Stem cell compartmentalization in diabetes and hig

Authors: 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

Publish Date: 2012/11/22

Volume: 108, Issue: 1, Pages: 313-

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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 datadriven approach to test candidate stem cell mobilizing mechanisms in preclinical models We found that PB and BM CD34+ cell counts were directly correlated and that most circulating CD34+ cells were viable nonproliferating and derived from the BM Thus we analyzed PB and BM CD34+ cell levels as a twocompartment model in 72 patients with or without cardiovascular disease Selforganizing maps showed that disturbed compartmentalization of CD34+ cells was associated with aging and cardiovascular risk factors especially diabetes High activity of DPP4 a regulator of the mobilizing chemokine SDF1α was associated with altered stem cell compartmentalization For validation of these findings we assessed the role of DPP4 in the BM mobilization response of diabetic rats Diabetes differentially affected DPP4 activity in PB and BM and impaired stem/progenitor cell mobilization after ischemia or GCSF administration DPP4 activity in the BM was required for the mobilizing effect of GCSF while in PB it blunted ischemiainduced mobilization Indeed DPP4 deficiency restored ischemia but not GCSFinduced 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 DPP4 dysregulation

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