 Mar;56(3):666-74
references.pmid: 17327434
references.citation: J Clin Invest. 2006 May;116(5):1195-201
references.pmid: 16670760
references.citation: Int J Cardiol. 2006 Aug 10;111(2):202-8
references.pmid: 16051386
references.citation: Blood. 2000 Feb 1;95(3):952-8
references.pmid: 10648408
references.citation: Blood. 1991 Aug 15;78(4):961-6
references.pmid: 1714329
references.citation: Cardiovasc Diabetol. 2010 Sep 21;9:55
references.pmid: 20858224
references.citation: Cell. 2002 May 31;109(5):625-37
references.pmid: 12062105
references.citation: Circulation. 2004 May 25;109(20):2454-61
references.pmid: 15148275
references.citation: Circulation. 1999 May 4;99(17):2239-42
references.pmid: 10226087
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19288-93
references.pmid: 19036927
references.citation: JAMA. 2002 Nov 27;288(20):2579-88
references.pmid: 12444865
references.citation: Clin Exp Pharmacol Physiol. 2009 Oct;36(10):e47-56
references.pmid: 19558529
references.citation: Blood. 1994 Jul 1;84(1):10-9
references.pmid: 7517203
references.citation: Diabetes. 2004 Jan;53(1):195-9
references.pmid: 14693715
references.citation: Circulation. 2005 Jun 7;111(22):2981-7
references.pmid: 15927972
references.citation: Arterioscler Thromb Vasc Biol. 2010 Mar;30(3):498-508
references.pmid: 20042708
references.citation: Diabetes Care. 2013 Apr;36(4):943-9
references.pmid: 23111057
references.citation: J Mol Cell Cardiol. 2005 Nov;39(5):733-42
references.pmid: 16199052
references.citation: Basic Res Cardiol. 2013 Jan;108(1):313
references.pmid: 23184393
references.citation: Thromb Haemost. 2003 Oct;90(4):570-6
references.pmid: 14515175
references.citation: Arterioscler Thromb Vasc Biol. 2010 Jun;30(6):1088-93
references.pmid: 20453167
references.citation: Diabetologia. 2013 Mar;56(3):644-53
references.pmid: 23192694
references.citation: Basic Res Cardiol. 2010 Nov;105(6):703-12
references.pmid: 20652278
references.citation: Circulation. 2002 Nov 26;106(22):2781-6
references.pmid: 12451003
references.citation: Cardiovasc Drugs Ther. 1998 Apr;12 Suppl 1:125-34
references.pmid: 9642486
references.citation: Nephrol Dial Transplant. 2008 Feb;23(2):483-91
references.pmid: 17989101
references.citation: Physiology (Bethesda). 2005 Oct;20:349-56
references.pmid: 16174874
references.citation: FASEB J. 2005 Dec;19(14):2005-7
references.pmid: 16223785
references.citation: Bone Marrow Transplant. 2002 May;29(10):825-32
references.pmid: 12058232
references.citation: J Clin Invest. 2007 May;117(5):1249-59
references.pmid: 17476357
references.citation: Arterioscler Thromb Vasc Biol. 2005 Feb;25(2):296-301
references.pmid: 15569821
references.citation: J Exp Med. 2009 Dec 21;206(13):2897-906
references.pmid: 19934019
references.citation: Diabetologia. 2006 Dec;49(12):3075-84
references.pmid: 17072586
references.citation: J Intern Med. 2009 Feb;265(2):238-49
references.pmid: 19019194
references.citation: Lancet. 2012 Mar 10;379(9819):933-942
references.pmid: 22405796
references.citation: Circ Res. 2004 Aug 20;95(4):343-53
references.pmid: 15321944
references.citation: Exp Diabetes Res. 2012;2012:742976
references.pmid: 22548049
references.citation: Nature. 2008 Mar 27;452(7186):442-7
references.pmid: 18256599
references.citation: Bone Marrow Transplant. 2011 Feb;46(2):278-84
references.pmid: 20479708
references.citation: Cell Stem Cell. 2009 Mar 6;4(3):263-74
references.pmid: 19265665
references.citation: Sci Transl Med. 2011 Oct 12;3(104):104ra101
references.pmid: 21998408
references.citation: Stem Cells Dev. 2009 Mar;18(2):229-34
references.pmid: 18491948
references.citation: EMBO J. 1999 Jul 15;18(14):3964-72
references.pmid: 10406801
references.citation: Pediatr Res. 1999 Aug;46(2):163-9
references.pmid: 10447109
references.citation: Cell. 2006 Jan 27;124(2):407-21
references.pmid: 16439213
references.citation: Haematologica. 2010 Jun;95(6):884-91
references.pmid: 20015889