Coronary heart disease is a major cause of mortality in the US and in our Veterans. Biological approaches to treat the diseased heart using cell delivery have shown only modest therapeutic benefit, in part due to poor cell survival and ineffective electromechanical coupling to the host myocardium. Our previous research demonstrates that delivery of therapeutic cells cultured in an extracellular matrix (ECM) can improve the survival and functionality of the transplanted cells, owing to the structural support of the ECM as a scaffold and the signaling cues they impart to the cells. In particular, we have previously demonstrated the potency of anisotropic nanofibrillar scaffolds in guiding cellular alignment along the direction of the nanofibrils, enhancing cell survival in ischemic tissues, and imparting signaling cues that confer cell function consistent with a non- diseased state. Anisotropic scaffolds may be well-suited for engineering cardiac tissue which also has highly organized cellular structure. In addition, induced pluripotent stem cells (iPSCs) may be a candidate cell source for the generation of autologous therapeutic cardiovascular cells. The long-term objectives of this research are to engineer a three-dimensional vascularized cardiac patch with pre-formed physiological cellular organization to repair ischemic heart disease; and to investigate the basic biological mechanisms underlying ECM-mediated cell-cell interactions that enhance cardioprotection under conditions of ischemia. We hypothesize that a three- dimensionally aligned iPSC-derived cardiac patch with endothelial interactions will provide more functional and viable engineered tissues for repair of myocardial infarction, due to more effective electrical coupling and organized tissue morphology, as well as the activation of cardioprotective nitric oxide signaling imparted by ECM nanopatterning. Accordingly, our specific aims are: 1) To engineer a vascularized aligned iPSC-derived cardiomyocyte (CM) patch and elucidating the molecular mechanisms of ECM-mediated nitric oxide signaling in enhancing iPSC-CM survival and phenotype. The iPSC-derived CMs (iPSC- CMs) and iPSC-derived endothelial cells (iPSC-ECs) will be co-cultured on three-dimensional oriented nanofibrillar collagen scaffolds with culture conditions optimized to promote iPSC-CM cell survival and function within the patch, when compared to patches that lack oriented nanopatterning or vascular interactions. The role of ECM-mediated nitric oxide signaling in enhancing iPSC-CM survival and phenotype will be investigated in the context of gain- and loss-of-function assays. 2) To determine the therapeutic effect of a vascularized aligned iPSC-CM patch for treatment of myocardial infarction. The vascularized oriented cardiac patch will be transplanted onto the epicardium of rats after myocardial infarction. The animals will be monitored over time for functional improvement in cardiac function, wall thickness, and electromechanical coupling. The role of nitric oxide in mediating the functional effects of the aligned vascularized cardiac patch will be quantified by measuring production of nitric oxide and related signaling molecules. The knowledge gained from these studies will provide a stronger foundation of basic knowledge and improved methods for clinical development of engineered cardiac patches, ultimately with the goal of restoring myocardial function to the diseased hearts of our Veterans.

Public Health Relevance

Cardiovascular disease is the leading cause of death in Americans and in the Veteran population. In particular, coronary heart disease (CHD) is characterized by narrowing of the blood vessels that supply blood flow to the heart, leading to heart attack and ultimately heart failure. Understanding how to engineer biological replacement cardiac tissue is important for developing effective treatments for CHD in our Veterans. We believe that using scaffolds that guide the organization of cardiac cells will help to scale-up the size of engineered tissues, due to the ability of the scaffolds to maintain cell survival and promote cardiac health. Importantly, we will examine the biochemical processes that help improve cardiac cell survival and function within the cardiac patches. Together, these studies offer great hope to the development of therapies that for treating Veterans with CHD.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
Project #
Application #
Study Section
Surgery (SURG)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Veterans Admin Palo Alto Health Care Sys
Palo Alto
United States
Zip Code
Nakayama, Karina H; Alcazar, Cynthia; Yang, Guang et al. (2018) Rehabilitative exercise and spatially patterned nanofibrillar scaffolds enhance vascularization and innervation following volumetric muscle loss. NPJ Regen Med 3:16
Foster, Abbygail A; Dewi, Ruby E; Cai, Lei et al. (2018) Protein-engineered hydrogels enhance the survival of induced pluripotent stem cell-derived endothelial cells for treatment of peripheral arterial disease. Biomater Sci 6:614-622
Zamani, Maedeh; Karaca, Esra; Huang, Ngan F (2018) Multicellular Interactions in 3D Engineered Myocardial Tissue. Front Cardiovasc Med 5:147
Zaitseva, Tatiana S; Alcazar, Cynthia; Zamani, Maedeh et al. (2018) Aligned Nanofibrillar Scaffolds for Controlled Delivery of Modified mRNA. Tissue Eng Part A :
Hou, Luqia; Kim, Joseph J; Wanjare, Maureen et al. (2017) Combinatorial Extracellular Matrix Microenvironments for Probing Endothelial Differentiation of Human Pluripotent Stem Cells. Sci Rep 7:6551
Wanjare, Maureen; Huang, Ngan F (2017) Regulation of the microenvironment for cardiac tissue engineering. Regen Med 12:187-201
Kim, Joseph J; Hou, Luqia; Yang, Guang et al. (2017) Microfibrous Scaffolds Enhance Endothelial Differentiation and Organization of Induced Pluripotent Stem Cells. Cell Mol Bioeng 10:417-432
Wanjare, Maureen; Hou, Luqia; Nakayama, Karina H et al. (2017) Anisotropic microfibrous scaffolds enhance the organization and function of cardiomyocytes derived from induced pluripotent stem cells. Biomater Sci 5:1567-1578
Hou, Luqia; Coller, John; Natu, Vanita et al. (2016) Combinatorial extracellular matrix microenvironments promote survival and phenotype of human induced pluripotent stem cell-derived endothelial cells in hypoxia. Acta Biomater 44:188-99
Hou, Luqia; Kim, Joseph J; Woo, Y Joseph et al. (2016) Stem cell-based therapies to promote angiogenesis in ischemic cardiovascular disease. Am J Physiol Heart Circ Physiol 310:H455-65

Showing the most recent 10 out of 15 publications