Despite current treatment regimens, heart failure remains the leading cause of morbidity and mortality in the US and developed world due to failure to adequately replace lost ventricular myocardium from ischemia- induced infarct. Adult mammalian ventricular cardiomyocytes have a limited capacity to divide, and this proliferation is insufficient to overcome the significant loss of myocardium from ventricular injury. However, zebrafish (Danio rerio) possess the remarkable capacity to regenerate a significant amount of myocardium in injured hearts, and thus, represent an emerging vertebrate model for regenerative medicine and cardiovascular research. While the small size of zebrafish system allows for high-throughput research, the small heart size (1-2 mm in length) renders it challenging to perform functional physiological analyses. Toward this end, our collaborated efforts have enabled the applications of the micro-electrical cardiogram (ECG) and high-frequency ultrasonic transducers (>45 MHz) to further investigate the electrical and mechanical attributes of regenerating myocardium in injured zebrafish hearts. We have observed that ventricular repolarization (ST intervals and T waves) failed to normalize despite fully regenerated myocardium at 60 days post ventricular amputation, suggesting further cardiac remodeling may be required to fully integrate regenerating myocardium with host myocardium. We hypothesize that early regenerating cardiomyocytes may lack the electrical and mechanical cardiac phenotypes, and thus may require additional cardiac cellular remodeling for full electrical and mechanical integration into injured hearts. To assess the restoration of cardiac function during cardiac regeneration, we propose to interface implantable flexible micro-electrode arrays with high- frequency ultrasonic transducers and optical voltage mapping to test the conduction and mechanical phenotypes, followed by mechanistic assessment by conditionally blocking or activating Wnt/2-catenin and FGF signaling pathways. The development and application of implantable and flexible micro-electrode arrays, high frequency ultrasonic transducers hold a great promise in the era of stem cell and regenerative medicine. In sum, our concerted efforts will likely provide both novel technology and new mechanistic insights into cardiac conduction and mechanical phenotypes in response to genetic, epigenetic, and pharmaceutical perturbations with relevance to regenerative medicine.
In the era of stem cell and regenerative medicine, there is a considerable interest to assess the phenotypes of injured and early regenerated cardiomyocytes. The advent of Micro-electro-mechanical systems (MEMS) sensors has enabled us to measure conduction and mechanical phenotypes of injured and regenerating hearts with both high spatial and temporal resolution in the small animal system. Thus, our goal is to test the hypothesis that regenerating myocardium may require additional cardiac cellular remodeling for full electrical and mechanical integration into injured hearts.
|Li, Rongsong; Beebe, Tyler; Jen, Nelson et al. (2014) Shear stress-activated Wnt-angiopoietin-2 signaling recapitulates vascular repair in zebrafish embryos. Arterioscler Thromb Vasc Biol 34:2268-75|
|Hsiai, Tzung; Li, Song; Bursac, Nenad (2014) Introduction to the special issue on tissue engineering and regenerative medicine. Ann Biomed Eng 42:1355-6|
|Dickover, Michael; Hegarty, Jeffrey M; Ly, Kim et al. (2014) The atypical Rho GTPase, RhoU, regulates cell-adhesion molecules during cardiac morphogenesis. Dev Biol 389:182-91|
|Cao, Hung; Yu, Fei; Zhao, Yu et al. (2014) Wearable multi-channel microelectrode membranes for elucidating electrophysiological phenotypes of injured myocardium. Integr Biol (Camb) 6:789-95|
|Cao, Hung; Yu, Fei; Zhao, Yu et al. (2014) Stretchable electrochemical impedance sensors for intravascular detection of lipid-rich lesions in New Zealand White rabbits. Biosens Bioelectron 54:610-6|
|Lee, Juhyun; Moghadam, Mahdi Esmaily; Kung, Ethan et al. (2013) Moving domain computational fluid dynamics to interface with an embryonic model of cardiac morphogenesis. PLoS One 8:e72924|
|Du, Yunfeng; Navab, Mohamad; Shen, Melody et al. (2013) Ambient ultrafine particles reduce endothelial nitric oxide production via S-glutathionylation of eNOS. Biochem Biophys Res Commun 436:462-6|
|Yu, Fei; Lee, Juhyun; Jen, Nelson et al. (2013) Elevated electrochemical impedance in the endoluminal regions with high shear stress: implication for assessing lipid-rich atherosclerotic lesions. Biosens Bioelectron 43:237-44|