Heart Development and Regeneration (2 Volume Set), Second Edition

cover......Page 1
i_Front-matter......Page 2
Front matter......Page 3
Color Plate......Page 4
Color Plate......Page 5
Copyright Page......Page 6
Dedication......Page 7
List of Contributors......Page 8
Foreword......Page 12
Preface......Page 13
 Introduction......Page 15
Macropumps or Specialized Pumping Organs......Page 16
What phylogenies tell us about the origins of pumping organs......Page 17
Peristaltic Pumps Arose in Connection With Blood Vascular Systems of Bilaterians......Page 18
Myoepithelial Cells, Myocytes and the Origin of the Ancestral Peristaltic Pump......Page 21
A gut origin for the ancestral peristaltic pump: an alternative view......Page 22
Homology, Analogy and Gene Regulatory Networks......Page 24
A Reappraisal of the Different Categories of Pumping Organs......Page 26
Hemodynamic constraints may have shaped modern pumping organs out of a primitive peristaltic pump......Page 28
Solutions to the Shortcomings of Peristaltic Pumps: A Mixed Bag of Tricks......Page 29
The Pumping Organs of Deuterostomes......Page 31
Cephalochordates......Page 33
Tunicates......Page 36
Extant Vertebrates......Page 37
The evolutionary origin of cardiac chambers......Page 38
Alternative Phylogenies for the Vertebrate Heart......Page 39
The Inflow/Outflow Organization......Page 40
The Sequential Hypothesis......Page 41
The Recruitment Hypothesis......Page 43
Challenges to the inflow/outflow patterning hypothesis......Page 44
Conflicting Evidence......Page 45
The Second Heart Field Goes Evolutionary......Page 46
Retinoic Acid Signaling and Cardiac Anterior–Posterior Patterning in Amphibians and Fish......Page 47
References......Page 50
Morphology and morphogenesis of the drosophila heart......Page 58
Embryology of Heart Development......Page 59
Genetic control of the formation and dorsal expansion of the mesoderm......Page 61
The Expression of tinman......Page 62
The Function of tinman Within the Dorsal Vessel......Page 63
Conserved Molecular Aspects of the Function and Regulation of tinman......Page 64
The GATA-Encoding Gene pannier......Page 65
The Zinc-Finger Encoding Gene zfh1 and the Homeobox Gene eve in Pericardial Cell Specification......Page 67
Dorsolateral Signaling Inputs by dpp......Page 68
Anterior–Posterior Signaling Inputs by wingless: Direct Effects on Cardiogenesis......Page 69
A Combinatorial Model for Specifying the Precardiac Mesoderm......Page 70
Early Diversification within the Cardiac Mesoderm......Page 72
msh Reinforces Restriction of Cardiac Cell Fates to the Dorsal Mesodermal Edge......Page 74
Axial patterning, diversification and differentiation of the myocardium......Page 75
Tbx20 Genes (mid/nmr2 and H15/nmr1) in Myocardial Diversification and Differentiation......Page 77
Axial Patterning and Subdivision of the Dorsal Vessel......Page 78
The MADS-Box Gene Mef2......Page 80
The Role of MicroRNAs in Cardiac Differentiation......Page 81
Slit/Robo......Page 82
Remodeling of the larval to the adult dorsal vessel......Page 83
Controls of the physiology and aging of the adult heart......Page 85
Control of the Heart Rhythm......Page 86
Pericardial Influences on Heart Function: even-skipped......Page 88
Insulin–TOR Signaling......Page 89
References......Page 90
The heart-forming region in the early embryo......Page 98
Sources of heart-inducing signals......Page 100
Inhibitory signals and the concept of a cardiac field......Page 101
Early Wnt Signaling Establishes Dorsoanterior Mesoderm......Page 102
Specification of the Heart Field by Wnt Antagonists, TGF family members and Cerberus......Page 103
Transcription Factor Control of Cardiac Muscle Gene Activity......Page 105
Formation and Closure of the Heart Tube......Page 106
The Three-Chambered Amphibian Heart......Page 108
References......Page 109
Experimental approaches for analysis of heart development in zebrafish......Page 114
Genetics......Page 115
Regulation of Gene Activity......Page 116
Imaging......Page 117
Overview of Stages of Zebrafish Development......Page 119
Cardiac Progenitor Specification......Page 120
Heart Tube Assembly......Page 122
Morphogenesis of the Cardiac Chambers and Atrioventricular Cushions......Page 123
Use of zebrafish as models of heart disease......Page 126
References......Page 127
Circulation, Chambers and Valves......Page 132
Coronary Circulation and Conduction......Page 133
Determination and earliest development......Page 134
Inducers of Cardiomyogenic Determination......Page 136
Early morphogenetic changes in the forming heart tube......Page 137
Diversification of Myogenic Cell Lineages......Page 138
Trabeculation and cardiac myocytes......Page 140
Summary......Page 142
Specification of the heart field......Page 145
Fibroblast Growth Factor Signaling and Heart Induction......Page 146
Directed Migration of Myocardial Progenitor Cells......Page 147
Heart Differentiation Network......Page 148
References......Page 149
Discovery and initial characterization of the second heart field......Page 151
The Mammalian Second Heart Field......Page 152
The Second Heart Field Paradigm......Page 154
Evaluating the contribution of the second heart field......Page 157
The Contribution of the Second Heart Field at the Venous Pole......Page 158
Endocardium and Epicardium......Page 159
Neural Crest Cells......Page 160
Transcriptional networks controlling the second heart field......Page 161
The Role of Pitx2c in the Second Heart Field......Page 162
Tbx1 Regulation of the Second Heart Field......Page 163
Signaling networks controlling the second heart field......Page 165
Bone Morphogenetic Protein Signaling......Page 167
Notch Signaling......Page 168
Outstanding questions concerning second heart field deployment......Page 169
The biomedical significance of the second heart field......Page 170
References......Page 172
Introduction......Page 178
Markers for the forming conduction system......Page 180
Pacemaker activity, polarity and the formation of the sinus node......Page 183
Chamber differentiation, atrioventricular canal specification and the formation of the atrioventricular node......Page 186
Internodal tracts and outflow tract......Page 188
The Formation of the Atrioventricular Bundle and Proximal Bundle Branches......Page 189
The Peripheral Ventricular Conduction System: Distal Bundle Branches and Purkinje Fiber Network......Page 190
How Does the Purkinje Fiber Network Develop?......Page 191
Formation of the conduction system components by recruitment or by early specification and outgrowth......Page 192
References......Page 194
Progenitor cell migration......Page 200
Formation of the myocardial epithelium......Page 202
Behavior of cells in the second heart field......Page 203
Formation of the cardiac tube......Page 205
Cell Proliferation......Page 208
Other Aspects of Cell Behavior......Page 210
Rotation of Outflow Tract Myocardium......Page 212
Concluding remarks......Page 214
References......Page 216
Introduction......Page 223
The cardiac chambers......Page 224
Chamber Development is a Local Process......Page 225
Fields, lineages and cardiac precursor cells......Page 227
Cardiac growth......Page 229
Growth of the Chambers......Page 230
Fate of Remaining Primary Myocardium......Page 233
Patterning and Formation of the Trabecular Ventricles......Page 234
The origin of the components of the chambers in the mature heart......Page 235
Concluding thoughts......Page 236
References......Page 237
Introduction......Page 241
Early heart morphogenesis and patterning......Page 243
Retinoic Acid and Anterior–Posterior Patterning of the Heart Tube......Page 244
Retinoic Acid and Left–Right Heart Looping Morphogenesis......Page 247
