The discovery of cardiac progenitor cells (CPCs) provides a potential new approach to the treatment of heart failure (HF), The initial results of our first-in-humans clinical study of CPCs in patients with HF (SCIPIO) are encouraging. However, CPC-based therapies are severely limited by the fact that almost all (at least 97%) of the transplanted CPCs die shortly after transplantation. This implies that increasing the survival of transplanted cells by preventing apoptosis will enhance the efficacy of CPC therapy. In the current funding period of this Program Project, we have found that carbon monoxide (CO) and nitric oxide (NO) exert powerful anti-apoptotic actions and form a closely inter-related functional module (CO-NO module), which is regulated by heme oxygenase-1 (HO-1), extracellular superoxide dismutase (ecSOD), and inducible NO synthase (iNOS). We will exploit this discovery to enhance cell-based therapies. The overall goal of Project 1 is to elucidate the role of the CO-NO module in regulating CPC function and to evaluate its therapeutic utility after myocardial infarction (Ml). We propose that augmenting this module will greatly potentiate the effectiveness of transplanted CPCs and dramatically enhance CPC-mediated cardiac repair. This Project represents the natural evolution of our previous work in this Program Project;having discovered that the CO- NO module affors powerful protection against mmyocardial ischemia, we will now build on this work to enhance the reparative ability of CPCs.
In Aim 1, we will determine the roles of HO-1 and CO in modulating CPC function.
In Aim 2, we will establish the role of ecSOD in regulating CPC function and mediating HO-1- induced protection of CPCs.
In Aim 3, we will determine the role of NO in modulating CPC function and the role of HO-1 and ecSOD in mediating the effects of NO on CPCs. Using both gain- and loss-of-function approaches, in all three Aims we will systematically evaluate fundamental parameters of CPC competence in vitro and the ability of CPCs to repair cardiac damage in vivo in a murine model of post-MI LV remodeling and dysfunction.
In Aim 4. we will elucidate the molecular mechanisms whereby CO and NO upregulate ecSOD, and NO upregulates HO-1 and ecSOD in CPCs, focusing on the transcription factor Nrf2. These will be the first studies to examine the role of CO and NO, and their supporting proteins HO-1, ecSOD, and INOS, in modulating CPC function. The results will be entirely new and will add a new dimension to our understanding of CPC biology. In addition, these studies will provide proof-of-principle for the therapeutic utility of manipulations that potentiate the CO-NO module in CPCs, which may lay the groundwork for future trials of genetically or pharmacologically enhanced CPCs in patients with HF.
In 2009 we started SCIPIO, a study of c-kit+ cardiac progenitor cells (CPCs) in patients with heart failure, and the initial results are encouraging. Project 1 builds on SCIPIO. We will test a new therapy - genetically- modified or preconditioned CPCs, which promise to be superior to the cells currently being used in SCIPIO. If the results confirm our working hypothesis, these studies will lay the groundwork for testing more effective CPCs for the treatment of heart failure and thus may facilitate translation of cell therapies to humans.
|Gibb, Andrew A; Epstein, Paul N; Uchida, Shizuka et al. (2017) Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth. Circulation 136:2144-2157|
|Jones, Steven P (2017) I'll Have the Rigor, but Hold the Mortis. Circ Res 120:1852-1854|
|Dassanayaka, Sujith; Brainard, Robert E; Watson, Lewis J et al. (2017) Cardiomyocyte Ogt limits ventricular dysfunction in mice following pressure overload without affecting hypertrophy. Basic Res Cardiol 112:23|
|Wysoczynski, Marcin; Adamiak, Mateusz; Suszynska, Malwina et al. (2017) Poor Mobilization in T-Cell-Deficient Nude Mice Is Explained by Defective Activation of Granulocytes and Monocytes. Cell Transplant 26:83-93|
|Bolli, Roberto (2017) Repeated Cell Therapy: A Paradigm Shift Whose Time Has Come. Circ Res 120:1072-1074|
|Guo, Yiru; Wysoczynski, Marcin; Nong, Yibing et al. (2017) Repeated doses of cardiac mesenchymal cells are therapeutically superior to a single dose in mice with old myocardial infarction. Basic Res Cardiol 112:18|
|Wysoczynski, Marcin; Guo, Yiru; Moore 4th, Joseph B et al. (2017) Myocardial Reparative Properties of Cardiac Mesenchymal Cells Isolated on the Basis of Adherence. J Am Coll Cardiol 69:1824-1838|
|Singh, Mahavir; Kapoor, Aniruddh; McCracken, James et al. (2017) Aldose reductase (AKR1B) deficiency promotes phagocytosis in bone marrow derived mouse macrophages. Chem Biol Interact 265:16-23|
|Kingery, Justin R; Hamid, Tariq; Lewis, Robert K et al. (2017) Leukocyte iNOS is required for inflammation and pathological remodeling in ischemic heart failure. Basic Res Cardiol 112:19|
|Eschenhagen, Thomas; Bolli, Roberto; Braun, Thomas et al. (2017) Cardiomyocyte Regeneration: A Consensus Statement. Circulation 136:680-686|
Showing the most recent 10 out of 174 publications