title: Stem cell compartmentalization in diabetes and high cardiovascular risk reveals the role of DPP-4 in diabetic stem cell mobilopathy.
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.
authors.affiliation: Department of Medicine, University of Padova, Via Giustiniani, 2, 35100 Padua, Italy. gianpaolofadini@hotmail.com
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Fadini
authors.forename: Mattia
authors.initials: M
authors.lastname: Albiero
authors.forename: Florian
authors.initials: F
authors.lastname: Seeger
authors.forename: Nicol
authors.initials: N
authors.lastname: Poncina
authors.forename: Lisa
authors.initials: L
authors.lastname: Menegazzo
authors.forename: Annalisa
authors.initials: A
authors.lastname: Angelini
authors.forename: Chiara
authors.initials: C
authors.lastname: Castellani
authors.forename: Gaetano
authors.initials: G
authors.lastname: Thiene
authors.forename: Carlo
authors.initials: C
authors.lastname: Agostini
authors.forename: Roberta
authors.initials: R
authors.lastname: Cappellari
authors.forename: Elisa
authors.initials: E
authors.lastname: Boscaro
authors.forename: Andreas
authors.initials: A
authors.lastname: Zeiher
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
authors.forename: Angelo
authors.initials: A
authors.lastname: Avogaro
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D001854:Bone Marrow Cells / Q000502:physiology; D002318:Cardiovascular Diseases / Q000209:etiology*; D002451:Cell Compartmentation; D054377:Chemokine CXCL12 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D018819:Dipeptidyl Peptidase 4 / Q000502:physiology*; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D008875:Middle Aged; D018919:Neovascularization, Physiologic; D051381:Rats; D011916:Rats, Inbred F344; D012307:Risk Factors; D013234:Stem Cells / Q000502:physiology*
chemical_list: D018952:Antigens, CD34; D054377:Chemokine CXCL12; D016179:Granulocyte Colony-Stimulating Factor; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse