Basic Research in Cardiology

, Volume 105, Issue 6, pp 703–712 | Cite as

Long-term diabetes impairs repopulation of hematopoietic progenitor cells and dysregulates the cytokine expression in the bone marrow microenvironment in mice

  • Alessia Orlandi
  • Emmanouil Chavakis
  • Florian Seeger
  • Marc Tjwa
  • Andreas M. Zeiher
  • Stefanie Dimmeler
Original Contribution


Diabetes is characterized by a chronic stage of hyperglycemia associated with endothelial progenitor cell dysfunction and reduced neovascularization in response to tissue ischemia. The underlying mechanisms are not entirely clear. The bone marrow niches provide the essential microenvironment for maintenance of stem cell function in the bone marrow. A disturbed stem cell niche might lead to stem cell dysfunction, thereby, impairing progenitor cell-dependent vascular repair. Therefore, we investigated the effects of streptozotocin-induced diabetes on the bone marrow stem cell niches and stem cell function in mice. Here, we show that long-term diabetes induced a reduction in LinSca-1+c-kit+ hematopoietic progenitor cells and reduced the repopulation capacity in a competitive engraftment experiment. Consistently, the expression of Bmi1, which prevents hematopoietic progenitor cell senescence, was significantly reduced in diabetic bone marrow cells. To address the mechanism underlying the progenitor cell dysfunction, we analyzed the composition of the stem cell niche and the cytokine environment. Although the morphology of the vascular and endosteal niche was not affected by diabetes, diabetic mice showed a significant deterioration of cytokine expression patterns in the bone marrow. In summary, these data indicate that diabetes imposes a long-term effect on the stem cell niche and affects important hematopoietic progenitor cell functions in mice.


Diabetes Progenitor cells Stem cell niche 



The study was supported by the excellence cluster cardiopulmonary system (Exc 147/-1) and the European Community’s Sixth Framework Programme contract (‘HeartRepair’) LSHM-CT-2005-018630. We appreciated the expert technical support of Tino Röxe, Ariane Fischer and Marion Muhly-Reinholz.


