Diabetes Impairs Bone Marrow Microenvironment Affecting Progenitor Cell Number, Mobilization and Engraftment in Humans.

Abstract 1482

Poster Board I-505

Alterations in cell trafficking and chemoattractive properties may represent basic mechanisms responsible for organ pathology in diabetes mellitus (DM). These functional events involving both inflammatory and progenitor cells may be translated in the proneness to major septic events and effaced reparative response characterizing the clinical course of the disease. To determine whether DM affects BM progenitor cell number and function, tissue resident and GSF mobilized disease-free BM CD34pos cells were evaluated in 19 DM and 38 non-diabetic control (CTR) biopsies and in 18 DM and 48 CTR patients undergoing autologous BM transplantation. DM was documented by the presence of glucose intolerance, HbA1C > 6 g% and need of high dose insulin treatment. CTR were selected on the basis of normal glucose tolerance and the absence of neoplastic infiltration and/or morphologic changes in cellular hematopoietic compartments compatible with hematologic disorders. Reduction in trabecular bone, fat accumulation, rearrangement of microvascular structures and marked DNA oxidative damage characterized BM structural and cellular remodelling in DM. Immunohistochemical and FACS analysis documented that DM produced a 50% reduction in the number of both BM resident and mobilized CD34pos Linneg cells. In addition only 16% of diabetic patients were able to mobilize >10 × 106 CD34pos cells/kg compared to 62% of CTR. After infusion of mobilized CD34pos progenitors, BM engraftment was partially prolonged in diabetic patients. Severe impairment of SC engraftment by DM was striking by the comparative analysis of the infusion of similar number of mononuclear cells (nearly 180 ×106/Kg) directly harvested from the bone marrow of DM and CTR patients. In this setting, PMN and Plts recovery was delayed by nearly 2 and 4 weeks, respectively. Thus, DM severely affects human progenitor cell function and BM microenvronment in vivo inevitably impairing the outcome of BM transplantation. Whether all these changes are due to specific perturbation of the GSF-dependent SDF-1/CXCR4 axis and whether drugs interfering with ROS mediated damage may reverse this phenomenon is under intense investigation.