To examine whether cardiac chemical exchange saturation transfer (CEST) imaging can be serially and noninvasively used to probe cell survival or rejection after intramyocardial implantation in mice.
Materials and Methods:
Experiments were compliant with the National Institutes of Health Guidelines on the Use of Laboratory Animals and approved by the Institutional Animal Care and Use Committee. One million C2C12 cells labeled with either europium (Eu) 10-(2-hydroxypropyl)-1,4,7-tetraazacyclododecane-1,4,7-triacetic acid (HP-DO3A) or saline via the hypotonic swelling technique were implanted into the anterior-lateral left ventricular wall in C57BL/6J (allogeneic model, n = 17) and C3H (syngeneic model, n = 13) mice. Imaging (frequency offsets of ±15 parts per million) was performed 1, 10, and 20 days after implantation, with the asymmetrical magnetization transfer ratio (MTRasym) calculated from image pairs. Histologic examination was performed at the conclusion of imaging. Changes in MTRasym over time and between mice were assessed by using two-way repeated-measures analysis of variance.
MTRasym was significantly higher in C3H and C57BL/6J mice in grafts of Eu-HP-DO3A–labeled cells (40.2% ± 5.0 vs 37.8% ± 7.0, respectively) compared with surrounding tissue (−0.67% ± 1.7 vs −1.8% ± 5.3, respectively; P < .001) and saline-labeled grafts (−0.4% ± 6.0 vs −1.2% ± 3.6, respectively; P < .001) at day 1. In C3H mice, MTRasym remained increased (31.3% ± 9.2 on day 10, 28.7% ± 5.2 on day 20; P < .001 vs septum) in areas of in Eu-HP-DO3A–labeled cell grafts. In C57BL/6J mice, corresponding MTRasym values (11.3% ± 8.1 on day 10, 5.1% ± 9.4 on day 20; P < .001 vs day 1) were similar to surrounding myocardium by day 20 (P = .409). Histologic findings confirmed cell rejection in C57BL/6J mice. Estimation of graft area was similar with cardiac CEST imaging and histologic examination (R2 = 0.89).
Cardiac CEST imaging can be used to image cell survival and rejection in preclinical models of cell therapy.
Digital Object Identifier (DOI)
Study supported by the National Institutes of Health (P20GM103527sub5039, R01HL128592). M.H.V. supported by a grant from the Slomo and Cindy Silvian Foundation.
Pumphrey, Ashley L.; Ye, Shaojing; Yang, Zhengshi; Simkin, Jennifer; Gensel, John C.; Abdel-Latif, Ahmed; and Vandsburger, Moriel H., "Cardiac Chemical Exchange Saturation Transfer MR Imaging Tracking of Cell Survival or Rejection in Mouse Models of Cell Therapy" (2017). Saha Cardiovascular Research Center Faculty Publications. 31.
Appendix E1: Supplemental Methods & Supplemental Discussion
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