  1. 1.
    Adams GB, Scadden DT (2006) The hematopoietic stem cell in its place. Nat Immunol 7:333–337CrossRefPubMedGoogle Scholar
  2. 2.
    Aicher A, Heeschen C, Mildner-Rihm C, Urbich C, Ihling C, Technau-Ihling K, Zeiher AM, Dimmeler S (2003) Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med 9:1370–1376CrossRefPubMedGoogle Scholar
  3. 3.
    Akbari CM, Saouaf R, Barnhill DF, Newman PA, LoGerfo FW, Veves A (1998) Endothelium-dependent vasodilatation is impaired in both microcirculation and macrocirculation during acute hyperglycemia. J Vasc Surg 28:687–694CrossRefPubMedGoogle Scholar
  4. 4.
    Awad O, Jiao C, Ma N, Dunnwald M, Schatteman GC (2005) Obese diabetic mouse environment differentially affects primitive and monocytic endothelial cell progenitors. Stem Cells 23:575–583CrossRefPubMedGoogle Scholar
  5. 5.
    Busik JV, Tikhonenko M, Bhatwadekar A, Opreanu M, Yakubova N, Caballero S, Player D, Nakagawa T, Afzal A, Kielczewski J, Sochacki A, Hasty S, Li Calzi S, Kim S, Duclas SK, Segal MS, Guberski DL, Esselman WJ, Boulton ME, Grant MB (2009) Diabetic retinopathy is associated with bone marrow neuropathy and a depressed peripheral clock. J Exp Med 206:2897–2906CrossRefPubMedGoogle Scholar
  6. 6.
    Caballero S, Sengupta N, Afzal A, Chang KH, Li Calzi S, Guberski DL, Kern TS, Grant MB (2007) Ischemic vascular damage can be repaired by healthy, but not diabetic, endothelial progenitor cells. Diabetes 56:960–967CrossRefPubMedGoogle Scholar
  7. 7.
    Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP, Schipani E, Divieti P, Bringhurst FR, Milner LA, Kronenberg HM, Scadden DT (2003) Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425:841–846CrossRefPubMedGoogle Scholar
  8. 8.
    Chen L, Tredget EE, Wu PY, Wu Y (2008) Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS ONE 3:e1886CrossRefPubMedGoogle Scholar
  9. 9.
    Cho HJ, Lee N, Lee JY, Choi YJ, Ii M, Wecker A, Jeong JO, Curry C, Qin G, Yoon YS (2007) Role of host tissues for sustained humoral effects after endothelial progenitor cell transplantation into the ischemic heart. J Exp Med 204:3257–3269CrossRefPubMedGoogle Scholar
  10. 10.
    Coon D, Gulati A, Cowan C, He J (2007) The role of cyclooxygenase-2 (COX-2) in inflammatory bone resorption. J Endod 33:432–436CrossRefPubMedGoogle Scholar
  11. 11.
    Davis ME, Hsieh PC, Takahashi T, Song Q, Zhang S, Kamm RD, Grodzinsky AJ, Anversa P, Lee RT (2006) Local myocardial insulin-like growth factor 1 (IGF-1) delivery with biotinylated peptide nanofibers improves cell therapy for myocardial infarction. Proc Natl Acad Sci USA 103:8155–8160CrossRefPubMedGoogle Scholar
  12. 12.
    Dernbach E, Randriamboavonjy V, Fleming I, Zeiher AM, Dimmeler S, Urbich C (2008) Impaired interaction of platelets with endothelial progenitor cells in patients with cardiovascular risk factors. Basic Res Cardiol 103:572–581CrossRefPubMedGoogle Scholar
  13. 13.
    Dimmeler S, Burchfield J, Zeiher AM (2008) Cell-based therapy of myocardial infarction. Arterioscler Thromb Vasc Biol 28:208–216CrossRefPubMedGoogle Scholar
  14. 14.
    Dimmeler S, Leri A (2008) Aging and disease as modifiers of efficacy of cell therapy. Circ Res 102:1319–1330CrossRefPubMedGoogle Scholar
  15. 15.
    Fadini GP, Boscaro E, de Kreutzenberg S, Agostini C, Seeger F, Dimmeler S, Zeiher A, Tiengo A, Avogaro A (2010) Time course and mechanisms of circulating progenitor cell reduction in the natural history of type 2 diabetes. Diabetes Care 33:1097–1102CrossRefPubMedGoogle Scholar
  16. 16.
    Fadini GP, Miorin M, Facco M, Bonamico S, Baesso I, Grego F, Menegolo M, de Kreutzenberg SV, Tiengo A, Agostini C, Avogaro A (2005) Circulating endothelial progenitor cells are reduced in peripheral vascular complications of type 2 diabetes mellitus. J Am Coll Cardiol 45:1449–1457CrossRefPubMedGoogle Scholar
  17. 17.
    Fadini GP, Sartore S, Albiero M, Baesso I, Murphy E, Menegolo M, Grego F, Vigili de Kreutzenberg S, Tiengo A, Agostini C, Avogaro A (2006) Number and function of endothelial progenitor cells as a marker of severity for diabetic vasculopathy. Arterioscler Thromb Vasc Biol 26:2140–2146CrossRefPubMedGoogle Scholar
  18. 18.
