Basic Research in Cardiology

, 108:313 | Cite as

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

  • Gian Paolo Fadini
  • Mattia Albiero
  • Florian Seeger
  • Nicol Poncina
  • Lisa Menegazzo
  • Annalisa Angelini
  • Chiara Castellani
  • Gaetano Thiene
  • Carlo Agostini
  • Roberta Cappellari
  • Elisa Boscaro
  • Andreas Zeiher
  • Stefanie Dimmeler
  • Angelo Avogaro
Original Contribution

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.

Keywords

Regeneration Bone marrow Endothelium Angiogenesis SDF-1 

Supplementary material

395_2012_313_MOESM1_ESM.doc (122 kb)
Supplementary material 1 (DOC 122 kb)
395_2012_313_MOESM2_ESM.ppt (13.7 mb)
Supplementary material 2 (PPT 14036 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Gian Paolo Fadini
    • 1
    • 2
  • Mattia Albiero
    • 2
  • Florian Seeger
    • 3
    • 4
  • Nicol Poncina
    • 1
    • 2
  • Lisa Menegazzo
    • 1
    • 2
  • Annalisa Angelini
    • 5
  • Chiara Castellani
    • 5
  • Gaetano Thiene
    • 5
  • Carlo Agostini
    • 1
    • 2
  • Roberta Cappellari
    • 2
  • Elisa Boscaro
    • 1
    • 2
  • Andreas Zeiher
    • 3
    • 4
  • Stefanie Dimmeler
    • 3
  • Angelo Avogaro
    • 1
    • 2
  1. 1.Department of MedicineUniversity of PadovaPaduaItaly
  2. 2.Venetian Institute of Molecular MedicinePaduaItaly
  3. 3.Institute for Cardiovascular RegenerationCentre of Molecular MedicineFrankfurtGermany
  4. 4.Department of Medicine IIIFrankfurt UniversityFrankfurtGermany
  5. 5.Department of Thoracic, Cardiac and Vascular SciencesUniversity of PadovaPaduaItaly

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