Investigations of Defective Outflow Tract Development......Page 249
Retinoic Acid Deficiency Affects Posterior Branchial Arch Development......Page 251
Regulation of myocardial cell proliferation and differentiation......Page 252
Retinoid Regulation of Heart Differentiation has Implications for Regeneration and Progenitor Cell Specification......Page 253
References......Page 254
Describing the cardiac components......Page 258
Describing the congenitally malformed heart......Page 260
The starting point for analysis......Page 261
Analysis of the atrioventricular junctions......Page 262
Analysis of the ventriculo–arterial junctions......Page 266
Cataloging the associated malformations......Page 276
References......Page 279
Overview of cardiac left–right development......Page 281
Left–right nomenclature......Page 282
Failure of Left–Right Morphogenesis......Page 283
Asymmetry in the Heart Tube......Page 284
An asymmetric signaling cascade controls cardiac left–right development......Page 285
Asymmetric Signaling in Chick: A Role for the Node......Page 286
Role of the Midline......Page 287
Discovery of Asymmetric Nodal Flow in Mouse......Page 288
Asymmetric Fluid Flow in Zebrafish: Ciliated Cells are Necessary for Left–Right Development......Page 289
How does Asymmetric Flow Send Left–Right Signals?......Page 290
Asymmetries that precede cilia-dependent asymmetric flow......Page 291
Conclusions and future perspectives......Page 292
References......Page 293
Overview......Page 297
Symmetry breaking by cilia and fluid flow......Page 298
Action of nodal flow......Page 299
The Nodal Signal is Transferred Directly from the Node to the Lateral Plate Mesoderm......Page 300
Molecular patterning by the asymmetric signals nodal and lefty......Page 301
The cellular basis of asymmetric morphogenesis......Page 303
Diversity among vertebrates......Page 304
References......Page 305
Left–right asymmetry and heart disease......Page 307
Cardiac disease and the nodal-lefty-pitx2 left–right asymmetry pathway......Page 308
PITX2 and cardiac morphogenesis......Page 309
Pitx2 Function: Evidence from Loss-of-Function Studies in Mice......Page 311
Pitx2, the Second Heart Field and Outflow Tract Development......Page 312
The Role of the Pitx2-Mediated Left–Right Asymmetry Pathway in Outflow Tract Growth......Page 313
Summary: Pitx2 in Outflow Tract Development......Page 314
Pitx2 in Branchiomeric Muscle: A Subpopulation of the Second Heart Field......Page 315
Pathways regulating pitx2 expression......Page 316
PITX Genes and transcriptional regulation......Page 317
References......Page 319
Introduction......Page 323
Induction and Specification of the Epicardial Anlagen......Page 324
Proepicardial Growth toward the Heart......Page 328
Epithelial-to-Mesenchymal Transformation......Page 330
Fate Diversity of Proepicardium and Epicardial Cells......Page 331
Wilms Tumor Gene 1 (Wt1)......Page 332
Serum Response Factor (SRF)......Page 333
Cited2 and Pbx Genes......Page 334
Evo–devo aspects......Page 335
Outlook......Page 336
References......Page 337
Midgestational Heart Development......Page 343
Function of the Epicardium......Page 345
Epicardial Control of Myocardial Growth......Page 346
Coronary vascular development......Page 347
An FGF-HH-VEGF/ANG Signaling Pathway Controls Coronary Development......Page 348
The Epicardium Acts as a Signaling Center for Heart Development......Page 349
FGF Regulation of HH Signaling......Page 350
Development of Coronary Arteries and Veins......Page 351
Developmental Signaling Pathways in the Treatment of Ischemic Heart Disease......Page 352
HH Signaling Mediates Coronary Vessel Growth in the Adult Heart......Page 353
References......Page 354
Origins and morphogenetic stages of valve–septal development......Page 358
Structure–Function Relationships of Early Cushions......Page 360
Cushion formation......Page 361
Dynamics of the Matrix......Page 362