    Fadini GP, Sartore S, Schiavon M, Albiero M, Baesso I, Cabrelle A, Agostini C, Avogaro A (2006) Diabetes impairs progenitor cell mobilisation after hindlimb ischaemia–reperfusion injury in rats. Diabetologia 49:3075–3084CrossRefPubMedGoogle Scholar
  19. 19.
    Friedrich EB, Werner C, Walenta K, Bohm M, Scheller B (2009) Role of extracellular signal-regulated kinase for endothelial progenitor cell dysfunction in coronary artery disease. Basic Res Cardiol 104:613–620CrossRefPubMedGoogle Scholar
  20. 20.
    Glajchen N, Epstein S, Ismail F, Thomas S, Fallon M, Chakrabarti S (1988) Bone mineral metabolism in experimental diabetes mellitus: osteocalcin as a measure of bone remodeling. Endocrinology 123:290–295CrossRefPubMedGoogle Scholar
  21. 21.
    He J, Tomlinson R, Coon D, Gulati A, Cowan C (2007) Proinflammatory cytokine expression in cyclooxygenase-2-deficient primary osteoblasts. J Endod 33:1309–1312CrossRefPubMedGoogle Scholar
  22. 22.
    Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, Finkel T (2003) Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 348:593–600CrossRefPubMedGoogle Scholar
  23. 23.
    Huang X, Cho S, Spangrude GJ (2007) Hematopoietic stem cells: generation and self-renewal. Cell Death Differ 14:1851–1859CrossRefPubMedGoogle Scholar
  24. 24.
    Ii M, Takenaka H, Asai J, Ibusuki K, Mizukami Y, Maruyama K, Yoon YS, Wecker A, Luedemann C, Eaton E, Silver M, Thorne T, Losordo DW (2006) Endothelial progenitor thrombospondin-1 mediates diabetes-induced delay in reendothelialization following arterial injury. Circ Res 98:697–704CrossRefPubMedGoogle Scholar
  25. 25.
    Kajstura J, Fiordaliso F, Andreoli AM, Li B, Chimenti S, Medow MS, Limana F, Nadal-Ginard B, Leri A, Anversa P (2001) IGF-1 overexpression inhibits the development of diabetic cardiomyopathy and angiotensin II-mediated oxidative stress. Diabetes 50:1414–1424CrossRefPubMedGoogle Scholar
  26. 26.
    Kaplan RN, Psaila B, Lyden D (2007) Niche-to-niche migration of bone-marrow-derived cells. Trends Mol Med 13:72–81CrossRefPubMedGoogle Scholar
  27. 27.
    Kelley KW, Meier WA, Minshall C, Schacher DH, Liu Q, VanHoy R, Burgess W, Dantzer R (1998) Insulin growth factor-I inhibits apoptosis in hematopoietic progenitor cells. Implications in thymic aging. Ann N Y Acad Sci 840:518–524CrossRefPubMedGoogle Scholar
  28. 28.
    Kiel MJ, Yilmaz OH, Iwashita T, Terhorst C, Morrison SJ (2005) SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121:1109–1121CrossRefPubMedGoogle Scholar
  29. 29.
    Kollet O, Dar A, Shivtiel S, Kalinkovich A, Lapid K, Sztainberg Y, Tesio M, Samstein RM, Goichberg P, Spiegel A, Elson A, Lapidot T (2006) Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat Med 12:657–664CrossRefPubMedGoogle Scholar
  30. 30.
    Kopp HG, Avecilla ST, Hooper AT, Rafii S (2005) The bone marrow vascular niche: home of HSC differentiation and mobilization. Physiology (Bethesda) 20:349–356Google Scholar
  31. 31.
    Krankel N, Adams V, Linke A, Gielen S, Erbs S, Lenk K, Schuler G, Hambrecht R (2005) Hyperglycemia reduces survival and impairs function of circulating blood-derived progenitor cells. Arterioscler Thromb Vasc Biol 25:698–703CrossRefPubMedGoogle Scholar
  32. 32.
    Loomans CJ, de Koning EJ, Staal FJ, Rookmaaker MB, Verseyden C, de Boer HC, Verhaar MC, Braam B, Rabelink TJ, van Zonneveld AJ (2004) Endothelial progenitor cell dysfunction: a novel concept in the pathogenesis of vascular complications of type 1 diabetes. Diabetes 53:195–199CrossRefPubMedGoogle Scholar
  33. 33.
    Moore KA, Lemischka IR (2006) Stem cells and their niches. Science 311:1880–1885CrossRefPubMedGoogle Scholar
  34. 34.
    Morrison SJ, Uchida N, Weissman IL (1995) The biology of hematopoietic stem cells. Annu Rev Cell Dev Biol 11:35–71CrossRefPubMedGoogle Scholar
  35. 35.
    Oikawa A, Siragusa M, Quaini F, Mangialardi G, Katare RG, Caporali A, van Buul JD, van Alphen FP, Graiani G, Spinetti G, Kraenkel N, Prezioso L, Emanueli C, Madeddu P (2010) Diabetes mellitus induces bone marrow microangiopathy. Arterioscler Thromb Vasc Biol 30:498–508CrossRefPubMedGoogle Scholar
  36. 36.
    Park IK, Morrison SJ, Clarke MF (2004) Bmi1, stem cells, and senescence regulation. J Clin Invest 113:175–179PubMedGoogle Scholar
  37. 37.
