Program Director/Principal Investigator (Last, First, Middle): Vyavahare Narendra R. Project summary The current inability to efficiently derive a sufficient number of mature cardiomyocytes from human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hIPSCs) has severely limited the application of human stem cell technology in treating cardiovascular disease, the leading cause of death worldwide. Significant research has been conducted to engineer soluble factors, such as growth factors and small molecules, to induce cardiac differentiation of hESCs and hIPSCs. In contrast, little work has been done to optimize insoluble factors, such as the substrates on which cells grow, to facilitate cardiac differentiation. Further, the current cardiomyocytes derived from hESCs and hIPSCs are structurally and functionally similar to human embryonic/neonatal stage cardiomyocytes (i.e., immature cardiomyocytes), which have limited clinical applications. Accordingly, we will pursue two specific aims: 1) high throughput assessment of polymeric substrates for enhanced cardiac differentiation of hESCs, and 2) promote terminal differentiation of hESC- derived immature cardiomyocytes by mimicking key aspects of biochemical and biophysical stimuli in developing hearts. We hypothesize in Aim 1 that with high throughput screening of a library of polymeric substrates known to promote hESC clonal growth, substrates capable to enhance cardiac differentiation of hESCs can be identified. We hypothesize in Aim 2 that we can promote maturation of hESC-derived immature cardiomyocytes by mimicking biochemical and biophysical stimuli in developing hearts. This study is innovative: For the first time, we will utilize an emerging polymer microarray technology to develop defined substrates in a high-throughput manner to facilitate cardiac differentiation of hESCs. Further, we will recapitulate key aspects of biochemical and biophysical stimuli of developing hearts to derive mature cardiomyocytes. My long-term career goal is to develop bioengineering approaches for the derivation of a sufficient number of mature cardiomyocytes from hESCs and hIPSCs for cardiac tissue regeneration. The objective of the current proposal is to develop a mechanistic understanding of the effects of environmental factors (e.g., substrates and electrical stimulation) with the intent to use this information in the future for stem- cell based cardiovascular regeneration. The study is significant in that it would allow for efficient derivation of fully mature cardiomyocytes from hESCs, which can have major impacts in drug development and cardiac tissue engineering. The study would tremendously benefit from my mentoring team: Dr. Thomas K. Borg, a well-established developmental biologist, and Dr. Kyu-Ho Lee, MD, a trained pediatric clinician and a faculty member in the Pediatric Cardiology division at MUSC Children's Hospital. The COBRE core facilities will provide a wide range of technical support from stem cell technology to studying hES cell-materials interactions.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
2P20GM103444-06
Application #
8742736
Study Section
Special Emphasis Panel (ZGM1)
Project Start
2014-07-01
Project End
2019-04-30
Budget Start
2014-07-01
Budget End
2015-04-30
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Clemson University
Department
Type
DUNS #
City
Clemson
State
SC
Country
United States
Zip Code
29634
Yang, Huaxiao; Schmidt, Lucas P; Wang, Zhonghai et al. (2016) Dynamic Myofibrillar Remodeling in Live Cardiomyocytes under Static Stretch. Sci Rep 6:20674
Barnes, Ralston M; Harris, Ian S; Jaehnig, Eric J et al. (2016) MEF2C regulates outflow tract alignment and transcriptional control of Tdgf1. Development 143:774-9
Jia, Jia; Coyle, Robert C; Richards, Dylan J et al. (2016) Development of peptide-functionalized synthetic hydrogel microarrays for stem cell and tissue engineering applications. Acta Biomater 45:110-120
Huang, Ting; Wang, Zhonghai; Wei, Lina et al. (2016) Microelectrode Array-evaluation of Neurotoxic Effects of Magnesium as an Implantable Biomaterial. J Mater Sci Technol 32:89-96
Uchida, Noriyuki; Sivaraman, Srikanth; Amoroso, Nicholas J et al. (2016) Nanometer-sized extracellular matrix coating on polymer-based scaffold for tissue engineering applications. J Biomed Mater Res A 104:94-103
Lehnert, Matthew S; Beard, Charles E; Gerard, Patrick D et al. (2016) Structure of the lepidopteran proboscis in relation to feeding guild. J Morphol 277:167-82
Nosoudi, Nasim; Chowdhury, Aniqa; Siclari, Steven et al. (2016) Reversal of Vascular Calcification and Aneurysms in a Rat Model Using Dual Targeted Therapy with EDTA- and PGG-Loaded Nanoparticles. Theranostics 6:1975-1987
Coyle, Robert; Jia, Jia; Mei, Ying (2016) Polymer microarray technology for stem cell engineering. Acta Biomater 34:60-72
Richards, Dylan; Jia, Jia; Yost, Michael et al. (2016) 3D Bioprinting for Vascularized Tissue Fabrication. Ann Biomed Eng :
Parasaram, Vaideesh; Nosoudi, Nasim; LeClair, Renee J et al. (2016) Targeted drug delivery to emphysematous lungs: Inhibition of MMPs by doxycycline loaded nanoparticles. Pulm Pharmacol Ther 39:64-73

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