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.

Public Health Relevance

- Relevance The Centers for Disease Control and Prevention reports that the leading cause of death in the U.S. is heart disease (1 in 4 deaths), with coronary heart disease (heart attack) being the most common, and that the public health burden for heart disease was an estimated $316.4 billion in 2010. Therefore, effective therapies to treat myocardial infarction must be developed and must target the root cause of the disease - the loss of contractile cardiac muscle. This proposal aims to develop such therapies using human induced pluripotent stem cell-derived cardiomyocytes in engineered tissues that utilize biodegradable materials to deliver therapeutic proteins and drugs for improving cardiomyocyte engraftment and contraction in the injured heart.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
4R00HL115123-03
Application #
8780806
Study Section
Special Emphasis Panel (NSS)
Program Officer
Carlson, Drew E
Project Start
2012-08-20
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
3
Fiscal Year
2014
Total Cost
$249,000
Indirect Cost
$95,769
Name
Brown University
Department
Type
Schools of Engineering
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Kant, Rajeev J; Coulombe, Kareen L K (2018) Integrated approaches to spatiotemporally directing angiogenesis in host and engineered tissues. Acta Biomater 69:42-62
Kaiser, Nicholas J; Munarin, Fabiola; Coulombe, Kareen L K (2018) Custom Engineered Tissue Culture Molds from Laser-etched Masters. J Vis Exp :
Munarin, Fabiola; Kaiser, Nicholas J; Kim, Tae Yun et al. (2017) Laser-Etched Designs for Molding Hydrogel-Based Engineered Tissues. Tissue Eng Part C Methods 23:311-321
Rupert, Cassady E; Chang, Heidi H; Coulombe, Kareen L K (2017) Hypertrophy changes 3D shape of hiPSC-cardiomyocytes: Implications for cellular maturation in regenerative medicine. Cell Mol Bioeng 10:54-62
Roberts, Meredith A; Tran, Dominic; Coulombe, Kareen L K et al. (2016) Stromal Cells in Dense Collagen Promote Cardiomyocyte and Microvascular Patterning in Engineered Human Heart Tissue. Tissue Eng Part A 22:633-44
Gerbin, Kaytlyn A; Yang, Xiulan; Murry, Charles E et al. (2015) Enhanced Electrical Integration of Engineered Human Myocardium via Intramyocardial versus Epicardial Delivery in Infarcted Rat Hearts. PLoS One 10:e0131446
Kaiser, Nicholas J; Coulombe, Kareen L K (2015) Physiologically inspired cardiac scaffolds for tailored in vivo function and heart regeneration. Biomed Mater 10:034003
Munarin, F; Coulombe, K L K (2015) A novel 3-dimensional approach for cardiac regeneration. Conf Proc IEEE Eng Med Biol Soc 2015:1741-4
Rupert, Cassady E; Coulombe, Kareen Lk (2015) The roles of neuregulin-1 in cardiac development, homeostasis, and disease. Biomark Insights 10:1-9
Coulombe, Kareen L K; Bajpai, Vivek K; Andreadis, Stelios T et al. (2014) Heart regeneration with engineered myocardial tissue. Annu Rev Biomed Eng 16:1-28

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