The Epithelial–Mesenchymal Transition Paradigm......Page 363
TGFβs as Mediators of Epithelial–Mesenchymal Transition......Page 365
TGFβ Receptor Activity in Mediating Arterioventricular Canal Epithelial–Mesenchymal Transition......Page 366
BMP Signaling in Epithelial–Mesenchymal Transition......Page 367
Notch as a Regulator of Epithelial–Mesenchymal Transition......Page 368
Receptor Tyrosine Kinase and Ras-MAPK Signaling During Epithelial–Mesenchymal Transition......Page 369
Calcium and VEGF as Regulators of Epithelial–Mesenchymal Transition......Page 370
Proliferation and Elongation......Page 371
Delamination and Formation of Supporting Valve Structures......Page 372
Regulation of post-epithelial–mesenchymal transition cushion morphogenesis: lessons from adult valve diseases......Page 373
The living valve......Page 374
References......Page 375
Valve anatomy and function......Page 383
Early embryogenesis of heart valves: the origins of cardiac valve cell populations......Page 386
Signaling pathways and effectors of endocardial epithelial-to-mesenchymal transformation and valve morphogenesis......Page 387
Bone Morphogenetic Proteins......Page 388
TGFβ Receptors and Smad Signaling Mediators......Page 389
Vascular Endothelial Growth Factor (VEGF)......Page 390
Calcineurin and Nuclear Factor of Activated T-Cells (NFATc)......Page 391
Sox9......Page 392
Notch......Page 393
Neurofibromatosis Type 1 (Nf1)......Page 395
Normal and abnormal signaling in valve development: the origin of congenital defects......Page 396
Fusion of Cushions and Valve Calcification......Page 397
The Paradigmatic Example of Ebstein’s Anomaly......Page 398
Noonan’s Syndrome......Page 399
Tissue engineering: in vitro generation of functional valvular tissue......Page 400
References......Page 401
Neural crest formation......Page 408
The cardiac neural crest......Page 409
Evolution of the cardiac neural crest......Page 411
Cardiac neural crest cells and morphogenesis of the heart and great vessels......Page 412
Interactions between cardiac neural crest and mesoderm......Page 414
Pharyngeal endoderm and the cardiac crest......Page 415
Genetic regulation of cardiac neural crest cell patterning......Page 416
Migration of the Cardiac Crest......Page 417
Aortic Arch Remodeling......Page 420
Outflow Tract Septation......Page 421
Differentiation of Cardiac Neural Crest......Page 422
Persistence of cardiac neural crest cells in the heart......Page 423
References......Page 425
Origin of the Neural Crest......Page 431
Pharyngeal Arch Arteries......Page 432
Cardiac neural crest and the formation of the arterial pole......Page 433
Formation of the Arterial Pole......Page 434
Cardiac neural crest ablation model......Page 435
Direct Defects: Outflow Septation, Aortic Arch Arteries and Pharyngeal Glands......Page 436
Indirect Defects: Role for Cardiac Neural Crest Cells to Modulate Signaling in the Caudal Pharynx......Page 437
Factors important in cardiac neural crest induction and function......Page 438
AP2......Page 439
Signaling Factors......Page 440
Endothelin (ET)......Page 441
Retinoic Acid (RA)......Page 442
Human syndromes that are likely to involve cardiac neural crest......Page 443
CHARGE Syndrome......Page 444
Conclusions and future perspectives......Page 445
References......Page 446
Introduction......Page 453
Coelomic Circulatory Systems......Page 455
Hemal Circulatory Systems......Page 456
Prostostomozoa......Page 457
Blood Cells in Invertebrates......Page 458
The Invertebrate Heart......Page 459
The Basic Anatomy of Vertebrate Vasculature......Page 460
Mechanisms of Vascular Formation and Growth: Angiogenesis versus Vasculogenesis......Page 461
Fine Features of Embryonic Vasculogenesis......Page 462
Origin and Differentiation of Vertebrate Angioblasts......Page 463
Endothelial Cell Types: The Paradigmatic Case of Cardiac Endothelial Lineages......Page 464