    Rivard A, Silver M, Chen D, Kearney M, Magner M, Annex B, Peters K, Isner JM (1999) Rescue of diabetes-related impairment of angiogenesis by intramuscular gene therapy with adeno-VEGF. Am J Pathol 154:355–363PubMedGoogle Scholar
  38. 38.
    Rosso A, Balsamo A, Gambino R, Dentelli P, Falcioni R, Cassader M, Pegoraro L, Pagano G, Brizzi MF (2006) p53 Mediates the accelerated onset of senescence of endothelial progenitor cells in diabetes. J Biol Chem 281:4339–4347CrossRefPubMedGoogle Scholar
  39. 39.
    Rundhaug JE (2005) Matrix metalloproteinases and angiogenesis. J Cell Mol Med 9:267–285CrossRefPubMedGoogle Scholar
  40. 40.
    Schatteman GC, Hanlon HD, Jiao C, Dodds SG, Christy BA (2000) Blood-derived angioblasts accelerate blood-flow restoration in diabetic mice. J Clin Invest 106:571–578CrossRefPubMedGoogle Scholar
  41. 41.
    Seeger FH, Haendeler J, Walter DH, Rochwalsky U, Reinhold J, Urbich C, Rossig L, Corbaz A, Chvatchko Y, Zeiher AM, Dimmeler S (2005) p38 mitogen-activated protein kinase downregulates endothelial progenitor cells. Circulation 111:1184–1191CrossRefPubMedGoogle Scholar
  42. 42.
    Seeger FH, Sedding D, Langheinrich AC, Haendeler J, Zeiher AM, Dimmeler S (2010) Inhibition of the p38 MAP kinase in vivo improves number and functional activity of vasculogenic cells and reduces atherosclerotic disease progression. Basic Res Cardiol 105:389–397CrossRefPubMedGoogle Scholar
  43. 43.
    Tamarat R, Silvestre JS, Le Ricousse-Roussanne S, Barateau V, Lecomte-Raclet L, Clergue M, Duriez M, Tobelem G, Levy BI (2004) Impairment in ischemia-induced neovascularization in diabetes: bone marrow mononuclear cell dysfunction and therapeutic potential of placenta growth factor treatment. Am J Pathol 164:457–466PubMedGoogle Scholar
  44. 44.
    Tepper OM, Galiano RD, Capla JM, Kalka C, Gagne PJ, Jacobowitz GR, Levine JP, Gurtner GC (2002) Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation 106:2781–2786CrossRefPubMedGoogle Scholar
  45. 45.
    Thum T, Fraccarollo D, Schultheiss M, Froese S, Galuppo P, Widder JD, Tsikas D, Ertl G, Bauersachs J (2007) Endothelial nitric oxide synthase uncoupling impairs endothelial progenitor cell mobilization and function in diabetes. Diabetes 56:666–674CrossRefPubMedGoogle Scholar
  46. 46.
    Torella D, Rota M, Nurzynska D, Musso E, Monsen A, Shiraishi I, Zias E, Walsh K, Rosenzweig A, Sussman MA, Urbanek K, Nadal-Ginard B, Kajstura J, Anversa P, Leri A (2004) Cardiac stem cell and myocyte aging, heart failure, and insulin-like growth factor-1 overexpression. Circ Res 94:514–524CrossRefPubMedGoogle Scholar
  47. 47.
    Urbich C, Dernbach E, Rossig L, Zeiher AM, Dimmeler S (2008) High glucose reduces cathepsin L activity and impairs invasion of circulating progenitor cells. J Mol Cell Cardiol 45:429–436CrossRefPubMedGoogle Scholar
  48. 48.
    Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H, Zeiher AM, Dimmeler S (2001) Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 89:E1–E7CrossRefPubMedGoogle Scholar
  49. 49.
    Walter DH, Haendeler J, Reinhold J, Rochwalsky U, Seeger F, Honold J, Hoffmann J, Urbich C, Lehmann R, Arenzana-Seisdesdos F, Aicher A, Heeschen C, Fichtlscherer S, Zeiher AM, Dimmeler S (2005) Impaired CXCR4 signaling contributes to the reduced neovascularization capacity of endothelial progenitor cells from patients with coronary artery disease. Circ Res 97:1142–1151CrossRefPubMedGoogle Scholar
  50. 50.
    Walter DH, Rochwalsky U, Reinhold J, Seeger F, Aicher A, Urbich C, Spyridopoulos I, Chun J, Brinkmann V, Keul P, Levkau B, Zeiher AM, Dimmeler S, Haendeler J (2007) Sphingosine-1-phosphate stimulates the functional capacity of progenitor cells by activation of the CXCR4-dependent signaling pathway via the S1P3 receptor. Arterioscler Thromb Vasc Biol 27:275–282CrossRefPubMedGoogle Scholar
  51. 51.
    Yin T, Li L (2006) The stem cell niches in bone. J Clin Invest 116:1195–1201CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Alessia Orlandi
    • 1
  • Emmanouil Chavakis
    • 2
  • Florian Seeger
    • 2
  • Marc Tjwa
    • 1
  • Andreas M. Zeiher
    • 2
  • Stefanie Dimmeler
    • 1
  1. 1.Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe University of FrankfurtFrankfurtGermany
  2. 2.Department of Internal Medicine IIICardiology Goethe UniversityFrankfurtGermany

Personalised recommendations