Abstract 15891: Effects of Cardiac Nerve Growth Factor Overexpression on Bone Marrow and Peripheral Blood Progenitor Cells after Myocardial Infarction
Progenitor cells (PCs) mobilization from the bone marrow (BM) requires many complex signals, including activation of osteoclasts and release of proteolytic enzymes that detach PCs from the endosteal niche allowing egression into the circulation. We recently demonstrated that nerve growth factor (NGF) gene transfer to the mouse peri-infarct myocardium promotes the expansion of cardiac linnegc-kitpos PCs. Here, we investigate whether NGF can also stimulate the mobilization of BM-derived PCs. Myocardial infarction (MI) was induced in male CD1 mice and the peri-infarct zone was injected with adenoviruses carrying the human NGF gene (Ad.hNGF, 108 p.f.u.) or an empty vector (Ad.Null) as control. Sham-operated mice receiving Ad.Null were used as reference. Immunohistochemical analyses showed that intra-myocardial Ad.hNGF increases the number of TRAPpos activated osteoclasts lining the endosteal surface (27.3±11 and 24.3±10 vs 11.4±6 and 13.7±8 cells/cm2 in Ad.Null at 1 and 2d post-MI, respectively; P<0.05 for both comparisons). MMP9pos cells were also increased in the BM of Ad.hNGF-treated mice at 2 and 3d post-MI (P<0.05 vs MI/Ad.Null for both comparisons). In addition, at 3d post-MI, Ad.hNGF increased the number of CD45negc-kitpos PCs in both the BM endosteal niche (2.0±0.6 vs 1.5±0.2 cell/105 total BM cells in MI/Ad.Null) and parenchyma (39.4±9 vs 26±5 cell/105, P<0.05 for both comparisons). Interestingly, FACS analyses of peripheral blood (PB) mononuclear cells (MNCs) isolated from acute MI (aMI) patients showed an increased number of CD34posc-kitpos cells co-expressing the NGF high-affinity TrkA receptor (P<0.05 vs healthy controls). Finally, in a transwell in vitro migration assay, NGF (50 and 100 ng/mL) attracted both freshly isolated MNCs and human “early EPCs”. Moreover, migration of PB-MNCs towards NGF enriched for both TrkApos cells and ckitpos cells (P<0.05 for both comparison vs 0.1% BSA). In conclusion, post-MI intra-myocardial NGF gene therapy induces activation of osteoclasts and proteolytic enzymes in the mouse BM. The increased number of circulating CD34posc-kitpos PCs expressing the TrkA receptor in aMI patients might suggest that NGF is a relevant factor for PCs mobilization.
- © 2010 by American Heart Association, Inc.