Molecular Regulation of Embryonic Vasculogenesis: Essential Elements......Page 465
A Hypothesis on the Origin of Endothelial Cells......Page 466
The Origin of Pericytes and Vascular Smooth Muscle......Page 467
Supporting Evidence......Page 468
References......Page 469
Introduction to vascular development......Page 475
Endothelial Origins in the Mesoderm......Page 476
Vascular Studies: Classical Embryology to Molecular Breakthroughs......Page 478
The hemangioblast......Page 479
In Vivo Studies......Page 481
Tubulogenesis......Page 482
Vasculogenesis and angiogenesis......Page 483
undefined......Page 485
TGF Signaling Pathways......Page 486
Collagens......Page 487
Vascular Endothelial-Cadherin......Page 488
Hedgehogs and Patched Receptor......Page 489
Angiogenic Remodeling......Page 490
Endothelial Regression......Page 492
Hemodynamic Forces......Page 493
Vascular Endothelial Growth Factor......Page 495
Patterning during Vasculogenesis: Primary Plexus Formation......Page 496
Patterning of the Intersegmental Vessels (ISV): Sprouting Angiogenesis......Page 497
Semaphorins and Plexin Receptors......Page 499
Vessel maturation and vascular wall formation......Page 500
The Vascular Wall......Page 502
Angiopoietins and Tie Receptors......Page 503
Sphingosine 1-Phosphate and the Sphingosine 1-Phosphate (Edg) Receptors......Page 504
Endothelial Cell Heterogeneity......Page 505
Conclusion......Page 506
References......Page 507
Ephrins and EPH Receptors......Page 517
Vascular Endothelial Growth Factor and the Notch Pathway in Zebrafish......Page 519
Vascular Endothelial Growth Factor and the Notch Pathway in Mice......Page 520
SOXF Subgroup Genes......Page 521
Chemical Genetic Screens in Zebrafish: Pathways Downstream of Vascular Endothelial Growth Factor......Page 522
In Vitro Differentiation of Endothelial Cells from Stem Cells......Page 523
Endothelial Cell Plasticity Revealed by Disruption of Hemodynamic Flow......Page 524
Hypoxia and Oxygen Tension......Page 525
References......Page 526
Lymphatic vessels: a historical perspective......Page 530
A comparison of lymphatic vessel and blood vessel architecture......Page 531
Lymphatic versus Blood Capillaries......Page 532
Junctions between Lymphatic Endothelial Cells......Page 533
A Venous Origin of Lymphatic Vessels......Page 534
A Mesenchymal Origin of Lymphatic Vessels......Page 535
Podoplanin......Page 536
Ccl21......Page 538
FoxC2......Page 539
Net......Page 540
Angiopoietin-1......Page 541
The Vascular Endothelial Growth Factor (VEGF) Family: VEGF-A, -B, -C and -D and PlGF......Page 542
PDGF-BB, FGF-2, HGF, IGF-1 and -2, Adm......Page 543
Hemopoietic Cells and Lymphangiogenic Signals......Page 544
Syk, SLP-76 and PLC2......Page 545
How does lymphatic vascular development go wrong in disease?......Page 546
References......Page 547
Introduction......Page 553
Molecular nature of NKX2-5......Page 555
NK-2 Specific Domain (NK2-SD)......Page 557
Post-translational Modifications of Nkx2-5......Page 558
Foxh1......Page 559
Nkx2-5 and Chromatin Remodeling Factors......Page 560
NKX2-5 and heart disease......Page 561
Phenotypes of NKX2-5 mutants in mice......Page 566
Nkx2-5 and the Patterning of the Vertebrate Heart......Page 567
Nkx2-5 in the Establishment and Maintenance of Boundaries......Page 569
Nkx2-5 and the Developing Ventricular Conduction System......Page 570
Studies of NKX2-5 in other vertebrate model systems......Page 571
VII. Tinman and the drosophila dorsal vessel......Page 572
Regulatory components of the NKX2-5 locus......Page 573
References......Page 575
General Properties......Page 582
The Two Subfamilies of Vertebrate GATA Proteins......Page 583
GATA Proteins in the Myocardium......Page 584
GATA Proteins in the Outflow Tract......Page 585
Regulation of Gene Expression......Page 586
Regulation of Protein Activity......Page 587
