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Lineage Dynamics in Cardiac and Pericardial Morphogenesis /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Lineage Dynamics in Cardiac and Pericardial Morphogenesis // Hannah Rose Moran.
Author:	Moran, Hannah Rose,
Description:	1 electronic resource (215 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-06, Section: B.
Contained By:	Dissertations Abstracts International86-06B.
Subject:	Developmental biology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31633077
ISBN:	9798346858416

Lineage Dynamics in Cardiac and Pericardial Morphogenesis /
Moran, Hannah Rose,

Lineage Dynamics in Cardiac and Pericardial Morphogenesis /Hannah Rose Moran. - 1 electronic resource (215 pages)

Source: Dissertations Abstracts International, Volume: 86-06, Section: B.

An estimated 1% of all newborns suffer from a congenital heart anomaly with at times complex syndromic co-morbidities. Understanding the molecular and cellular mechanisms that drive the formation of the heart as functional unit is critical to expand our understanding of the causes, diagnostic opportunities, and therapeutic interventions in congenital heart disease. During vertebrate development, the heart is the first functional organ to form, initiating the circulatory system required to support the growth and survival of the embryo. The cardiovascular system integrates a wide array of cell types and tissues, necessitating a tightly regulated orchestration of developmental processes to ensure proper assembly and function. The heart is composed of myocardial, endocardial, and conduction system cells, all enclosed within the protective, multi-layered mesothelial pericardium. Despite the importance of forming a unified and functional cardiovascular system, comparably little research has focused on how these distinct cell lineages and tissues integrate into forming the functional heart. Unraveling the complex interactions between these cell and tissue types is key to understanding the origins of congenital heart disease, as well as unlocking the heart's inherent regenerative potential for therapeutic applications. In this dissertation, I have: 1) uncovered how zebrafish myocardial progenitors resolve from the first heart field throughout embryogenesis and into adulthood, 2) determined the origins and lineage dynamics of the pericardium, and 3) established a functional contribution of canonical Wnt/β-catenin signaling to regulating pericardial morphology and tissue stiffness, highlighting its role in cardiac disease.To define the regionalization of first heart field (FHF)-derived cardiomyocytes, I used leading lineage tracing approaches and in vivo imaging to show that early loxP reporter recombination leads to preferential labeling of FHF-derived cells in the ventricle, particularly in the atrio-ventricular canal and right side of the zebrafish ventricle- consistent with known FHF origins. My quantifications show that the lineage labeled cells contribute significantly to the ventricle across developmental stages, with nearly half of cardiomyocytes retaining the lineage label at 5 and 22 days post fertilization. In adult zebrafish, we observed asymmetric lineage labeling in the ventricle, particularly in regions distant from the atrium. My work indicates a persistent compartmentalization of FHF-derived myocardium from embryogenesis and into adulthood, despite zebrafish having a single ventricle that lacks any physical septation. My data broaden our understanding of cardiomyocyte patterning during development, serve as a model for studying how these processes malfunction in congenital heart disease, and highlight that the zebrafish ventricle is more similar to the human ventricle than previous work has established.Building on this first part of my dissertation work, I aimed at disentangling the lineage origins of the pericardium and the myocardium during cardiogenesis. Using in vivo imaging approaches, I documented the heterogeneous territory of pericardial and cardiac progenitors prior to heart tube formation. I found that the outermost cells surrounding the heart field form as an extension of the continuous mesothelium at the lateral edge of the developing lateral plate mesoderm (LPM) and confirmed these findings using light sheet microscopy and cell tracking. By back-tracking myocardial and pericardial cells from their developed tissues to their progenitors, I uncovered distinct migratory trajectories and cellular properties between these populations. Building upon these data, I found that pericardial and myocardial precursors have unique gene expression signatures that can be detected early on in LPM patterning and diverge prior to the formation of the heart tube.In the final part of this thesis, I address the mechanisms contributing to pericardial morphology and its potential impact on pediatric cardiac disease. Using the pericardial gene expression signature that I defined, along with live-imaging, I showed that canonical Wnt signaling is active during the establishment and migration of pericardial cells. To test the functional requirements of Wnt/β-catenin signaling on the development of the pericardium, I used chemical inhibitors following heart tube migration to discern any changes in pericardial morphology. I found that the cell number and density of the pericardium is decreased upon treatment with a Wnt inhibitor, and that this phenotype is distinct from pericardial edema that results from reduced cardiac function. We showed that this change in cellular architecture further translates into a neonatal rat model, and treatment with a Wnt antagonist found in pediatric dilated cardiomyopathy (DCM) increases pericardial stiffness. This indicates a possible additional factor contributing to DCM outcomes in patients with long-term exposure to Wnt antagonists, and that changes to pericardial elasticity may hinder efficient ventricular relaxation, worsening the impaired function of the chamber.Altogether, the cellular processes and mechanisms that I have identified in my thesis work have allowed me to expand our conceptual understanding of the diverse lineages that contribute to zebrafish cardiac development. I have further defined the FHF compartmentalization within the zebrafish myocardium, showing the existence of a persistent separation akin to the physical septation seen in the four-chambered mammalian heart. Additionally, I have elucidated the developmental origins of the pericardium for the first time, revealing that it is a distinct mesothelial tissue that develops independently of the cardiac muscle.Finally, I have linked canonical Wnt signaling to pericardial morphology and integrity, further emphasizing the underappreciated role of the pericardium in cardiomyopathies. Collectively, this work is pivotal to advancing our knowledge on how cardiac lineages resolve within the myocardium, as well as amongst the many tissues involved in the cardiovascular system.

