Myocardial substrate and route of administration determine acute cardiac retention and lung bio-distribution of cardiosphere-derived cells

Abstract

Background Quantification of acute myocardial retention and lung bio-distribution of cardiosphere-derived cells (CDCs) following transplantation is important to improve engraftment. Methods and results We studied acute(1 hour) cardiac/lung retention in 4 groups (n = 25) of rats (normal—NL, acute ischemia-reperfusion—AI-RM, acute permanent ligation—PL, and chronic infarct by ischemia-reperfusion—CI-R) using intra-myocardial delivery, 1 group using intracoronary delivery (acute ischemia-reperfusion, AI-RC, n = 5) and 1 group using intravenous delivery (acute ischemia-reperfusion, AI-RV, n = 5) of CDCs by PET. Cardiac retention was similar in the NL, AI-RM, CI-R, and A-IRC groups (13.6% ± 2.3% vs 12.0% ± 3.9% vs 9.9 ± 2.8 vs 15.4% ± 5.5%; P = NS), but higher in PL animals (22.9% ± 5.2%; P < .05). Low cardiac retention was associated with significantly higher lung activity in NL and AI-RM groups (43.3% ± 5.6% and 39.9% ± 9.3%), compared to PL (28.5% ± 5.9%), CI-R (20.2% ± 9.3%), and A-IRC (19.9% ± 5.6%) animals (P < .05 vs AI-RM and NL). Lung activity was highest following intravenous CDC delivery (55.1% ± 9.3%, P < .001) and was associated with very low cardiac retention (0.8% ± 1.06%). Two-photon microscopy indicated that CDCs escaped to the lungs via the coronary veins following intra-myocardial injection. Conclusions Acute cardiac retention and lung bio-distribution vary with the myocardial substrate and injection route. Intra-myocardially injected CDCs escape into the lungs via coronary veins, an effect that is more pronounced in perfused myocardium.

The effect of encapsulation of cardiac stem cells within matrix-enriched hydrogel capsules on cell survival, post-ischemic cell retention and cardiac function

“…Recently, transplantation of ex vivo proliferated cardiac stem cells (CSC) has garnered attention as a promising means of improving left ventricle function while reducing infarct size [2,3]. Despite these developments, the full capacity of CSCs to repair myocardium is limited by modest retention immediately after transplant into the vascular heart which, in part results in very low long term survival [4,5]. This notion is supported by several recent papers demonstrating early CSC engraftment predicts later cardiac recovery from myocardial infarction while methods targeted towards boosting the early retention of transplanted cells enhance cells-mediated cardiac repair [6][7][8][9].…”

SPECT and PET to optimize cardiac stem cell therapy

“…Experimental and clinical studies of stem cell transplantation in the heart reveal that stem cells can differentiate into cardiac myocytes, endothelial cells, and secrete paracrine factors that reduce myocyte death, improve the microcirculation, attenuate adverse remodeling, and boost the regenerative capacity of the heart postinfarct. Unfortunately, the functional benefit seen following transplantation is modest at best, 1,7,9,13,16,[19][20][21]29 irrespective of the cell type and mode of delivery, because of very low levels of engraftment stemming from cell egress from the heart immediately following intra-myocardial cell delivery (low acute retention 30 ) and continued cell loss due to anoikis/apoptosis and necrosis (low engraftment 31,32 ). Low levels of cell engraftment results in small numbers of cells being available for cardiac differentiation and for secretion of paracrine factors.…”

“…[52][53][54][55] Nuclear imaging of cells expressing the herpes simplex virus thymidine kinase (HSV-tk) 56 or human sodium-iodide symporter (hNIS) [57][58][59] has been used for cell tracking in the heart. Additionally, direct or ex vivo cell labeling prior to cell transplantation, with 111 indium-oxine [44][45][46] and [ 99m Tc] hexamethylpropylenamine oxime ( 99m Tc-HMPAO), 60 has been used in conjunction with single-photon emission computed tomography (SPECT), and 64 Cu-PTSM (copper-64-pyruvaldehyde-bis(N 4 -methylthiosemicarbazone ( 64 Cu-PTSM)) 47 and 18 F-fluoro-deoxy-glucose ( 18 FDG) 30 with positron emission tomography (PET) for tracking various cell types following transplantation. The reporter gene strategy is superior to ex vivo labeling of cells for longterm assessment of engraftment, because transplanted cell viability is a prerequisite for reporter gene expression.…”

The Role ofNotch 1Activation in Cardiosphere Derived Cell Differentiation

“…Cardiosphere derived cells (CDC), a major source of cardiac multipotent stem cells, express GATA4 and Nestin and can differentiate into cardiomyocytes and typical neural crest-derived cells, including neurons, glia, and SMC [8]. CDC have proven functional benefits in cardiac regeneration and can be isolated from human atrium or endomyocardial biopsy specimens [9][10][11][12][13][14][15][16]. However, the mechanisms that regulate the differentiation of CDC into cardiovascular cells are poorly understood.…”