GATA4......Page 588
GATA6......Page 589
GATA4 and Cardiomyocyte Hypertrophy......Page 590
GATA6 and Vascular Remodeling......Page 591
Cell-Specific GATA Collaborators......Page 592
GATA factors as integrators and regulators of cell signaling in the heart......Page 594
Conclusion and perspectives......Page 595
References......Page 596
Serum response factor......Page 600
Embryonic serum response factor expression is largely restricted to cardiac and skeletal muscle tissues......Page 602
Myogenic Contractile Proteins are Downregulated in Serum Response Factor-Null Embryonic Stem Cells......Page 603
Serum Response Factor Directs the Expression of Many MicroRNAs......Page 605
Inhibitory Serum Response Factor is Generated by Caspase 3 Cleavage in Human Heart Failure......Page 606
Serum response factor gene autoregulation......Page 607
Tbx Factors Regulate Serum Response Factor Gene Activity through its 3UTR Gene Enhancer......Page 608
Serum Response Factor-Dependent Transactivation of DNA Targets Correlates Well With the Quality and Quantity of Serum Response Factor-Binding Sites......Page 611
Serum Response Factor Target Genes Raf1, Map4k4 and Bicc1 Play Roles in Mesoderm Formation......Page 612
Combinatorial interactions of serum response factor-accessory proteins......Page 613
Recruitment of the Tinman Homolog Nkx2-5 by Serum Response Factor-Activated Cardiac -Actin Gene Transcription......Page 616
Serum Response Factor and GATA4 are Mutual Co-Regulators......Page 617
Competition between Negatively Acting YY1 versus Positively Acting Serum Response Factor Regulates α-Actin Promoter Activity......Page 618
Cysteine-rich protein lim factors bridge serum response factor with gata6 and activate smooth muscle genes......Page 620
Serum response factor co-activator myocardin is required for vascular smooth muscle development......Page 622
Myocardin Sumoylation Transactivates Cardiogenic Genes......Page 623
Role of Histone Deacetylases (HDACs) and Histone Acetyl-transferases (HATs) in Serum Response Factor-Dependent Muscle Gene Activity......Page 625
Mimicking Phosphorylation of S162 in the MADS-box Permits c-fos Promoter Activity......Page 626
References......Page 628
Brachyury and the t-box family of proteins......Page 633
Tbx1......Page 634
Tbx3......Page 636
Tbx5......Page 637
Tbx18......Page 638
Tbx20......Page 639
T-Box genes and the cardiac cell-cycle......Page 640
T-Box Proteins Act as Repressors and Activators......Page 642
T-Box Protein Transcriptional Partners......Page 643
Upstream Regulatory Pathways That Control T-Box Gene Expression......Page 644
Holt-Oram Syndrome......Page 645
DiGeorge Syndrome......Page 646
References......Page 647
Introduction......Page 654
The MEF2 Family in the Context of the MADS Domain Superfamily......Page 655
Structure of MEF2 Proteins......Page 656
MEF2 Functions as a Transcriptional Co-Factor......Page 658
Chromatin Remodeling by MEF2 through Interaction with Histone Deacetylases......Page 659
MEF2 Functions as a Signal-Dependent Transcriptional Switch......Page 661
MEF2 Proteins are Expressed in Multiple Lineages During Development and in Adulthood......Page 663
Genetic Analyses of Mef2 Gene Function......Page 664
Direct Transcriptional Targets of MEF2 in the Heart......Page 666
Mef2 Gene Regulation as a Paradigm for Modular Transcriptional Control......Page 668
Regulation of Mef2 Transcription in the Drosophila Heart......Page 669
Regulation of Mef2c Transcription in the Mammalian Heart......Page 670
Future directions......Page 672
References......Page 673
Histone-Modifying Proteins......Page 681
Histone Acetyl Transferases......Page 684
Histone Methylation/Demethylation......Page 685
Pc Complexes in Stem Cells: Poising Genes for Lineage Activation?......Page 686
Swi/Snf (BAF) Complexes: Baf60c and Heart Development......Page 687
BAF Complexes: Baf250a and Heart Development......Page 688
