Zebrafish vasculature: A blueprint for understanding and treating human disease.
The human heart pumps 5 to 7 liters of blood around the body every minute, 20% of which serves the brain. Both require their own specialized blood and lymphatic vascular systems to meet their physiological demands. The overarching goal of our lab is to determine how this critical vasculature develops and how it regenerates after injury. We also study what functions blood and lymphatic vessels have beyond fluid transport. We are particularly interested in coronary vessels and cerebral vasculature's roles in promoting natural regenerative responses of heart and brain tissue. We primarily use the zebrafish as a discovery model, taking advantage of its ease of genetic manipulation and imaging. Advancing our understanding of the factors that drive vasculature formation and reformation, in addition to the roles of blood and lymphatic vasculature during tissue repair will highlight new concepts in regenerative medicine. Zebrafish have enhanced repair compared to mice and humans. The study of these natural processes in zebrafish can identify pathways that can be utilized to accelerate regeneration in mammals.
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.
Lymphatic Vessels and Inflammation
Development of the lymphatic system and its role in heart and brain regeneration
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 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 in both the heart and brain after injury.
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.
B.Sc - University of Pune
Ph.D. - IISER
B.Sc - Sastra University
Ph.D. - Keio University
B.Sc - National Taiwan Ocean University
M.S. - National Taiwan University
Ph.D. - National Yang Ming Chiao Tung University and Academia Sinica
Laila Abd Elmagid
Research Assistant II (Post-bacc)
B.Sc - Cornell University
Research Assistant (Post-bacc)
B.Sc - Vanderbilt University
Fang Zhou Yu
Clinical Research Associate
B.Sc - University of St Andrews
MBChB - Edinburgh University
B.Sc - Hunter College
B.Sc - Edinburgh University
Ph.D. - Sheffield University
Postdoc - Children's Hospital Los Angeles, USC
Undergraduate Student Researcher (2022/23)
B.Sc - Hunter College
Current: Research Assistant at Project Renewal, Inc.
Intramyocardial Injection for the Study of Cardiac Lymphatic Function in Zebrafish.
Laila Abd Elmagid, Nishant Mittal, Isaac Bakis, Ching-Ling Lien, Michael Harrison#. JoVE. 2022 10.3791/64504
Heterogeneous pdgfrb+ cells regulate coronary vessel development and revascularization during heart regeneration.
Subir Kapuria, Haipeng Bai, Juancarlos Fierrosm Ying Huang, Feiyang Ma, Tyler Yoshida, Antonio Aguayo, Fatma Fok, Katir M Wiens, Joycelyn K Yip, Megan L McCain, Mattei Pellegrini, Mikiko Nagashima, Peter Hitchcock, Naoki Mochizuki, Nathan D Lawson, Michael R Harrison#, Ching-Ling Lien#. Development. 2022 149(4):dev199752
The Lymphatic System in Zebrafish Heart Development, Regeneration and Disease Modeling.
Xidi Feng, Stanislao Travisano, Caroline A Pearson, Ching-Ling Lien#, Michael R M Harrison#. Journal of Cardiovascular Development and Disease 2021 8(2):21
zLOST: CRISPR/Cas9-mediated precise genome modification by a long single-stranded DNA template in zebrafish.
Haipeng Bai, Lijun Liu, Ke An, Xiaochan Lu, Michael Harrison, Yanqiu Zhao, Ruibin Yan, Zhijie Lu, Song, Shuo Lin, Fang Liang, and Wei Qin#. BMC Genomics 2020 21: 67
Extended Culture and Imaging of Normal and Regenerating Adult Zebrafish Hearts in a Fluidic Device.
Joycelyn K. Yip*, Michael Harrison*, Andrew Petersen, G. Esteban Fernandez, Ching-Ling Lien, Megan L. McCain. Lab Chip. 2020 20: 274-284
Late developing cardiac lymphatic vasculature supports adult zebrafish heart function and regeneration.
Michael Harrison#, Guqin Mo, Xidi Feng, Antonio Aguayo, Tyler Yoshida, Caroline A. Pearson, Stefan Schulte-Merker, Ching-Ling Lien#. elife 2019 8:e42762/eLife Digest/Biomedical picture of the day
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
# corresponding author, *equal contribution