Abstract
We compared the functional outcome of Isl-1+ cardiac progenitors, CD90+ bone marrow-derived progenitor cells, and the combination of the two in a rat myocardial infarction (MI) model. Isl-1+ cells were isolated from embryonic day 12.5 (E12.5) rat hearts and expanded in vitro. Thy-1+/CD90+ cells were isolated from the bone marrow of adult Sprague-Dawley rats by immunomagnetic cell sorting. Six-week-old female Sprague-Dawley rats underwent permanent left anterior descending (LAD) coronary artery ligation and received intramyocardial injection of either saline, Isl-1+ cells, CD90+ cells, or a combination of Isl-1+ and CD90+ cells, at the time of infarction. Cells were delivered transepicardially to the peri-infarct zone. Left ventricular function was assessed by transthoracic echocardiography at 1- and 4-week post-MI and by Millar catheterization (-dP/dt and +dP/dt) at 4-week post-MI. Fluorescence in situ hybridization (Isl-1+cells) and monochrystalline iron oxide nanoparticles labeling (MION; CD90+ cells) were performed to assess biodistribution of transplanted cells. Only the combination of cells demonstrated a significant improvement of cardiac function as assessed by anterior wall contractility, dP/dt (max), and dP/dt (min), compared to Isl-1+ or CD90+ cell monotherapies. In the combination cell group, viable cells were detected at week 4 when anterior wall motion was completely restored. In conclusion, the combination of Isl-1+ cardiac progenitors and adult bone marrow-derived CD90+ cells shows prolonged and robust myocardial tissue repair and provides support for the use of complementary cell populations to enhance myocardial repair.
Highlights
Despite recent advances in medical therapy, ischemic heart disease remains one of the leading causes of morbidity and mortality worldwide
The hearts from embryonic day 12.5 (ED12.5) rats were cut into four pieces, washed repeatedly in ice-cold Hank’s balanced salt solution (HBSS) without Ca2+, and predigested overnight in 0.5 mg/ml trypsin in HBSS at 4°C, under constant shaking, to remove blood and dead cells
monochrystalline iron oxide nanoparticles labeling (MION) incorporation would facilitate in vivo tracking of these cells
Summary
Despite recent advances in medical therapy, ischemic heart disease remains one of the leading causes of morbidity and mortality worldwide. The optimal stem cell type for regenerating the heart has been under debate for many years. The adult heart contains its own reservoir of endogenous cardiac stem cells that can, to some extent, generate new cardiomyocytes [1, 2]. Stem Cells International [5, 6], side population (SP) cells expressing Abcg2 [7], and first and second heart field cells (Tbx5+ and LIM homeodomain transcription factor Islet-1 (Isl-1), respectively) [2, 8,9,10,11]. Isl was found to distinguish this key stem cell population derived from the second heart field [8]
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