Etiology and Morphogenesis of Congenital Heart Disease From Gene Function and Cellular Interaction to Morphology

Preface
Contents
Part I: From Molecular Mechanism to Intervention for Congenital Heart Diseases, Now and the Future
	Perspective
	1: Reprogramming Approaches to Cardiovascular Disease: From Developmental Biology to Regenerative Medicine
		1.1 Introduction
		1.2 Molecular Networks Regulate Cardiac Cell Fate
		1.3 Cardiac Fibroblasts in the Normal and Remodeling Heart
		1.4 Direct Cardiac Reprogramming In Vitro
		1.5 Direct Cardiac Reprogramming In Vivo
		1.6 Direct Cardiac Reprogramming in Human Fibroblasts
		1.7 Challenges and Future Directions
		References
	2: The Arterial Epicardium: A Developmental Approach to Cardiac Disease and Repair
		2.1 Origin of the Epicardium
		2.2 Epicardium-Derived Cells (EPDCs)
		2.3 Heterogeneity of Epicardial Cells
			2.3.1 The Cardiac Fibroblast
			2.3.2 Arterial Smooth Muscle Cell
			2.3.3 Endothelial Cells
			2.3.4 Cardiomyocytes
			2.3.5 The Purkinje Fiber
		2.4 Congenital and Adult Cardiac Disease
			2.4.1 Non-compaction
			2.4.2 Conduction System Anomalies
			2.4.3 Valvulopathies
			2.4.4 Coronary Vascular Anomalies
		2.5 Cardiovascular Repair
		2.6 Future Directions and Clinical Applications
		References
	3: Cell Sheet Tissue Engineering for Heart Failure
		3.1 Introduction
		3.2 Cell Sheet Engineering
		3.3 Cardiac Tissue Reconstruction
		3.4 Cell Sheet Transplantation in Small Animal Models
		3.5 Cell Sheet Transplantation in Preclinical and Clinical Studies
		3.6 Conclusions
		References
	4: Future Treatment of Heart Failure Using Human iPSC-Derived Cardiomyocytes
		4.1 Introduction
		4.2 Cardiac Differentiation from Human iPSCs
		4.3 Nongenetic Methods for Purifying Cardiomyocytes
		4.4 Transplantation of Human PSC-Derived Cardiomyocytes
		4.5 Future Directions
		References
	5: Congenital Heart Disease: In Search of Remedial Etiologies
		5.1 Introduction
			5.1.1 Emerging Concepts
			5.1.2 Hub Hypothesis
		5.2 Searching for Candidate Signaling Hubs in Heart Development
			5.2.1 Nodal Signaling Kinases
			5.2.2 Filamin A
			5.2.3 Relevance of Signaling Hubs to CHD
		5.3 Lineage Is a Key to Remedial Therapy
			5.3.1 Postnatal Origin of Cardiac Fibroblasts
			5.3.2 A Strategy to Use Fibroblast Progenitors to Carry Genetic Payloads
				5.3.2.1 This Strategy Calls for a Conceptual Revision in Our Thinking About Fibroblasts
		5.4 Remedial Therapies: Delivering Genetic ``Payloads´´
			5.4.1 Preliminary Studies
		References
Part II: Left-Right Axis and Heterotaxy Syndrome
	6: Left-Right Asymmetry and Human Heterotaxy Syndrome
		6.1 Introduction
		6.2 Molecular and Cellular Mechanisms of Left-Right Determination
			6.2.1 Node Cell Monocilia Create Leftward ``Nodal Flow´´ and Activate Asymmetry Signaling Around the Node
			6.2.2 Asymmetry Signaling Transmits to the Left Lateral Plate Mesoderm
			6.2.3 Genes Associated with the Human Heterotaxy Syndrome
		6.3 Clinical Manifestation of the Heterotaxy Syndrome
			6.3.1 Right Isomerism
			6.3.2 Left Isomerism
		6.4 Long-Term Prognosis of Heterotaxy Patients
			6.4.1 Protein-Losing Enteropathy
			6.4.2 Arrhythmias
			6.4.3 Heart Failure
			6.4.4 Hepatic Dysfunction
			6.4.5 Management of Failing Fontan Patients
		6.5 Future Direction and Clinical Implications
		References
	7: Roles of Motile and Immotile Cilia in Left-Right Symmetry Breaking
		7.1 Introduction
		7.2 Symmetry Breaking by Motile Cilia and Fluid Flow
		7.3 Sensing of the Fluid Flow by Immotile Cilia
		7.4 Readouts of the Flow
		7.5 Future Directions
		References
	8: Role of Cilia and Left-Right Patterning in Congenital Heart Disease
		8.1 Introduction
			8.1.1 Heterotaxy, Primary Ciliary Dyskinesia, and Motile Cilia Defects