English

ISBN: 9798346858416Subjects--Topical Terms:

592588
Developmental biology.
Subjects--Index Terms:

Cardiac development

Lineage Dynamics in Cardiac and Pericardial Morphogenesis /
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502 $b Ph.D. $c University of Colorado Denver, Anschutz Medical Campus $d 2024.
520 $a An estimated 1% of all newborns suffer from a congenital heart anomaly with at times complex syndromic co-morbidities. Understanding the molecular and cellular mechanisms that drive the formation of the heart as functional unit is critical to expand our understanding of the causes, diagnostic opportunities, and therapeutic interventions in congenital heart disease. During vertebrate development, the heart is the first functional organ to form, initiating the circulatory system required to support the growth and survival of the embryo. The cardiovascular system integrates a wide array of cell types and tissues, necessitating a tightly regulated orchestration of developmental processes to ensure proper assembly and function. The heart is composed of myocardial, endocardial, and conduction system cells, all enclosed within the protective, multi-layered mesothelial pericardium. Despite the importance of forming a unified and functional cardiovascular system, comparably little research has focused on how these distinct cell lineages and tissues integrate into forming the functional heart. Unraveling the complex interactions between these cell and tissue types is key to understanding the origins of congenital heart disease, as well as unlocking the heart's inherent regenerative potential for therapeutic applications. In this dissertation, I have: 1) uncovered how zebrafish myocardial progenitors resolve from the first heart field throughout embryogenesis and into adulthood, 2) determined the origins and lineage dynamics of the pericardium, and 3) established a functional contribution of canonical Wnt/β-catenin signaling to regulating pericardial morphology and tissue stiffness, highlighting its role in cardiac disease.To define the regionalization of first heart field (FHF)-derived cardiomyocytes, I used leading lineage tracing approaches and in vivo imaging to show that early loxP reporter recombination leads to preferential labeling of FHF-derived cells in the ventricle, particularly in the atrio-ventricular canal and right side of the zebrafish ventricle- consistent with known FHF origins. My quantifications show that the lineage labeled cells contribute significantly to the ventricle across developmental stages, with nearly half of cardiomyocytes retaining the lineage label at 5 and 22 days post fertilization. In adult zebrafish, we observed asymmetric lineage labeling in the ventricle, particularly in regions distant from the atrium. My work indicates a persistent compartmentalization of FHF-derived myocardium from embryogenesis and into adulthood, despite zebrafish having a single ventricle that lacks any physical septation. My data broaden our understanding of cardiomyocyte patterning during development, serve as a model for studying how these processes malfunction in congenital heart disease, and highlight that the zebrafish ventricle is more similar to the human ventricle than previous work has established.Building on this first part of my dissertation work, I aimed at disentangling the lineage origins of the pericardium and the myocardium during cardiogenesis. Using in vivo imaging approaches, I documented the heterogeneous territory of pericardial and cardiac progenitors prior to heart tube formation. I found that the outermost cells surrounding the heart field form as an extension of the