Linqi Jin
BME PhD Proposal Presentation
Date: 2024-09-23
Time: 12:00-2:00 PM
Location / Meeting Link: HSRB I E160; https://emory.zoom.us/j/92760898026
Committee Members:
Vahid Serpooshan, PhD (Advisor) Sean Wu, MD, PhD Holly Bauser-Heaton, MD, PhD Lakshmi Prasad Dasi, PhD Michael Davis, PhD
Title: Studying Flow Regulated Pathogenesis of Hypoplastic Left Heart Syndrome in a 3D Bioprinted Model of Developing Human Heart
Abstract:
Hypoplastic left heart syndrome (HLHS) is an etiologically multifactorial congenital heart defect (CHD) characterized by severe underdevelopment of the left heart. Various factors have been identified as critical contributors to the manifestation of HLHS, including intrinsic genetics, cardiac tissue structure, and flow hemodynamics during embryonic stages. The potential onset of HLHS can be traced back to the linear heart tube stage when the human heart begins pumping blood (days 21-22), introducing hemodynamic and biomechanical stimulations to the developing human heart. The prevalent “no flow, no grow” theory suggests that decreased blood flow passing through the developing heart will cause HLHS via abnormal cardiac growth and remodeling. However, due to suboptimal experimental models, the underlying mechanisms of genetics, dynamic cell-microenvironment interactions, and their critical roles in HLHS pathogenesis remain elusive. Advances in 3D bioprinting and stem cell technologies have enabled the fabrication of cardiac tissues with complex structural, cellular, molecular, and extracellular matrix (ECM) components. The overarching goal of this research is to study the roles of intrinsic genetics and extrinsic hemodynamics in human heart development and HLHS, using a novel 3D in vitro model of human embryonic heart tube (eHT) composed of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and endothelial cells (ECs). In Aim 1, we will establish a perfusable 3D in vitro model of human eHT using 3D bioprinting, hiPSC differentiation, and perfusion bioreactor technologies. In Aim 2, the roles of intrinsic genetics and extrinsic flow hemodynamics in HLHS pathogenesis will be examined by incorporating HLHS hiPSC-CMs, ECs, and flow alterations into our eHT model. In Aim 3, we will evaluate the impact of interventional and pharmaceutical treatments on HLHS rescue. Computational fluid dynamics (CFD) and particle image velocimetry (PIV) will be implemented for flow pattern characterization. Single-cell RNA-seq and immunohistochemistry will be performed for gene expression analysis. Results from this study will offer a robust 3D in vitro platform for modeling human heart development, advance the understanding of cellular mechanisms underlying HLHS pathogenesis, and enlighten potential therapeutic approaches for the prenatal intervention of HLHS.