			8.1.2 Motile Respiratory Cilia Defects in Other Ciliopathies
			8.1.3 Ciliary Dysfunction in Congenital Heart Disease Patients with Heterotaxy
			8.1.4 Respiratory Complications in Heterotaxy Patients with Ciliary Dysfunction
			8.1.5 Left-Right Patterning and the Pathogenesis of Congenital Heart Disease
			8.1.6 Ciliome Gene Enrichment Among Mutations Causing Congenital Heart Disease
			8.1.7 Ciliary Dysfunction in Congenital Heart Disease Patients Without Heterotaxy
			8.1.8 Future Directions and Clinical Implications
		References
	9: Pulmonary Arterial Hypertension in Patients with Heterotaxy/Polysplenia Syndrome
		References
	Perspective
Part III: Cardiomyocyte and Myocardial Development
	10: Single-Cell Expression Analyses of Embryonic Cardiac Progenitor Cells
		10.1 Introduction
		10.2 CPCs of the Two Heart Fields
		10.3 CPC Specification
		10.4 The Potential of Single-Cell Transcriptomics in the Study of CPC Specification
		10.5 Future Direction and Clinical Implication
		References
	11: Meis1 Regulates Postnatal Cardiomyocyte Cell Cycle Arrest
		11.1 Introduction
		11.2 Results
			11.2.1 Expression of Meis1 During Neonatal Heart Development and Regeneration
			11.2.2 Cardiomyocyte Proliferation Beyond Postnatal Day 7 Following Meis1 Deletion
			11.2.3 MI in Meis1 Overexpressing Heart Limits Neonatal Heart Regeneration
			11.2.4 Regulation of Cyclin-Dependent Kinase Inhibitors by Meis1
		11.3 Future Direction and Clinical Implications
		References
	12: Intercellular Signaling in Cardiac Development and Disease: The NOTCH pathway
		12.1 Introduction
		12.2 Left Ventricular Non-compaction (LVNC)
		12.3 The NOTCH Signaling Pathway
		12.4 NOTCH in Ventricular Chamber Development
		12.5 Future Directions and Clinical Implications
		References
	13: The Epicardium in Ventricular Septation During Evolution and Development
		13.1 Introduction
		13.2 Septum Components in the Completely Septated Heart
		13.3 The Presence of the Epicardium in Amniotes
		13.4 The Epicardium in the Avian Heart
		13.5 Disturbance of the Epicardium
		13.6 Septum Components in Reptilian Hearts
		13.7 Tbx5 Expression Patterns
		13.8 Discussion
		References
	14: S1P-S1p2 Signaling in Cardiac Precursor Cells Migration
		References
	15: Myogenic Progenitor Cell Differentiation Is Dependent on Modulation of Mitochondrial Biogenesis through Autophagy
	16: The Role of the Thyroid in the Developing Heart
		References
	Perspective
Part IV: Valve Development and Diseases
	17: Atrioventricular Valve Abnormalities: From Molecular Mechanisms Underlying Morphogenesis to Clinical Perspective
		17.1 Introduction
		17.2 RV-TV Dysplastic Syndrome
			17.2.1 Anatomic Features of the Heart in Ebstein´s Anomaly Patients
			17.2.2 Morphogenetic Features of the Heart in Patients with Uhl´s Anomaly
			17.2.3 Absence of the TV
		17.3 Bone Morphogenetic Proteins (BMPs) and Their Important Role in Cushion Formation
			17.3.1 Role of BMP2 in Cushion Mesenchymal Cell (CMC) Migration
			17.3.2 BMP2 Induces CMC Migration and Id and Twist Expression
			17.3.3 BMP2 Induces Expression of ECM Proteins in the Post-EMT Cushion
		17.4 The Role of BMP2 for Cardiomyocytes Formation
		17.5 Future Direction
		References
	18: Molecular Mechanisms of Heart Valve Development and Disease
		18.1 Introduction
		18.2 Heart Valve Development
		18.3 Heart Valve Disease
			18.3.1 Calcific Aortic Valve Disease (CAVD)
			18.3.2 Myxomatous Valve Disease
		18.4 Signaling Pathways in Heart Valve Development and Disease
		18.5 Future Directions and Clinical Implications
		References
	19: A Novel Role for Endocardium in Perinatal Valve Development: Lessons Learned from Tissue-Specific Gene Deletion of the Tie...