continuous mesothelium at the lateral edge of the developing lateral plate mesoderm (LPM) and confirmed these findings using light sheet microscopy and cell tracking. By back-tracking myocardial and pericardial cells from their developed tissues to their progenitors, I uncovered distinct migratory trajectories and cellular properties between these populations. Building upon these data, I found that pericardial and myocardial precursors have unique gene expression signatures that can be detected early on in LPM patterning and diverge prior to the formation of the heart tube.In the final part of this thesis, I address the mechanisms contributing to pericardial morphology and its potential impact on pediatric cardiac disease. Using the pericardial gene expression signature that I defined, along with live-imaging, I showed that canonical Wnt signaling is active during the establishment and migration of pericardial cells. To test the functional requirements of Wnt/β-catenin signaling on the development of the pericardium, I used chemical inhibitors following heart tube migration to discern any changes in pericardial morphology. I found that the cell number and density of the pericardium is decreased upon treatment with a Wnt inhibitor, and that this phenotype is distinct from pericardial edema that results from reduced cardiac function. We showed that this change in cellular architecture further translates into a neonatal rat model, and treatment with a Wnt antagonist found in pediatric dilated cardiomyopathy (DCM) increases pericardial stiffness. This indicates a possible additional factor contributing to DCM outcomes in patients with long-term exposure to Wnt antagonists, and that changes to pericardial elasticity may hinder efficient ventricular relaxation, worsening the impaired function of the chamber.Altogether, the cellular processes and mechanisms that I have identified in my thesis work have allowed me to expand our conceptual understanding of the diverse lineages that contribute to zebrafish cardiac development. I have further defined the FHF compartmentalization within the zebrafish myocardium, showing the existence of a persistent separation akin to the physical septation seen in the four-chambered mammalian heart. Additionally, I have elucidated the developmental origins of the pericardium for the first time, revealing that it is a distinct mesothelial tissue that develops independently of the cardiac muscle.Finally, I have linked canonical Wnt signaling to pericardial morphology and integrity, further emphasizing the underappreciated role of the pericardium in cardiomyopathies. Collectively, this work is pivotal to advancing our knowledge on how cardiac lineages resolve within the myocardium, as well as amongst the many tissues involved in the cardiovascular system.
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590 $a School code: 1639
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650 4 $a Aquatic sciences. $3 3174300
650 4 $a Cellular biology. $3 3172791
650 4 $a Molecular biology. $3 517296
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653 $a Heart
653 $a Pericardium
653 $a Zebrafish
653 $a Cardiovascular system
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690 $a 0379
690 $a 0307
690 $a 0792
710 2 $a University of Colorado Denver, Anschutz Medical Campus. $b Cell Bio, Stem Cells, and Development. $e degree granting institution. $3 3816984
720 1 $a Mosimann, Christian $e degree supervisor.
720 1 $a Fantauzzo, Katherine $e degree supervisor.
773 0 $t Dissertations Abstracts International $g 86-06B.
790 $a 1639
791 $a Ph.D.
792 $a 2024
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