References......Page 689
Histone acetyl transferases and histone deacetylases......Page 693
Histone Deacetylases as Repressors of MEF2-Mediated Transcription......Page 694
The Development–Hypertrophy Connection......Page 695
Protein Kinase D......Page 696
Mark Kinases......Page 697
HDAC9 and HDAC5 Knockout Mice......Page 698
HDAC7 Knockout Mouse......Page 699
HDAC4 Knockout Mouse......Page 700
Perspectives on Therapeutics......Page 701
References......Page 702
Introduction......Page 706
Biogenesis, organization and target recognition of miRNA......Page 707
Cardiac- and muscle-specific miRNAs......Page 708
Function of miR-1 during Cardiogenesis......Page 709
miR-1 and Heart Morphogenesis......Page 711
The Postnatal Heart and miR-1: Cardiac Electrophysiology and Cell-Cycle......Page 712
Function of miR-206 and miR-181......Page 713
Cardiac stress-responsive miRNAs......Page 714
References......Page 715
Conventional Methods for Cardiovascular Gene Discovery......Page 718
Complementary DNA (cDNA) Microarrays......Page 719
RNA Amplification......Page 720
Data analysis and bioinformatics......Page 721
Global Gene Expression in the Developing Heart......Page 722
Global Gene Expression in the Post-Injured Heart......Page 723
References......Page 725
Congenital heart disease......Page 728
Modeling congenital heart disease in mice......Page 729
Forward genetic screens......Page 733
Frontal Views......Page 734
Transverse Views......Page 736
Ultrasound detection of cardiovascular defects......Page 737
Diagnosis of structural heart defects......Page 739
Noncardiac defects......Page 740
Mapping mutations and strain modifier effects......Page 741
Mutation identification......Page 745
Mutation in megf8 causes single ventricle spectrum of complex congenital heart disease......Page 746
DnaH5 mutation, heterotaxy and primary ciliary dyskinesia......Page 750
References......Page 751
The limits of histology......Page 754
The promise of optical projection tomography......Page 755
Episcopic imaging......Page 756
High resolution episcopic microsocopy......Page 757
High-throughput phenotyping......Page 759
Magnetic resonance imaging......Page 761
Conclusions: a phenotyping pipeline......Page 763
References......Page 764
Proteomics and cardiac disease......Page 767
Proteomic identification of cardiac transcription factors......Page 768
Source Material......Page 769
Transcription Factor Enrichment......Page 770
Transcription Factor Identification by Quantitative Proteomics......Page 771
Future prospects......Page 774
References......Page 775
Introduction......Page 779
Purification of Multiprotein Complexes......Page 781
Identification of protein complex components by mass spectrometry......Page 784
Mass spectrometry instrumentation......Page 786
Fourier Transform......Page 787
Identification of A mef2a interacting protein......Page 788
Proteomic analysis of reversible phosphorylation: a rheostatic control mechanism for transcription factor activity......Page 789
Multiple Reaction Monitoring......Page 790
Phosphopeptide Analysis of MEF2A......Page 792
A transition-state model of MEF2 regulation......Page 793
References......Page 794
Phylogeny of animals......Page 799
Distribution of Regenerative Ability......Page 801
Annelid Regeneration......Page 803
Urodele Limb Regeneration......Page 804
Liver......Page 805
Conclusions......Page 807
References......Page 808
Regeneration......Page 810
The Mammalian Heart......Page 811
The Zebrafish Heart......Page 812
New Cardiomyocytes are Born during Heart Regeneration......Page 813
Participation of Progenitor Cells......Page 814
Nonmyocardial cells and heart regeneration......Page 816
Molecular genetic approaches to zebrafish heart regeneration......Page 818
Why does the zebrafish heart regenerate?......Page 820
References......Page 822
What is a stem cell?......Page 825