		19.1 Introduction
		19.2 Model for Valvar Endocardial-Specific Gene Deletion
		19.3 Tie1 Is Required for Late-Gestational and Early Postnatal Aortic Valve Remodeling
		19.4 Future Directions
		References
	20: The Role of the Epicardium in the Formation of the Cardiac Valves in the Mouse
		20.1 Introduction
			20.1.1 The AV Valves and Their Leaflets
			20.1.2 The Epicardium and Epicardially Derived Cells (EPDCs)
			20.1.3 The Contribution of EPDCs to the Developing AV Valves
		20.2 The Role of Bmp Signaling in Regulating the Contribution of EPDC to the AV Valves
			20.2.1 Epicardial-Specific Deletion of the Bmp Receptor BmpR1A/Alk3 Leads to Disruption of AV Junction Development
			20.2.2 Discussion
			20.2.3 Future Direction and Clinical Implications
		References
	21: TMEM100: A Novel Intracellular Transmembrane Protein Essential for Vascular Development and Cardiac Morphogenesis
		References
	22: The Role of Cell Autonomous Signaling by BMP in Endocardial Cushion Cells in AV Valvuloseptal Morphogenesis
		References
	Perspective
Part V: The Second Heart Field and Outflow Tract
	23: Properties of Cardiac Progenitor Cells in the Second Heart Field
		23.1 Introduction
		23.2 Demarcating the First and Second Heart Fields and Their Contributions to the Heart
		23.3 New Insights into the Role and Regulation of Noncanonical Wnt Signaling in the Second Heart Field and the Origins of Cono...
		23.4 Involvement of the Second Heart Field in Atrial and Atrioventricular Septal Defects
		23.5 Future Directions and Clinical Implications
		References
	24: Nodal Signaling and Congenital Heart Defects
		24.1 Introduction
		24.2 The Nodal Signaling Pathway
		24.3 Requirement for Nodal in Development
		24.4 Congenital Heart Defects Associated with Perturbations in Nodal Signaling
		References
	25: Utilizing Zebrafish to Understand Second Heart Field Development
		25.1 Introduction
		25.2 Late-Differentiating Cardiomyocytes Originate from the SHF in Zebrafish
		25.3 Mechanisms Regulating Outflow Tract Development in Zebrafish
		25.4 Mechanisms Regulating Inflow Tract Development in Zebrafish
		25.5 Future Directions and Clinical Implications
		References
	26: A History and Interaction of Outflow Progenitor Cells Implicated in ``Takao Syndrome´´
		26.1 Introduction
		26.2 The 22q11.2 Deletion Syndrome (Takao Syndrome)
		26.3 Identification of TBX1
		26.4 Expression of TBX1
		26.5 Mutations of GATA6
		26.6 Future Direction: Elucidating the Interaction Between CNC and SHF
		References
	27: The Loss of Foxc2 Expression in the Outflow Tract Links the Interrupted Arch in the Conditional Foxc2 Knockout Mouse
		References
	28: Modification of Cardiac Phenotype in Tbx1 Hypomorphic Mice
		References
	Perspective
Part VI: Vascular Development and Diseases
	29: Extracellular Matrix Remodeling in Vascular Development and Disease
		29.1 Introduction
		29.2 Extracellular Matrix in Vascular Wall
		29.3 Tenascin-C in Vascular System
			29.3.1 Development of Aorta and Tenascin-C
			29.3.2 Development of Coronary Artery and Tenascin-C
		29.4 Future Direction and Clinical Implications
		References
	30: The ``Cardiac Neural Crest´´ Concept Revisited
		30.1 Introduction
		30.2 Cardiac Neural Crest Arising from the Postotic Region
