Stem cell compartmentalization in diabetes and high cardiovascular risk reveals the role of DPP-4 in diabetic stem cell
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ORIGINAL CONTRIBUTION
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
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Received: 30 July 2012 / Revised: 18 October 2012 / Accepted: 9 November 2012 / Published online: 22 November 2012 Ó Springer-Verlag Berlin Heidelberg 2012
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
Electronic supplementary material The online version of this article (doi:10.1007/s00395-012-0313-1) contains supplementary material, which is available to authorized users.
risk factors especially diabetes. High activity of DPP-4, a regulator of the mobilizing chemokine SDF-1a, 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 tissuespecific DPP-4 dysregulation.
G. P. Fadini (&) N. Poncina L. Menegazzo C. Agostini E. Boscaro A. Avogaro Department of Medicine, University of Padova, Via Giustiniani, 2, 35100 Padua, Italy e-mail: [email protected]; [email protected]
Keywords Regeneration Bone marrow Endothelium Angiogenesis SDF-1
G. P. Fadini M. Albiero N. Poncina L. Menegazzo C. Agostini R. Cappellari E. Boscaro A. Avogaro Venetian Institute of Molecular Medicine, 35100 Padua, Italy
Bone marrow (BM) derived stem and progenitor cells contribute to cardiovascular homeostasis through several mechanisms including differentiation into vascular phenotypes and paracrine signals [3, 22, 23, 30, 31]. The cross-talks between cardiovascular disease (CVD) and the BM system
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