Zebrafish cardiac vasculature: A blueprint for understanding and treating human disease.
The human heart pumps 5 to 7 liters of blood around the body every minute, placing continual stress on the cardiac muscle that requires its own specialized cardiac vascular system to meet this demand. The overarching goal of our lab is to determine how this critical cardiac vasculature develops and how it supports heart regeneration after injury. Advancing our understanding of the factors that encourage the formation of cardiac vasculature and its roles and signaling during tissue repair will highlight new concepts in regenerative medicine. We utilize novel imaging techniques in zebrafish genetic models to dissect the cues driving vascularization and vascular mediation of heart regeneration at the tissue and molecular level. Zebrafish have enhanced cardiac repair compared to mice and humans. The study of these natural processes in zebrafish can highlight dormant pathways that can be utilized to accelerate regeneration in mammals.
Cardiac Blood and Lymphatic Vasculature
Understanding formation and function to develop new therapies
Coronary Vessel Development
Chemokine regulation of zebrafish coronary vasculature development
The zebrafish heart lacks coronary vessels until 1-month post-fertilization when a subset of endocardial cells sprout through the myocardium at the junction between the atrium and ventricle and form an immature coronary vessel in juvenile zebrafish. The ventricle, but not atrium, becomes vascularized by angiogenesis from this vessel. This is dependent on myocardial to endothelial cell-cell communication and we identified Cxcr4-Cxcl12 signaling as a key component of this process. Myocardial integration, coronary vascular endothelial cell specification and subtype differentiation are important processes involved in the establishment of an integrated functional coronary vascular tree. We aim to identify the developmental signals that drive these processes.
Cardiac Lymphatic Vessels and Inflammation
Development of the cardiac lymphatic system and its role in scar resolution
We have demonstrated that in zebrafish the cardiac lymphatic system develops in two steps. Initially, prior to the development of coronary vessels, a lymphatic endothelial population is established on the outflow tract of the heart. Only once coronary vessel development is completed, does the lymphatic vasculature then branch down onto the ventricle along the newly established coronary arteries. In adult zebrafish, this system functions to reduce myocardial scarring during heart regeneration. The role of the cardiac lymphatic system in modulating a regenerative response has been largely under-appreciated; we are currently investigating its role post-injury and how its response is stimulated.
Coronary Vessel Regeneration
Imagining Revascularization after injury
Following resection of the apex of the ventricle, the lost heart tissue regenerates, and new coronary vessels are formed. We designed and fabricated a fluidic device to culture explanted injured hearts on a live imaging microscope to continuously record the myocardial revascularization process over several days. The regenerated blood vasculature is derived from the uninjured vasculature that is proximal to the wound site. We are currently determining the process of this de novo coronary vessel formation after injury, including the cell lineages and pro-angiogenic cues that mediate it.
A fully funded postdoctoral position is available in Dr Michael Harrison’s lab (labharrison.com) in the Cardiovascular Research Institute of Weill Medical College, Cornell University (WCM) in New York City. The lab is focused on the coronary vessels that supply the heart with blood and...
Chemokine guided angiogenesis directs coronary vasculature formation in zebrafish.
Michael Harrison, Jeroen Bussmann, Long Zhao, Ying Huang, Arthela Osorio, C. Geoffrey Burns, Caroline E. Burns, Henry M. Sucov, Arndt F. Siekmann, Ching-ling Lien#. Developmental Cell 2015 33(4): 442-454.
Shear Stress-Activated Wnt-Angiopoietin-2 Signaling Recapitulates Vascular Repair in Zebrafish Embryos.
Rongsong Li, Tyler Beebe, Nelson Jen, Fei Yu, Wakako Takabe, Michael Harrison, Hung Cao, Juhyun Lee, Hongbo Yang, Peidong Han, Kevin Wang, Hirohito Shimizu, Jaunian Chen, Ching-Ling Lien, Neil C Chi, Tzung K Hsiai#. ATVB 2014 10: 2268-2275.
High Frequency Photoacoustic Imaging Techniques for Visualizing Blood Flow of a Zebrafish Heart In-Vivo.
Jinhyoung Park, Thomas M. Cummins, Michael Harrison, Jungwoo Lee, Qifa Zhou, Ching-Ling Lien and K. K. Shung#. Optics Express 2013 21(12): 14636-14642
Igf Signaling is Required for Zebrafish Heart Development and Cardiomyocyte Proliferation during Regeneration.
Ying Huang, Michael Harrison, Arthela Osorio, Jieun Kim, Arron Baugh, Cumming Duan, Henry Sucov, Ching-Ling Lien#. PlosONE 2013 8(6): e67266