Abstract 612: Regulation of Bone Marrow Stem/Progenitor Cell Mobilization by Leptin
Background: Leptin, an adipocyte-derived hormone, elicits a variety of physiological functions by acting on leptin receptor (LepR). LepR is expressed in bone marrow hematopoietic stem/progenitor cells (BMSPCs) as well as in mesenchymal stromal cells, which play an important role in the maintenance and retention of BMSPCs. Cytokines such as G-CSF induce mobilization of BMSPCs, in part, via acting on MSCs.
Aim: In this study the role of leptin in the physiological, and G-CSF-induced mobilization of BMSPCs was evaluated.
Methods: The study was carried out in control and streptozotocin (STZ)-induced diabetic mice (C57Bl/6j), and in mice with genetic ablation of leptin receptor (LepR+/- and LepR-/- (db/db) mice). Circulating white blood cells (WBCs), lineage- cells (Lin-), and Lin-Sca-1+cKit+ (LSK), cells were enumerated by flow cytometry in different treatment groups. Mobilization of different cell populations was induced by G-CSF (125μg/Kg, s.c., twice a day, 4 days). Effects of leptin (600μg/Kg, i.p., 5 days) or LepR antagonist, PESLAN-1 (5mg/Kg, s.c., once-in-two-days, 14 days, were evaluated on basal as wells as G-CSF-mobilized levels of different cell populations.
Results: Leptin treatment increased basal levels of WBCs (P<0.005), and decreased Lin- (P<0.05) or LSK (P<0.05) cells compared to the control (n=5). Leptin treatment also decreased Lin- (P<0.005) and LSK (P<0.005) cells but WBCs mobilized by G-CSF. PESLAN-1 exacerbated G-CSF-induced mobilization of LSK cells (P<0.05 vs PESLAN-1-untreated). G-CSF-mobilized WBCs, Lin- and LSK cells were higher in LepR+/- or LepR-/- (P<0.05 to 0.001, n=6) mice compared to wild-type (WT) control (LepR+/+) mice. Since db/db mice are diabetic, we verified the effect of diabetes in WT/LepR+/+ mice. In STZ-induced diabetic mice (n=7), G-CSF- induced mobilization was reduced (WBCs (P<0.05), Lin- (P<0.005), and LSK (P<0.001) compared to nondiabetic, n=7) in contrast to the observations in diabetic LepR-/- mice.
Conclusions: These results suggest that in physiological conditions, leptin-LepR signaling tends to retain BMSPCs, and oppose G-CSF-induced mobilization. Furthermore, these results imply that LepR blockade could overcome diabetes-induced dysfunction of BMSPC mobilization.
Author Disclosures: Y.P.R. Jarajapu: None. G. Vasam: None.
This research has received full or partial funding support from the American Heart Association.
- © 2015 by American Heart Association, Inc.