Regenerating the Heart with Engineered Human Cardiac Tissue

Summary

Principal Investigator: KAREEN LOUISE KREUTZIGER COULOMBE
Abstract: DESCRIPTION (provided by applicant): Heart failure after a myocardial infarction is primarily due to death of cardiomyocytes, suggesting that successful cell-based therapies will replace cardiomyocytes to restore heart function. To that end, this proposal focuses on generating large human cardiac grafts using human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes in engineered cardiac tissue with biomaterial delivery of therapeutic growth factors and small molecule drugs. We have developed scaffold-free engineered cardiac tissue with hiPSC- cardiomyocytes and the extracellular matrix that they secrete. These cardiac tissue "patches" are implanted on the epicardial surface of infarcted hearts, but integration with the host is minimal and improved cardiac function is absent. Therefore, this proposal aims to improve host vascularization of the graft (Aim 1), survival and proliferation of hiPSC-derived cardiomyocytes (Aim 2), and force generation by hiPSC-cardiomyocytes (Aim 3). In Aim 1, we will develop biodegradable alginate microspheres loaded with the angiogenic proteins vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). These will be optimized in vitro and in vivo for controlled protein release and incorporated into cardiac patches for implantation in the infarcted rat heart. In Aim 2, we will use alginate microspheres loaded with insulin-like growth factor-1 (IGF-1), neuregulin-1 (NRG-1), and Y27632 (a small molecule inhibitor of Rho-associated kinase) to improve hiPSC- cardiomyocyte survival and proliferation during cardiac patch formation and after implantation. In Aim 3, we use chemical, electrical, and mechanical conditioning to promote hiPSC-cardiomyocyte hypertrophy and contractile strength. The current proposal aims to address deficiencies in cell-based cardiac therapy and is innovative in its approach, using degradable biomaterials for therapeutic protein/drug delivery within engineered cardiac tissue. These immediate research goals will encourage my development as an independent investigator. During the mentored K99 phase, I will learn to fabricate alginate microspheres loaded with proteins and drugs. Integrating controlled-release systems with cardiac tissue engineering will result in a unique niche for my research career. It is my long-term career goal to establish an interdisciplinary cardiovascular bioengineering lab that approaches biological and medical problems with novel technologies in tissue engineering, biomaterials, physiology, biophysics, and stem cell biology.
Funding Period: 2012-08-20 - 2013-12-31
more information: NIH RePORT