		30.3 Endothelin Signal and Neural Crest Development
		30.4 Preotic Neural Crest Contributing to Heart Development
		30.5 Future Direction and Clinical Implications
		References
	31: Roles of Endothelial Hrt Genes for Vascular Development
		References
	32: Inositol Trisphosphate Receptors in the Vascular Development
		References
	33: Tissue Remodeling in Vascular Wall in Kawasaki Disease-Related Vasculitis Model Mice
		References
	Perspective
Part VII: Ductus Arteriosus
	34: Progerin Expression during Normal Closure of the Human Ductus Arteriosus: A Case of Premature Ageing?
		34.1 Introduction
		34.2 Material and Methods
		34.3 Results
		34.4 Discussion
		34.5 Future Directions and Clinical Applications
		References
	35: The Multiple Roles of Prostaglandin E2 in the Regulation of the Ductus Arteriosus
		35.1 Introduction
		35.2 The Molecular Mechanisms of Intimal Thickening of the Ductus Arteriosus
			35.2.1 Hyaluronan-Mediated Intimal Thickening
			35.2.2 Epac-Mediated SMC Migration
			35.2.3 Regulation of Elastogenesis
		35.3 Future Direction and Clinical Implications
		References
	36: Developmental Differences in the Maturation of Sarcoplasmic Reticulum and Contractile Proteins in Large Blood Vessels Infl...
	37: Fetal and Neonatal Ductus Arteriosus Is Regulated with ATP-Sensitive Potassium Channel
		References
	Perspective
Part VIII: Conduction System and Arrhythmia
	38: Regulation of Vertebrate Conduction System Development
		38.1 Introduction
		38.2 Genetic Pathways Controlling SAN and AVC Development
		38.3 Transcriptional Regulation of CCS Genes
		38.4 Common Genomic Variants Influence CCS Function
		38.5 3D Architecture Regulates Transcription
		38.6 Regulation of Tbx3 by a Large Regulatory Domain
		38.7 Assigning Function to Genomic Variation
		References
	39: Cardiac Pacemaker Development from a Tertiary Heart Field
		39.1 Introduction
		39.2 Pacemaking Site Transitions From Left To Right During Heart Looping
		39.3 A Novel Cell Population That Juxtaposes the Right Atrium Takes Over Pacing Function by Mid-heart Looping Stage
		39.4 The Right-Sided Pacemaking Cells Indeed Differentiate into SAN Pacemaker Cells
		39.5 Pacemaker Cell Fate Specification Has Already Completed Prior to Heart Morphogenesis
		39.6 PF Explants Are Sensitive to Blockers Specific for Pacemaking Ion Channel
		39.7 Current Models for Molecular Regulation of SAN Pacemaker Differentiation
		39.8 A Novel Role of Wnt Signaling for Pacemaker Cell Fate Specification
		39.9 Concluding Remarks
		References
	40: Endothelin Receptor Type A-Expressing Cell Population in the Inflow Tract Contributes to Chamber Formation
		References
	41: Specific Isolation of HCN4-Positive Cardiac Pacemaking Cells Derived from Embryonic Stem Cells
		Reference
	Perspective
Part IX: Current Molecular Mechanism in Cardiovascular Development
	42: Combinatorial Functions of Transcription Factors and Epigenetic Factors in Heart Development and Disease
		42.1 Transcription Factors in Heart Development
		42.2 Chromatin Factors and Cardiac Differentiation
		42.3 Future Directions and Clinical Implications
		References
	43: Pcgf5 Contributes to PRC1 (Polycomb Repressive Complex 1) in Developing Cardiac Cells
		43.1 Introduction
