Cardiosphere-Derived Cells Improve Function in the Infarcted Rat Heart for at Least 16 Weeks – an MRI Study

Abstract

AimsEndogenous cardiac progenitor cells, expanded from explants via cardiosphere formation, present a promising cell source to prevent heart failure following myocardial infarction. Here we used cine-magnetic resonance imaging (MRI) to track administered cardiosphere-derived cells (CDCs) and to measure changes in cardiac function over four months in the infarcted rat heart.Methods and ResultsCDCs, cultured from neonatal rat heart, comprised a heterogeneous population including cells expressing the mesenchymal markers CD90 and CD105, the stem cell marker c-kit and the pluripotency markers Sox2, Oct3/4 and Klf-4. CDCs (2×106) expressing green fluorescent protein (GFP+) were labelled with fluorescent micron-sized particles of iron oxide (MPIO). Labelled cells were administered to the infarcted rat hearts (n = 7) by intramyocardial injection immediately following reperfusion, then by systemic infusion (4×106) 2 days later. A control group (n = 7) was administered cell medium. MR hypointensities caused by the MPIOs were detected at all times and GFP+ cells containing MPIO particles were identified in tissue slices at 16 weeks. At two days after infarction, cardiac function was similar between groups. By 6 weeks, ejection fractions in control hearts had significantly decreased (47±2%), but this was not evident in CDC-treated hearts (56±3%). The significantly higher ejection fractions in the CDC-treated group were maintained for a further 10 weeks. In addition, CDC-treated rat hearts had significantly increased capillary density in the peri-infarct region and lower infarct sizes. MPIO-labelled cells also expressed cardiac troponin I, von Willebrand factor and smooth muscle actin, suggesting their differentiation along the cardiomyocyte lineage and the formation of new blood vessels.ConclusionsCDCs were retained in the infarcted rat heart for 16 weeks and improved cardiac function.

Isolation and characterization of resident endogenous c-Kit+ cardiac stem cells from the adult mouse and rat heart

“…Early trials of cardiac repair and regeneration via transplantation of bone marrow-derived stem/progenitor cells have given mixed and modest results (for review see 37 ), indicating that a better understanding of the relevant cell biology is required to provide a consistently effective therapeutic option for stem cell-based regenerative treatments in the heart. The presence of resident eCSCs in the adult heart, including human, has been determined by several groups 2,4,6,[8][9][10]12,14,17,[38][39][40][41][42] . These cells can be isolated and propagated in vitro to produce large numbers of cells without reaching growth arrest or their being a change in cell characteristic.…”

Acute Preconditioning of Cardiac Progenitor Cells with Hydrogen Peroxide Enhances Angiogenic Pathways Following Ischemia-Reperfusion Injury

“…These data suggest that there may be improvements in certain measures of heart function with H 2 O 2 preconditioned CPCs, specifically those related to diastolic contractility/ relaxation, but these did not translate to global changes in the ejection fraction. While this may initially seem confusing, some prior studies have demonstrated that changes in function may be more apparent at longer time points [33][34][35]. Moreover, the fact that H 2 O 2 preconditioned CPCs are not generating large amounts of new myocytes may also contribute to this phenomenon.…”

Cellular and Molecular Characterization of Human Cardiac Stem Cells Reveals Key Features Essential for Their Function and Safety

“…Several studies have been carried out to isolate and characterize cardiac precursor cells (mainly c-Kit + , Sca-1 + , and cardiospheres) from normal and pathologic fetal and adult heart biopsies [12][13][14][15]. Different protocols have been developed to improve CSC isolation methods, resulting in the generation of a specific population of CSCs [16][17][18][19]. In addition to cell sorting and culture of explants, clonogenic expansion of cells has been described as another CSCs isolation method [20].…”