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Stem cell compartmentalization in diabetes and high cardiovascular risk reveals the role of DPP-4 in diabetic stem cell mobilopathy

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Abstract

Bone marrow (BM) derived stem and progenitor cells contribute to cardiovascular homeostasis and are affected by cardiovascular risk factors. We devised a clinical data-driven approach to test candidate stem cell mobilizing mechanisms in pre-clinical models. We found that PB and BM CD34+ cell counts were directly correlated, and that most circulating CD34+ cells were viable, non-proliferating and derived from the BM. Thus, we analyzed PB and BM CD34+ cell levels as a two-compartment model in 72 patients with or without cardiovascular disease. Self-organizing maps showed that disturbed compartmentalization of CD34+ cells was associated with aging and cardiovascular risk factors especially diabetes. High activity of DPP-4, a regulator of the mobilizing chemokine SDF-1α, was associated with altered stem cell compartmentalization. For validation of these findings, we assessed the role of DPP-4 in the BM mobilization response of diabetic rats. Diabetes differentially affected DPP-4 activity in PB and BM and impaired stem/progenitor cell mobilization after ischemia or G-CSF administration. DPP-4 activity in the BM was required for the mobilizing effect of G-CSF, while in PB it blunted ischemia-induced mobilization. Indeed, DPP-4 deficiency restored ischemia (but not G-CSF)-induced stem cell mobilization and improved vascular recovery in diabetic animals. In conclusion, the analysis of stem cell compartmentalization in humans led us to discover mechanisms of BM unresponsiveness in diabetes determined by tissue-specific DPP-4 dysregulation.

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References

  1. Albiero M, Menegazzo L, Boscaro E, Agostini C, Avogaro A, Fadini GP (2011) Defective recruitment, survival and proliferation of bone marrow-derived progenitor cells at sites of delayed diabetic wound healing in mice. Diabetologia 54:945–953. doi:10.1007/s00125-010-2007-2

    Article  PubMed  CAS  Google Scholar 

  2. Angelini A, Castellani C, Tona F, Gambino A, Caforio AP, Feltrin G, Della Barbera M, Valente M, Gerosa G, Thiene G (2007) Continuous engraftment and differentiation of male recipient Y-chromosome-positive cardiomyocytes in donor female human heart transplants. J Heart Lung Transplant 26:1110–1118. doi:10.1016/j.healun.2007.08.004

    Article  PubMed  Google Scholar 

  3. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967. doi:10.1126/science.275.5302.964

    Article  PubMed  CAS  Google Scholar 

  4. Assmus B, Iwasaki M, Schachinger V, Roexe T, Koyanagi M, Iekushi K, Xu Q, Tonn T, Seifried E, Liebner S, Kranert WT, Grunwald F, Dimmeler S, Zeiher AM (2011) Acute myocardial infarction activates progenitor cells and increases Wnt signalling in the bone marrow. Eur Heart J 33:1911–1919. doi:10.1093/eurheartj/ehr388

    Article  PubMed  Google Scholar 

  5. Bertolini F, Shaked Y, Mancuso P, Kerbel RS (2006) The multifaceted circulating endothelial cell in cancer: towards marker and target identification. Nat Rev Cancer 6:835–845. doi:10.1038/nrc1971

    Article  PubMed  CAS  Google Scholar 

  6. Bolego C, Rossoni G, Fadini GP, Vegeto E, Pinna C, Albiero M, Boscaro E, Agostini C, Avogaro A, Gaion RM, Cignarella A (2010) Selective estrogen receptor-alpha agonist provides widespread heart and vascular protection with enhanced endothelial progenitor cell mobilization in the absence of uterotrophic action. FASEB J 24:2262–2272. doi:10.1096/fj.09-139220

    Article  PubMed  CAS  Google Scholar 

  7. 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 206:2897–2906. doi:10.1084/jem.20090889

    Article  PubMed  CAS  Google Scholar 

  8. Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10:858–864. doi:10.1038/nm1075

    Article  PubMed  CAS  Google Scholar 

  9. Christopherson KW, Cooper S, Hangoc G, Broxmeyer HE (2003) CD26 is essential for normal G-CSF-induced progenitor cell mobilization as determined by CD26-/- mice. Exp Hematol 31:1126–1134. doi:S0301472X0300256X