Detail Information

Research Grants31

  1. Function and Integration of Stem Cell-derived Cardiac Tissue Patch
    Nenad Bursac; Fiscal Year: 2013
    ..The knowledge obtained in this project will allow us to pursue in the future engineering of a functional cardiac tissue patch made of human stem cells for potential clinical applications. ..
  2. Cardiac Fibrillation: Mechanisms and Therapy
    James N Weiss; Fiscal Year: 2013
    ..Together, these studies will provide critical groundwork necessary to develop and advance novel therapies for this major complication and cause of mortality from heart disease. ..
  3. Elafin Therapy for Lung Diseases
    Marlene Rabinovitch; Fiscal Year: 2013
    ..The Administrative Core facilitates exchange of information and postdoctoral training in Lung Translational Medicine, and facilitates our strategy to move elafin into clinical trial in the next cycle. ..
  4. Novel Therapies for Muco-Obstructive Lung Diseases
    RICHARD CHARLES BOUCHER; Fiscal Year: 2013
    ..abstract_text> ..
  5. Engineering vascularized cardiac muscle.
    Gordana Vunjak-Novakovic; Fiscal Year: 2013
    ..We believe that this work has significance for quantitative biological research and the development of practical tissue-engineering modalities for treating heart disease. ..
  6. Diverse Roles of Reactive Oxygen Species and Inflammation in Vascular Disease
    Kathy K Griendling; Fiscal Year: 2013
    ..Ultimately, this research may establish new unifying concepts linking conditions that alter vascular oxidant stress and inflammation to the molecular processes underlying vasculopathies. (End of Abstract) ..
  7. Neuro-Circulatory Function in Chronic Heart Failure
    Irving H Zucker; Fiscal Year: 2013
    ..The role of exercise training in modulating ROS generation and antioxidant enzymes in animals with CHF will also be investigated in this project. ..
  8. Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease
    PAUL WESLEY NOBLE; Fiscal Year: 2013
    ..Each of these projects shares the common theme that interactions of host factors regulates inflammatory and fibrotic lung diseases. ..
  9. 3D combinatorial microenvironments for effective cell based therapy
    Ronglih Liao; Fiscal Year: 2013
    ..Our investigator team has a longstanding and productive track record and will work together to achieve the ultimate goal of therapeutic cardiac regeneration by maximizing stem/progenitor cells engraftment, survival, and differentiation. ..
  10. Biologically inspired engineering of hierarchical vascular networks
    George Eng; Fiscal Year: 2013
    ..abstract_text> ..
  11. Fabrication of 3D Cardiac Patches for Myocardial Recovery
    RAVI KUMAR BIRLA; Fiscal Year: 2013
    ..abstract_text> ..
  12. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  13. Cell-Based Cardiac Repair
    Charles E Murry; Fiscal Year: 2013
    ..These experiments will advance our understanding of human heart development and make clinical trials of heart regeneration more feasible. ..
  14. Rebuilding the Failing Heart
    Piero Anversa; Fiscal Year: 2013
    ..abstract_text> ..
  15. iPS cells-derived progenitor cells for angiomyogenesis
    Yigang Wang; Fiscal Year: 2013
    ..These studies will provide new insights into the development of engineered iPSC-derived cardiac tissue patches as a viable therapy for cardiac muscle regeneration. ..
  16. INNATE AND ADAPTIVE IMMUNE RESPONSES IN TH2-HIGH ASTHMA
    John V Fahy; Fiscal Year: 2013
    ..Including studies in human biospecimens in a PPG that promises to advance understanding of airway TH2 inflammation in ways that are highly relevant to patients with asthma. ..
  17. Scalable Units for Building Vascularized Cardiac Graft
    Lisa E Freed; Fiscal Year: 2013
    ..g., cardiac, skeletal and smooth muscle, liver, kidney), and (iii) anisotropic scaffolds for regenerating other anisotropic, load-bearing tissues (e.g., blood vessel, ligament, tendon, cartilage, and bone). ..
  18. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
    ..3. Recruit promising junior investigators and provide mentoring by established NIH-funded researchers. 4. Support a multidisciplinary research program led by junior investigators in translational infectious diseases immunology. ..
  19. Center for Neuroplasticity at the University of Puerto Rico
    Steven N Treistman; Fiscal Year: 2013
    ..This UPR COBRE Center should define pathways and benchmarks for basic and translational research across the UPR system for the next decades. ..
  20. Polyketals to encapsulate a small molecule p38 inhibitor for cardiac regeneration
    Michael E Davis; Fiscal Year: 2013
    ..This proposal will demonstrate that p38 inhibition with polyketals can be used to help regenerate cardiac tissue following myocardial infarction. ..
  21. Cardiac Regeneration through Growth Factor Eluting Microrod Scaffolds
    Paul H Goldspink; Fiscal Year: 2013
    ....
  22. Blood Pressure Regulation: Novel Roles for the Kidney
    Pablo A Ortiz; Fiscal Year: 2013
    ..Thus it will accelerate acquisition of knowledge of the novel mechanisms by which the kidney regulates blood pressure, and may provide new targets for anti-hypertensive drugs. ..
  23. Discovery and Development of Therapeutic Genes for CHF
    H Kirk Hammond; Fiscal Year: 2013
    ..Four Cores will support the Program: Digital Imaging (Dr. Farquhar);Vector Production (Dr. Miyanohara);Translational Systems (Dr. Hammond) and Clinical &Administrative (Dr. Hammond). ..
  24. Infarct Repair with Mesenchymal Stem Cell Subpopulation
    Buddhadeb Dawn; Fiscal Year: 2013
    ....
  25. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..