Altered SDF-1-mediated differentiation of bone marrow-derived endothelial progenitor cells in diabetes mellitus
Elena De Falco
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
These authors contributed equally.
Search for more papers by this authorDaniele Avitabile
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
These authors contributed equally.
Search for more papers by this authorPierangela Totta
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
These authors contributed equally.
Search for more papers by this authorStefania Straino
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Search for more papers by this authorFrancesco Spallotta
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Search for more papers by this authorChiara Cencioni
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Search for more papers by this authorAnna Rita Torella
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Search for more papers by this authorRoberto Rizzi
Laboratorio di Biologia Vascolare e Terapia Genica, Centro Cardiologico Monzino – IRCCS, Milan, Italy
Search for more papers by this authorDaniele Porcelli
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Search for more papers by this authorAntonella Zacheo
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Search for more papers by this authorLuca Di Vito
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Search for more papers by this authorGiulio Pompilio
Laboratorio di Biologia Vascolare e Terapia Genica, Centro Cardiologico Monzino – IRCCS, Milan, Italy
Search for more papers by this authorMonica Napolitano
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Search for more papers by this authorGuido Melillo
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Search for more papers by this authorMaurizio C. Capogrossi
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Search for more papers by this authorCorresponding Author
Maurizio Pesce
Laboratorio di Biologia Vascolare e Terapia Genica, Centro Cardiologico Monzino – IRCCS, Milan, Italy
Correspondence to: Maurizio PESCE, Centro Cardiologico Monzino – IRCCS, Via Parea 4, 20138 Milan, Italy.Tel.: +39-0258002019Fax: +39-0258002623E-mail: [email protected]Search for more papers by this authorElena De Falco
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
These authors contributed equally.
Search for more papers by this authorDaniele Avitabile
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
These authors contributed equally.
Search for more papers by this authorPierangela Totta
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
These authors contributed equally.
Search for more papers by this authorStefania Straino
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Search for more papers by this authorFrancesco Spallotta
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Search for more papers by this authorChiara Cencioni
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Search for more papers by this authorAnna Rita Torella
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Search for more papers by this authorRoberto Rizzi
Laboratorio di Biologia Vascolare e Terapia Genica, Centro Cardiologico Monzino – IRCCS, Milan, Italy
Search for more papers by this authorDaniele Porcelli
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Search for more papers by this authorAntonella Zacheo
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Search for more papers by this authorLuca Di Vito
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Search for more papers by this authorGiulio Pompilio
Laboratorio di Biologia Vascolare e Terapia Genica, Centro Cardiologico Monzino – IRCCS, Milan, Italy
Search for more papers by this authorMonica Napolitano
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Search for more papers by this authorGuido Melillo
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Search for more papers by this authorMaurizio C. Capogrossi
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
Search for more papers by this authorCorresponding Author
Maurizio Pesce
Laboratorio di Biologia Vascolare e Terapia Genica, Centro Cardiologico Monzino – IRCCS, Milan, Italy
Correspondence to: Maurizio PESCE, Centro Cardiologico Monzino – IRCCS, Via Parea 4, 20138 Milan, Italy.Tel.: +39-0258002019Fax: +39-0258002623E-mail: [email protected]Search for more papers by this authorAbstract
In diabetic patients and animal models of diabetes mellitus (DM), circulating endothelial progenitor cell (EPC) number is lower than in normoglycaemic conditions and EPC angiogenic properties are inhibited. Stromal cell derived factor-1 (SDF-1) plays a key role in bone marrow (BM) c-kit+ stem cell mobilization into peripheral blood (PB), recruitment from PB into ischemic tissues and differentiation into endothelial cells. The aim of the present study was to examine the effect of DM in vivo and in vitro, on murine BM-derived c-kit+ cells and on their response to SDF-1. Acute hindlimb ischemia was induced in streptozotocin-treated DM and control mice; circulating c-kit+ cells exhibited a rapid increase followed by a return to control levels which was significantly faster in DM than in control mice. CXCR4 expression by BM c-kit+ cells as well as SDF-1 protein levels in the plasma and in the skeletal muscle, both before and after the induction of ischemia, were similar between normoglycaemic and DM mice. However, BM-derived c-kit+ cells from DM mice exhibited an impaired differentiation towards the endothelial phenotype in response to SDF-1; this effect was associated with diminished protein kinase phosphorylation. Interestingly, SDF-1 ability to induce differentiation of c-kit+ cells from DM mice was restored when cells were cultured under normoglycaemic conditions whereas c-kit+ cells from normoglycaemic mice failed to differentiate in response to SDF-1 when they were cultured in hyperglycaemic conditions. These results show that DM diminishes circulating c-kit+ cell number following hindlimb ischemia and inhibits SDF-1-mediated AKT phosphorylation and differentiation towards the endothelial phenotype of BM-derived c-kit+ cells.
Supporting Information
Fig. S1 Scatter plots of physical properties and gating of PB cells from control and DM mice assessed by flow cytometry analysis.
Fig. S2 Surgical manipulation does not induce c-kit+ cell mobilization.
Fig. S3 Plasma and skeletal muscle SDF-1 levels.
Fig. S4 Flow cytometry determination of lineage markers expression into PB from non-diabetic animals.
Fig. S5 Effect of SDF-1 on immunophenotypical characterization and Ac-LDL-DiI uptake of cultured c-kit+ cells.
Fig. S6 DM does not alter stem cell markers expression in BMderived c-kit+ cells.
Fig. S7 DM does not modulate BM-derived c-kit+ cells clonogenicity and migration in response to SDF-1.
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