Cell therapy is promising for repair of damaged myocardium. But moderate and variable functional benefits in clinical trials emphasize the need for a better understanding of therapeutic mechanisms and for specific imaging techniques which provide insights beyond cardiac function. Frequently, only a small fraction of transplanted cells engrafts in injured myocardium, limiting therapeutic efficacy and providing a potential explanation for the variability of functional benefits. The myocardial microenvironment is considered to be a critical contributor to successful cell engraftment and constitutes a suitable target for molecular imaging. In this proposal, we aim at developing strategies to facilitate successful stem cell engraftment. Our central hypothesis is that molecular-targeted nuclear imaging prior to cell delivery can characterize an optimal biologic environment which is supportive of cell engraftment after delivery, and thus predictive of successful myocardial regeneration. This hypothesis will be tested in 3 specific aims. Quantitative nuclear imaging techniques will be employed to characterize both, myocardial environment, as well as stem cell engraftment in a rat model of myocardial infarction. Therapy outcome will be defined by serial echocardiography and histologic workup.
Aim 1 will define the role of tissue perfusion, metabolism and viability in the target area of stem cell delivery, for successful engraftment of cardiac-derived stem cells, an innovative cell type with documented regenerative potential.
Aim 2 will investigate the role of expression of the adhesion molecule 1v23 integrin in the target area, as determined by molecular imaging, for successful cardiac stem cell engraftment.
In aim 3, cardiac stem cells as a newer cell type will then be compared with the longer established mesenchymal stem cells under conditions of optimal imaging-defined microenvironmental conditions. These studies will provide unique new insights into the contribution of the biologic environment to the success of stem cell based myocardial regeneration. More importantly, they will also provide imaging techniques which may assist in therapeutic decision making by guiding the timing and regional targeting of cell delivery. The ultimate goal of the project is to optimize cell therapeutic benefit based on imaging of individual disease biology.

Public Health Relevance

/ Relevance Cardiac stem cell therapy is considered to be a very promising approach for repair of damaged myocardium, but the benefit in clinical trials is currently still variable. In this proposal, molecular imaging techniques are introduced which aim at improving cell therapy by providing information about myocardial microenvironmental conditions which are most suitable for stem cell engraftment. Such biologic imaging strategies have the potential to guide individual therapeutic decisions, and are thus highly relevant to optimize the benefit of stem cell therapy in the clinical management of heart disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Adhikari, Bishow B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Medicine
United States
Zip Code
Lu, Dai-Yin; Yalçin, Hulya; Yalçin, Fatih et al. (2018) Stress Myocardial Blood Flow Heterogeneity Is a Positron Emission Tomography Biomarker of Ventricular Arrhythmias in Patients With Hypertrophic Cardiomyopathy. Am J Cardiol 121:1081-1089
Afzal, Junaid; Chan, Angel; Karakas, Mehmet Fatih et al. (2017) Cardiosphere-Derived Cells Demonstrate Metabolic Flexibility That Is Influenced by Adhesion Status. JACC Basic Transl Sci 2:543-560
Chan, Angel T; Karakas, Mehmet F; Vakrou, Styliani et al. (2015) Hyaluronic acid-serum hydrogels rapidly restore metabolism of encapsulated stem cells and promote engraftment. Biomaterials 73:1-11
Luo, Hong-Chang; Dimaano, Veronica L; Kembro, Jackelyn M et al. (2015) Exercise heart rates in patients with hypertrophic cardiomyopathy. Am J Cardiol 115:1144-1150
Higuchi, Takahiro; Rischpler, Christoph; Fukushima, Kenji et al. (2013) Targeting of endothelin receptors in the healthy and infarcted rat heart using the PET tracer 18F-FBzBMS. J Nucl Med 54:277-82
Chang, Connie; Chan, Angel; Lin, Xiaoping et al. (2013) Cellular bioenergetics is an important determinant of the molecular imaging signal derived from luciferase and the sodium-iodide symporter. Circ Res 112:441-50
Rischpler, Christoph; Fukushima, Kenji; Isoda, Takuro et al. (2013) Discrepant uptake of the radiolabeled norepinephrine analogues hydroxyephedrine (HED) and metaiodobenzylguanidine (MIBG) in rat hearts. Eur J Nucl Med Mol Imaging 40:1077-83
Kshitiz; Hubbi, Maimon E; Ahn, Eun Hyun et al. (2012) Matrix rigidity controls endothelial differentiation and morphogenesis of cardiac precursors. Sci Signal 5:ra41
Kshitiz; Hubbi, Maimon E; Ahn, Eun Hyun et al. (2012) Matrix rigidity controls endothelial differentiation and morphogenesis of cardiac precursors. Sci Signal 5:ra41
Bravo, Paco E; Pozios, Iraklis; Pinheiro, Aurélio et al. (2012) Comparison and effectiveness of regadenoson versus dipyridamole on stress electrocardiographic changes during positron emission tomography evaluation of patients with hypertrophic cardiomyopathy. Am J Cardiol 110:1033-9

Showing the most recent 10 out of 20 publications