    PubMed  CAS  Google Scholar 

  10. DiPersio JF (2011) Diabetic stem-cell “mobilopathy”. N Engl J Med 365:2536–2538. doi:10.1056/NEJMcibr1112347

    Article  PubMed  CAS  Google Scholar 

  11. Dong L, Kang L, Ding L, Chen Q, Bai J, Gu R, Li L, Xu B (2011) Insulin modulates ischemia-induced endothelial progenitor cell mobilization and neovascularization in diabetic mice. Microvasc Res 82:227–236. doi:10.1016/j.mvr.2011.09.006

    PubMed  CAS  Google Scholar 

  12. Fadini GP (2008) An underlying principle for the study of circulating progenitor cells in diabetes and its complications. Diabetologia 51:1091–1094. doi:10.1007/s00125-008-1021-0

    Article  PubMed  CAS  Google Scholar 

  13. Fadini GP, Agostini C, Sartore S, Avogaro A (2007) Endothelial progenitor cells in the natural history of atherosclerosis. Atherosclerosis 194:46–54. doi:10.1016/j.atherosclerosis.2007.03.046

    Article  PubMed  Google Scholar 

  14. Fadini GP, Albiero M, Menegazzo L, de Kreutzenberg SV, Avogaro A (2011) The increased dipeptidyl peptidase-4 activity is not counteracted by optimized glucose control in type 2 diabetes, but is lower in metformin-treated patients. Diabetes Obes Metab 14:518–522. doi:10.1111/j.1463-1326.2011.01550.x

    Article  Google Scholar 

  15. Fadini GP, Avogaro A (2011) Cardiovascular effects of DPP-4 inhibition: beyond GLP-1. Vascul Pharmacol 55:10–16. doi:10.1016/j.vph.2011.05.001

    Article  PubMed  CAS  Google Scholar 

  16. Fadini GP, Boscaro E, Albiero M, Menegazzo L, Frison V, de Kreutzenberg S, Agostini C, Tiengo A, Avogaro A (2010) The oral dipeptidyl peptidase-4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes: possible role of stromal-derived factor-1alpha. Diabetes Care 33:1607–1609. doi:10.2337/dc10-0187

    Article  PubMed  CAS  Google Scholar 

  17. 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 33:1097–1102. doi:10.2337/dc09-1999

    Article  PubMed  Google Scholar 

  18. Fadini GP, Losordo D, Dimmeler S (2012) Critical reevaluation of endothelial progenitor cell phenotypes for therapeutic and diagnostic use. Circ Res 110:624–637. doi:10.1161/CIRCRESAHA.111.243386

    Article  PubMed  CAS  Google Scholar 

  19. Fadini GP, Sartore S, Agostini C, Avogaro A (2007) Significance of endothelial progenitor cells in subjects with diabetes. Diabetes Care 30:1305–1313. doi:10.2337/dc06-2305

    Article  PubMed  CAS  Google Scholar 

  20. 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 49:3075–3084. doi:10.1007/s00125-006-0401-6

    Article  PubMed  CAS  Google Scholar 

  21. Ferraro F, Lymperi S, Mendez-Ferrer S, Saez B, Spencer JA, Yeap BY, Masselli E, Graiani G, Prezioso L, Rizzini EL, Mangoni M, Rizzoli V, Sykes SM, Lin CP, Frenette PS, Quaini F, Scadden DT (2011) Diabetes impairs hematopoietic stem cell mobilization by altering niche function. Sci Transl Med 3:104ra101. doi:10.1126/scitranslmed.3002191

    Article  PubMed  Google Scholar 

  22. Iekushi K, Seeger F, Assmus B, Zeiher AM, Dimmeler S (2012) Regulation of cardiac microRNAs by bone marrow mononuclear cell therapy in myocardial infarction. Circulation 125:1765–1773. doi:10.1161/CIRCULATIONAHA.111.079699

    Article  PubMed  CAS  Google Scholar 

  23. Ohtani K, Dimmeler S (2011) Control of cardiovascular differentiation by microRNAs. Basic Res Cardiol 106:5–11. doi:10.1007/s00395-010-0139-7

    Article  PubMed  CAS  Google Scholar 

  24. 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 30:498–508. doi:10.1161/ATVBAHA.109.200154

    Article  PubMed  CAS  Google Scholar 

  25. Orlandi A, Chavakis E, Seeger F, Tjwa M, Zeiher AM, Dimmeler S (2010) Long-term diabetes impairs repopulation of hematopoietic progenitor cells and dysregulates the cytokine expression in the bone marrow microenvironment in mice. Basic Res Cardiol 105:703–712. doi:10.1007/s00395-010-0109-0

