Abstract 17145: Non-invasive Tracking of Endogenous Bone Marrow Cell Recruitment After Myocardial Infarction in Mice
Limited clinical benefit of exogenous stem cell therapy has renewed interest in strategies to enhance endogenous cell recruitment after myocardial infarction (MI). Nuclear imaging of stem cell trafficking has been restricted to exogenous stem cells, and may be compromised by low cell retention and continuous expression of reporter genes. We evaluated the feasibility of transplanting reporter gene-labeled endogenous bone marrow under an inducible promoter as a platform for imaging endogenous cell recruitment in MI. Sodium iodide symporter (NIS) was cloned into a lentiviral vector under constitutive (c-NIS) or doxycycline-inducible (i-NIS) promoter. Hematopoetic stem cells (HSCs) were transduced with c-NIS, i-NIS, or a null lentivirus. C57Bl/6 mice (n=57) underwent bone marrow ablation by irradiation and bone marrow was replaced with transduced HSCs (5x105). After 8 weeks, mice underwent coronary artery ligation. Doxycycline (dox) was provided to a subset of i-NIS mice 4d before surgery. Serial SPECT imaging demonstrated increased radioiodine uptake in the perfusion defect of c-NIS compared to NIS-null mice (TBR infarct: MI+3d, 3.0±0.3 v 1.6±0.1 p<0.001; MI+7d, 3.1±0.9 v 1.4±0.3 p<0.01), and comparable uptake in i-NIS transplanted mice. Infarct-to-remote-myocardium radioiodine uptake ratio was 6.5±0.2% higher in c-NIS versus NIS null (p<0.05). Dox-induced i-NIS mice exhibited increased radioiodine uptake in whole myocardium compared to non-induced i-NIS at 1d post-MI (TBR: 2.0±0.3 v 1.6±0.3, p=0.04). This difference dissipated at 7d (TBR 1.5±0.5 v 1.3±0.1, p=0.27). Multi-isotope autoradiography confirmed the presence of radioiodine within the infarct region, associated with histologic markers of inflammation. Bone marrow transplant with NIS reporter gene-labeled HSCs enabled tracking of cell homing post-MI. The inducible construct has the advantage for delivery and/or monitoring of a therapeutic agent with exquisite temporal control.
Author Disclosures: J.T. Thackeray: None. M. Korf-Klingebiel: None. Y. Wang: None. O.S. Kustikova: None. J.P. Bankstahl: None. K.C. Wollert: None. F.M. Bengel: None.
- © 2015 by American Heart Association, Inc.