		43.2 PcG Functions in Cardiac Development
		43.3 Diversity of PcG Proteins
		43.4 Pcgf5 Expression in the Developing Heart
		43.5 Conclusions
		References
	44: Noncoding RNAs in Cardiovascular Disease
		44.1 Introduction
		44.2 miRNAs in Cardiac Development
		44.3 Cardiac Regeneration, Remodeling, and Ischemia Regulated by miRNAs
		44.4 LncRNAs in Cardiac Development
		44.5 Noncoding RNAs in Cardiac Disease
		References
	Perspective
Part X: iPS Cells and Regeneration in Congenital Heart Diseases
	45: Human Pluripotent Stem Cells to Model Congenital Heart Disease
		45.1 Introduction
		45.2 Modeling Fetal Cardiac Reprogramming in Hypoplastic Left Heart Syndrome (HLHS)
		45.3 hiPSCs to Model Williams-Beuren Syndrome (WBS)
		45.4 Future Directions and Clinical Applications
		References
	46: Engineered Cardiac Tissues Generated from Immature Cardiac and Stem Cell-Derived Cells: Multiple Approaches and Outcomes
		46.1 Introduction
		46.2 A Broad View of Bioengineering Cardiac Tissues
		46.3 Immature Cells for Engineered Cardiac Tissues
		46.4 Various Formulations for Engineered Cardiac Tissues
		46.5 In Vitro ECT Findings
		46.6 In Vivo ECT Findings
		46.7 Future Directions
		References
	47: Dissecting the Left Heart Hypoplasia by Pluripotent Stem Cells
		References
	48: Lentiviral Gene Transfer to iPS Cells: Toward the Cardiomyocyte Differentiation of Pompe Disease-Specific iPS Cells
		Reference
	49: Molecular Analysis of Long-Term Cultured Cardiac Stem Cells for Cardiac Regeneration
		References
	50: Minor Contribution of Cardiac Progenitor Cells in Neonatal Heart Regeneration
		References
	Perspective
Part XI: Current Genetics in Congenital Heart Diseases
	51: Genetic Discovery for Congenital Heart Defects
		51.1 Introduction
		51.2 De Novo Mutations
		51.3 Copy Number Variants
		51.4 Future Directions
		References
	52: Evidence That Deletion of ETS-1, a Gene in the Jacobsen Syndrome (11q-) Cardiac Critical Region, Causes Congenital Heart D...
		52.1 Introduction
		52.2 Evidence for a Role for ETS-1 in the Cardiac Neural Crest in Mice
			52.2.1 Expression of ETS-1 in Cardiac Lineages During Murine Heart Development
			52.2.2 ETS-1 Mutant Mice Have a Double Outlet Right Ventricle (DORV) Phenotype
			52.2.3 Lost of ETS-1 Causes Decreased Expression of Sox10
		52.3 Establishment of an Explanted cNCC ``Ex Vivo´´ Culture System
			52.3.1 Loss of ETS-1 in C57/B6 Mice Causes Decreased NCC Numbers and Decreased Migration
		52.4 Cardiac Neural Crest Cell Number and Migration Are Preserved in ETS-1-/- Mice in an FVBN-1 Background
		52.5 Summary, Future Directions, and Clinical Implications
		References
	53: Notch Signaling in Aortic Valve Development and Disease
		53.1 Introduction
		53.2 NOTCH1 Mutations and Aortic Valve Disease
		53.3 Notch1 Signaling and Aortic Valve Calcification
		53.4 Future Directions and Clinical Implications
		References
	54: To Detect and Explore Mechanism of CITED2 Mutation and Methylation in Children with Congenital Heart Disease
		References
	Perspective
Erratum to: Etiology and Morphogenesis of Congenital Heart Disease
	Erratum to: T. Nakanishi et al. (eds.), Etiology and Morphogenesis of Congenital Heart Disease, https://doi.org/10.1007/978-4-...
Index