Original Contribution

Basic Research in Cardiology

, 108:313

First online:

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

  • Gian Paolo FadiniAffiliated withDepartment of Medicine, University of PadovaVenetian Institute of Molecular Medicine Email author 
  • , Mattia AlbieroAffiliated withVenetian Institute of Molecular Medicine
  • , Florian SeegerAffiliated withInstitute for Cardiovascular Regeneration, Centre of Molecular MedicineDepartment of Medicine III, Frankfurt University
  • , Nicol PoncinaAffiliated withDepartment of Medicine, University of PadovaVenetian Institute of Molecular Medicine
  • , Lisa MenegazzoAffiliated withDepartment of Medicine, University of PadovaVenetian Institute of Molecular Medicine
  • , Annalisa AngeliniAffiliated withDepartment of Thoracic, Cardiac and Vascular Sciences, University of Padova
  • , Chiara CastellaniAffiliated withDepartment of Thoracic, Cardiac and Vascular Sciences, University of Padova
  • , Gaetano ThieneAffiliated withDepartment of Thoracic, Cardiac and Vascular Sciences, University of Padova
  • , Carlo AgostiniAffiliated withDepartment of Medicine, University of PadovaVenetian Institute of Molecular Medicine
    • , Roberta CappellariAffiliated withVenetian Institute of Molecular Medicine
    • , Elisa BoscaroAffiliated withDepartment of Medicine, University of PadovaVenetian Institute of Molecular Medicine
    • , Andreas ZeiherAffiliated withInstitute for Cardiovascular Regeneration, Centre of Molecular MedicineDepartment of Medicine III, Frankfurt University
    • , Stefanie DimmelerAffiliated withInstitute for Cardiovascular Regeneration, Centre of Molecular Medicine
    • , Angelo AvogaroAffiliated withDepartment of Medicine, University of PadovaVenetian Institute of Molecular Medicine

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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.

Keywords

Regeneration Bone marrow Endothelium Angiogenesis SDF-1