Differentiation......Page 826
Transdifferentiation and Dedifferentiation......Page 827
Self-Maintenance......Page 828
Spiral Model of Stem Cell Differentiation......Page 829
Are Ependymal Cells Stem Cells?......Page 831
Are Stem Cells a Subtype of Astrocytes?......Page 835
References......Page 838
A brief overview of human embryonic stem cells......Page 844
Embryoid bodies and the generation of cardiomyocytes from embryonic stem cells......Page 846
Directed Differentiation of Cardiomyocytes......Page 847
Ultrastructural and Electrophysiological Properties......Page 849
Purification of Cardiomyocytes from Human Embryonic Stem Cell Cultures......Page 851
Transplantation studies......Page 854
Transplantation for Electrophysiological Repair......Page 855
Myocardial Infarct Repair......Page 856
Proliferation in human embryonic stem cell-derived cardiomyocytes......Page 853
Minimizing Nonhuman Components and the Need for Scalability......Page 857
Achieving Immune Tolerance......Page 858
References......Page 859
Background......Page 864
New Concepts of Cardiac Homeostasis and Repair......Page 865
Embryonic versus adult stem cells: which way to go?......Page 866
Hematopoietic Stem Cells......Page 867
Endothelial Progenitor Cells......Page 868
Mesenchymal Stem Cells......Page 870
Mechanisms of action of bone marrow-derived stem cells in cardiac repair......Page 872
Cardiomyocyte Regeneration......Page 877
Vasculogenesis......Page 881
Paracrine Effects......Page 882
Clinical studies testing bone marrow-derived cells for ischemic heart disease......Page 886
Outstanding issues......Page 893
References......Page 894
Introduction......Page 901
Concomitant induction of vascular structures augments survival and function of cardiomyocyte precursors......Page 902
Characterization of endothelial progenitor cells (epc) in human adult bone marrow and their use in cardiac ischemia......Page 903
Role of chemokines in endothelial precursor cell-homing to ischemic myocardium......Page 904
Role of proteases in endothelial precursor cell mobilization and homing......Page 905
Adult bone marrow contains a population of multipotent, highly proliferative and clonogenic mesenchymal lineage progenitors with pericyte-like properties......Page 906
Human mesenchymal precursor cells as progenitors of the vascular network......Page 907
Stro-1bright pericyte-like cells for induction of neovascularization and treatment of ischemic heart disease......Page 908
Conclusions......Page 910
References......Page 911
Stem Cell-Regulated Organs......Page 915
Stem Cell Aging......Page 916
Regenerative Capacity of Adult Organs......Page 918
Replicative Senescence......Page 920
Replicative Senescence and the Myocardium......Page 921
The Aging Myocardium......Page 924
The Aging Myocardium and the Telomerase–Telomere System......Page 926
The Aging Myocardium and Cardiac Stem Cells......Page 928
Myocardial Aging and Cardiac Stem/Progenitor Cell Niches......Page 931
Myocardial Aging, Cardiac Stem/Progenitor Cell Niche Homeostasis and Cardiomyogenesis......Page 934
Myocardial Aging and Cardiac Stem/Progenitor Cell Ablation and Repopulation......Page 937
Concluding remarks......Page 938
References......Page 939
Introduction......Page 945
Cyclin A2......Page 946
IGF-1......Page 947
Granulocyte-Colony-Stimulating Factor (G-CSF)......Page 949
Extracellular Matrix Components and Other Secreted Proteins......Page 950
Survivin......Page 951
Thymosin β4......Page 952
Lentiviruses......Page 953
Adeno-Associated Viruses (AAV)......Page 954
Use of Cells as Carriers......Page 955
Future view......Page 956
References......Page 957
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H......Page 974
I......Page 976
L......Page 977
M......Page 978
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O......Page 982
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