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. 2009 Mar 15;87(5):642-52.
doi: 10.1097/TP.0b013e31819609d9.

Comparison of transplantation of adipose tissue- and bone marrow-derived mesenchymal stem cells in the infarcted heart

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Comparison of transplantation of adipose tissue- and bone marrow-derived mesenchymal stem cells in the infarcted heart

Koen E A van der Bogt et al. Transplantation. .

Abstract

Background: Mesenchymal stem cells hold promise for cardiovascular regenerative therapy. Derivation of these cells from the adipose tissue might be easier compared with bone marrow. However, the in vivo fate and function of adipose stromal cells (ASC) in the infarcted heart has never been compared directly to bone marrow-derived mesenchymal cells (MSC).

Methods: ASC and MSC were isolated from transgenic FVB mice with a beta-actin promoter driving firefly luciferase and green fluorescent protein double fusion reporter gene, and they were characterized using flow cytometry, microscopy, bioluminescence imaging and luminometry. FVB mice (n=8 per group) underwent myocardial infarction followed by intramyocardial injection of 5x10(5) ASC, MSC, fibroblasts (Fibro, positive control), or saline (negative control). Cell survival was measured using bioluminescence imaging for 6 weeks and cardiac function was monitored by echocardiography and pressure-volume analysis. Ventricular morphology was assessed using histology.

Results: ASC and MSC were CD34(-), CD45(-), c-Kit(-), CD90(+), Sca-1(+), shared similar morphology and had a population doubling time of approximately 2 days. Cells expressed Fluc reporter genes in a number-dependent fashion as confirmed by luminometry. After cardiac transplantation, both cell types showed drastic donor cell death within 4 to 5 weeks. Furthermore, transplantation of either cell type was not capable of preserving ventricular function and dimensions, as confirmed by pressure-volume-loops and histology.

Conclusion: This is the first study comparing the in vivo behavior of both cell types in the infarcted heart. ASC and MSC do not tolerate well in the cardiac environment, resulting in acute donor cell death and a subsequent loss of cardiac function similar to control groups.

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Figures

Figure 1
Figure 1. In vitro assessment of cell surface marker expression
(a) After 8−10 passages, flow cytometry showed that the ASC population was depleted from hematopoietic cells. Moreover, these cells tested negative for CD106, but positive for the stem cell antigen (Sca-1). (b) MSC also showed negative hematopoietic expression, but differed from their adipose tissue-derived counterparts regarding a positive expression for CD106. Dotted, light grey areas represent isotype controls. (c) Both ASC and MSC expressed the mesenchymal-specific marker CD90 (Black areas represent isotype controls).
Figure 2
Figure 2. In vitro characterization of morphology, expansion time, and reporter gene expression
(a) When kept into culture, all cell types shared a spindle-shaped morphology (Bright-field Hoffman modulated contrast image, bar represents 20μm). (b) After an initial period of relatively slower in vitro growth of MSC, all cell types had mutual doubling times of approximately 2 days at passage 9. Bars represent mean ± SEM. (c) In vitro optical bioluminescence imaging (BLI) signal from firefly luciferase (Fluc) expression of increasing numbers of cells in 24-well plates show a correlative increase in signal intensity. Scale bars represent peak signal in photons/s/cm2/sr. (d) Lysates from the cell populations shown in figure 2c also showed robust correlation of cell number with Fluc enzyme on conventional luminometry.
Figure 3
Figure 3. Longitudinal in vivo optical bioluminescence imaging (BLI) of intramyocardially transplanted cells in living mice
(a) Representative figures of animals within each group show that, after an initial strong cardiac signal 2 days after transplantation, robust cell death resulted in a remarkable decrease in signal over 4 weeks. Scale bars represent BLI signal in photons/s/cm2/sr. (b-d) Graphic representation of decreasing signals in the (b) ASC, (c) MSC, and (d) Fibro groups which are indicative of cell death. Background signals (dotted line) were reached between week 3 (Fibro) to week 5 (MSC) (n>7 in all groups, * indicates P<0.05 compared to the signal on day 2, ANOVA). (e) Normalized graph of reporter gene signals from transplanted cells showing that, when compared over time and controlled for initial differences in signal between cell types, there were no significant differences between ASC, MSC, and cellular control groups (Bars represent mean ± SEM, p=NS, repeated measurements ANOVA).
Figure 4
Figure 4. In vivo measurements of cardiac function over time
(a) Representative M-mode traced two-dimensional picture taken at the level of the papillary muscle whereby left ventricular diastolic and systolic diameters can be measured. (b,c) Cell transplantation after myocardial infarction was not capable of preventing an increase in left ventricular diastolic (LVdd, b) or systolic diameters (LVsd, c). (d) Left ventricular performance, as measured by left ventricular fractional shortening (LVFS), was preserved only in the short term after cell transplantation. The dotted line represents the mean pre-operative fractional shortening of all operated animals. Six weeks after transplantation, there was a comparable LVFS in the ASC and MSC groups. Although cardiac function was slightly better than control groups, there was no significant difference when controlled for the trend over time (Bars represent means ± SEM, n>7 in all groups, p=NS, repeated measurements ANOVA).
Figure 5
Figure 5. Invasive steady-state pressure-volume measurements of cardiac performance
(a,b) Pressure-volume recordings of (a) a normal, non-operated animal, and (b) PBS control animal 6 weeks after infarction with typical right shift. (c) Mean values of left ventricular volumes, as measured by pressure-volume loops, were correlative with the earlier acquired left ventricular diameters, as measured by echocardiography (dots represent mean measured values from each group). (d, e) Although transplantation of ASC and MSC resulted in a similar trend of preservation of (d) stroke work and (e) cardiac output compared to the PBS group, there was no significant difference compared to the cellular control. (f) Although maximum dP/dt was not different among groups, there was a (g) trend towards better minimum dP/dt, which is indicative of better ventricular relaxation. (h) Similarly, there was a trend towards lower afterload, as shown by lower arterial elastance, in all cellular groups compared to the PBS group (Bars represent means ± SEM, n>6 in every group, p=NS, ANOVA).
Figure 6
Figure 6. Macroscopic pictures of representative explanted hearts show no prevention of cardiac remodeling after cell transplantation
6 weeks after transplantation of (a) ASC, (b) MSC, and (c) Fibro there are no gross signs of tissue preservation compared to (d) PBS (H&E stained slides of representative hearts).

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