    Article  PubMed  CAS  Google Scholar 

  26. Sanganalmath SK, Abdel-Latif A, Bolli R, Xuan YT, Dawn B (2011) Hematopoietic cytokines for cardiac repair: mobilization of bone marrow cells and beyond. Basic Res Cardiol 106:709–733. doi:10.1007/s00395-011-0183-y

    Article  PubMed  CAS  Google Scholar 

  27. Sorrentino SA, Doerries C, Manes C, Speer T, Dessy C, Lobysheva I, Mohmand W, Akbar R, Bahlmann F, Besler C, Schaefer A, Hilfiker-Kleiner D, Luscher TF, Balligand JL, Drexler H, Landmesser U (2011) Nebivolol exerts beneficial effects on endothelial function, early endothelial progenitor cells, myocardial neovascularization, and left ventricular dysfunction early after myocardial infarction beyond conventional beta1-blockade. J Am Coll Cardiol 57:601–611. doi:10.1016/j.jacc.2010.09.037

    Article  PubMed  CAS  Google Scholar 

  28. Takahashi T, Kalka C, Masuda H, Chen D, Silver M, Kearney M, Magner M, Isner JM, Asahara T (1999) Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med 5:434–438. doi:10.1038/7434

    Article  PubMed  CAS  Google Scholar 

  29. Tepper OM, Carr J, Allen RJ Jr, Chang CC, Lin CD, Tanaka R, Gupta SM, Levine JP, Saadeh PB, Warren SM (2010) Decreased circulating progenitor cell number and failed mechanisms of stromal cell-derived factor-1 alpha mediated bone marrow mobilization impair diabetic tissue repair. Diabetes 59:1974–1983. doi:10.2337/db09-0185

    Article  PubMed  CAS  Google Scholar 

  30. Urbich C, Aicher A, Heeschen C, Dernbach E, Hofmann WK, Zeiher AM, Dimmeler S (2005) Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells. J Mol Cell Cardiol 39:733–742. doi:10.1016/j.yjmcc.2005.07.003

    Article  PubMed  CAS  Google Scholar 

  31. Wu J, Li J, Zhang N, Zhang C (2011) Stem cell-based therapies in ischemic heart diseases: a focus on aspects of microcirculation and inflammation. Basic Res Cardiol 106:317–324. doi:10.1007/s00395-011-0168-x

    Article  PubMed  Google Scholar 

  32. Zaruba MM, Theiss HD, Vallaster M, Mehl U, Brunner S, David R, Fischer R, Krieg L, Hirsch E, Huber B, Nathan P, Israel L, Imhof A, Herbach N, Assmann G, Wanke R, Mueller-Hoecker J, Steinbeck G, Franz WM (2009) Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction. Cell Stem Cell 4:313–323. doi:10.1016/j.stem.2009.02.013

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by a European Foundation for the Study of Diabetes (EFSD)/Lilly Fellowship grant to GPF. There are no relationships with industry.

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Authors and Affiliations

  1. Department of Medicine, University of Padova, Via Giustiniani, 2, 35100, Padua, Italy

    Gian Paolo Fadini, Nicol Poncina, Lisa Menegazzo, Carlo Agostini, Elisa Boscaro & Angelo Avogaro

  2. Venetian Institute of Molecular Medicine, 35100, Padua, Italy

    Gian Paolo Fadini, Mattia Albiero, Nicol Poncina, Lisa Menegazzo, Carlo Agostini, Roberta Cappellari, Elisa Boscaro & Angelo Avogaro

  3. Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, 60590, Frankfurt, Germany

    Florian Seeger, Andreas Zeiher & Stefanie Dimmeler

  4. Department of Medicine III, Frankfurt University, 60590, Frankfurt, Germany

    Florian Seeger & Andreas Zeiher

  5. Department of Thoracic, Cardiac and Vascular Sciences, University of Padova, 35100, Padua, Italy

    Annalisa Angelini, Chiara Castellani & Gaetano Thiene

Authors
  1. Gian Paolo Fadini
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  2. Mattia Albiero
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  14. Angelo Avogaro
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Corresponding author

Correspondence to Gian Paolo Fadini.

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Fadini, G.P., Albiero, M., Seeger, F. et al. Stem cell compartmentalization in diabetes and high cardiovascular risk reveals the role of DPP-4 in diabetic stem cell mobilopathy. Basic Res Cardiol 108, 313 (2013). https://doi.org/10.1007/s00395-012-0313-1

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  • DOI: https://doi.org/10.1007/s00395-012-0313-1

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