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Multimodality Noninvasive Imaging Demonstrates In Vivo Cardiac Regeneration After Mesenchymal Stem Cell Therapy

Luciano C. Amado, MD^_*,, Karl H. Schuleri, MD^_*,, Anastasios P. Saliaris, MD^_*,, Andrew J. Boyle, MBBS, PhD^_*,, Robert Helm, MD^_*, Behzad Oskouei, MD^_*,, Marco Centola, MD^_*,, Virginia Eneboe, VT^_*,, Randell Young, MVD, Joao A.C. Lima, MD^_*, Albert C. Lardo, PhD^_*, Alan W. Heldman, MD^_*, and Joshua M. Hare, MD^_*,,1,_*

^_* Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Institute for Cell Engineering (ICE), Johns Hopkins University School of Medicine, Baltimore, Maryland
OsirisTherapeutics, Baltimore, Maryland

View larger version (56K): [in this window] [in a new window] [Download PPT slide]   Figure 1 Multi-detector computed tomography scan of a pig 1 week after myocardial infarction. The different tissue densities of the infarct scar and the sub-endocardial rim of viable tissue are clearly apparent. The sub-endocardial rim has a density similar to the myocardium outside the infarct zone. The relative densities in Hounsfield units (HU) are also represented. MSC = mesenchymal stem cell.

View larger version (78K): [in this window] [in a new window] [Download PPT slide]   Figure 2 Multi-detector computed tomography scan of the same mesenchymal stem cell (MSC)-treated animal at 5 days (A), 4 weeks (B), and 8 weeks (C) after MSC injection. There is a time-dependent reduction in the thickness of the infarct scar and a corresponding increase in the thickness of the sub-endocardial rim of tissue over the 8-week follow-up.

View larger version (75K): [in this window] [in a new window] [Download PPT slide]   Figure 3 (A) Multi-detector computed tomography scan of representative myocardial infarcts at weeks 1 and 8 after stem cell injection. As indicated by the arrows, both infarct zones are characterized by the presence of a rim of myocardial tissue on their endocardial surface. However, the thickness of this rim progressively increases in mesenchymal stem cell (MSC)-treated animals and remains unchanged in control subjects. (B) Representative pathology specimens from control and MSC-treated animals confirm increased sub-endocardial rim thickness in the treated animals.

View larger version (99K): [in this window] [in a new window] [Download PPT slide]   Figure 4 Hematoxylin and eosin (H&E) stain of tissue obtained from the subendocardial rim (A) and the remote zone (B) of mesenchymal stem cell (MSC)-treated animals. As shown, the rim of tissue is made up of cardiomyocytes with normal ultrastructural architecture. (C) There is no difference in the size of myocytes taken from the remote myocardium of both control and MSC hearts. However, the myocytes from the infarct rim are significantly smaller in MSC-treated animals versus control animals (n = 2 each, >100 cells/heart), suggesting that the enhanced rim size in MSC animals might be due to new cardiomyocyte regeneration. *p < 0.001 MSC rim versus control rim.

View larger version (69K): [in this window] [in a new window] [Download PPT slide]   Figure 5 Color map depicting non-contractile and dysfunctional areas of myocardium detected by tagging magnetic resonance imaging. Bar color demonstrates the spectrum in change of systolic cardiac function: blue and green colors identify normal contractile areas and red colors represent dysfunctional areas. Non-treated animals exhibited worsening regional systolic function during the 8-week period, whereas a visual improvement was noticed in the mesenchymal stem cell (MSC)-treated animals.

View larger version (17K): [in this window] [in a new window] [Download PPT slide]   Figure 6 Plot of peak circumferential strain (peak Ecc) over time comparing mesenchymal stem cell (MSC)-treated and non-treated animals for 3 myocardial layers (endocardial, epicardial, mid-wall layers). Peak negative Ecc values represent myocardial shortening, whereas increasingly positive values reflect relative myocardial dysfunction. As can be appreciated, peak negative Ecc values at the endocardial and mid-wall layers for MSC-treated infarct regions decrease (i.e., improve) over the 8-week follow-up period compared with the control group, which remained dysfunctional. p < 0.05 difference within the group; p < 0.05 difference between groups; n = 6 in each group. MI = myocardial infarction.

View larger version (15K): [in this window] [in a new window] [Download PPT slide]   Figure 7 Impact of mesenchymal stem cell (MSC) therapy on global ventricular function. Ejection fraction assessed by cine magnetic resonance imaging (MRI). Ejection fraction is markedly reduced in both groups at baseline and remains depressed in non-treated animals. However, a progressive improvement in the course of 8 weeks is observed in MSC-treated animals. *p < 0.05 versus day 2 after injection (time 0); p < 0.05 versus non-treated (n = 6).