Kidney Development, Disease, Repair and Regeneration - 1st Edition - ISBN: 9780128001028, 9780128004388

Kidney Development, Disease, Repair and Regeneration

1st Edition

Editors: Melissa Little
eBook ISBN: 9780128004388
Hardcover ISBN: 9780128001028
Imprint: Academic Press
Published Date: 3rd September 2015
Page Count: 614
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Kidney Development, Disease, Repair and Regeneration focuses on the molecular and cellular basis of kidney development, exploring the origins of kidney lineages, the development of kidney tissue subcompartments, as well as the genetic and environmental regulation of kidney development. Special coverage is given to kidney stem cells and possible steps towards kidney repair and regeneration. Emphasis is placed on the fetal origins of postnatal renal disease and our current understanding of the molecular basis of damage and repair. Biomedical researchers across experimental nephrology and developmental biology will find this a key reference for learning how the underlying developmental mechanisms of the kidney will lead to greater advances in regenerative medicine within nephrology.

Key Features

  • Offers researchers a single comprehensive resource written by leaders from both the developmental biology and the experimental nephrology communities
  • Focuses on understanding the molecular basis of organogenesis in the kidney as well as how this can be affected both genetically and environmentally
  • Explains the underlying developmental mechanisms which influence the kidney’s inherent repair capacity
  • Demonstrates how a deeper understanding of mechanisms will lead to greater advances in regenerative medicine


Researchers in renal disease, experimental and clinical nephrologists, developmental biologists, geneticists, bioengineers, and stem cell biologists

Table of Contents

  • Foreword
  • Acknowledgments
  • Section I. Development
    • Introduction
    • Chapter 1. Zebrafish Renal Development and Regeneration
      • Overview
      • The Zebrafish Pronephros as a Model of Nephron Development and Injury
      • Development and Repair of the Zebrafish Mesonephros
      • Conclusions
    • Chapter 2. Early Specification and Patterning of the Intermediate Mesoderm: Genetics and Epigenetics
      • Introduction
      • Early Development of the Kidney
      • Epigenetic Regulation during Kidney Development
      • Role of Epigenetics in the Adult Kidney
      • Conclusions
    • Chapter 3. The Human Kidney: Parallels in Structure, Spatial Development, and Timing of Nephrogenesis
      • Introduction
      • Anatomic Structure of the Mature Human Kidney
      • Anatomic Development of the Kidney
      • Other Mammalian Species: How They Differ
      • Nephron Endowment
      • Conclusion
    • Chapter 4. RET Signaling in Ureteric Bud Formation and Branching
      • Short Introduction to Ureteric Bud Formation and Branching
      • The Role of GDNF/GFRα1/RET Signaling in Mouse Kidney Development
      • Mutations in RET, GFRA1, and GDNF in Human Congenital Kidney Defects
      • Regulation of Ret and Gdnf Gene Expression
      • Signaling Pathways Downstream of RET
      • Effects of Point Mutations That Remove RET Tyrosine Residues Involved in Signal Transduction
      • Genes That Act Downstream of GDNF/GFRα1/RET Signaling
      • Cooperation Between GDNF and FGF10 Signaling in UB Outgrowth and Branching
      • Does GDNF/RET Signaling Specify the Normal Pattern of UB Branching?
      • Cellular Mechanisms of Branching Morphogenesis and the Role of RET Signaling
    • Chapter 5. Quantification of Developmental Branching Morphogenesis
      • General Introduction
      • Stereotypy in Renal Branching
      • Challenges in Translating Renal Branching Knowledge
    • Chapter 6. Transcriptional Regulation of the Nephrogenic Mesenchyme and Its Progeny
      • Introduction
      • Counteraction and Cooperation Between Six2 and Wnt/β-Catenin Signaling in Regulation of Nephron Progenitors
      • Identification of Direct Transcriptional Targets of Six2 and β-Catenin in Nephron Progenitors
      • Cooperation Between Six2 and Osr1 in the Repression of Wnt4
      • Sall1 and Wt1 in Nephron Progenitor Programs
      • Maintenance of Nephron Progenitors
      • Gene Regulatory Networks Established by Transient Activation of Wnt/β-Catenin Signaling
      • Closing Remarks
    • Chapter 7. The Role of Growth Factors in Balancing Cap Mesenchyme Survival and Differentiation
      • The Cap Mesenchyme
      • Growth Factor Signaling in Cap Mesenchyme Differentiation
      • Fibroblast Growth Factor Signaling
      • Wnt Signaling
      • Bone Morphogenetic Protein Signaling
      • Intersections between FGF, Wnt, and BMP Pathways
      • Future Perspectives
    • Chapter 8. Notch Signaling in Nephron Segmentation
      • Introduction
      • Signal Transduction of Notch Signaling
      • Notch Signaling Acts after Wnt/β-Catenin Signaling during Nephrogenesis
      • Nephron Segmentation
      • Rbpj-Dependent Notch Signaling Is Essential for Nephron Segmentation
      • Notch Gain-of-Function Studies
      • Notch2 Is Activated More Effectively Than Notch1
      • Alagille Syndrome and Notch
      • Conclusion
    • Chapter 9. Genetic and Epigenetic Regulation of Nephron Number in the Human
      • Overview
      • Monogenic Disorders Causing Suboptimal Ureteric Bud Branching
      • Monogenic Disorders Affecting the Renal Progenitor Cell Pool
      • Subtle Renal Hypoplasia and Common Polymorphic Variants of Genes That Affect Ureteric Bud Branching
      • Subtle Renal Hypoplasia and Common Polymorphic Gene Variants That Regulate the Renal Progenitor Cell Pool
      • Epigenetic Regulation of Renal Progenitor Cells
      • Conclusion
    • Chapter 10. Formation and Maintenance of a Functional Glomerulus
      • Introduction
      • Patterning of Nephrons and Specification of Glomeruli
      • Development of Podocytes and SD
      • Formation of Glomerular Vasculature
      • Structure and Development of the GBM
      • Development of the Mesangium
      • Development of PECs and Bowman’s Capsule
      • Summary and Perspectives
    • Chapter 11. Maturation and Roles of Collecting Ducts and Loops of Henle in Renal Medulla Development
      • Introduction
      • Composition and Organization of the Renal Medulla
      • Overview of Renal Medulla Development
      • Medullary Collecting Ducts
      • The Loop of Henle
      • Medullary Microvasculature
      • Concluding Remarks
    • Chapter 12. Developmental Roles of the Stroma
      • What Is the Renal Stroma?
      • Developmental Origins of Renal Stromal Cells
      • Role of Stroma in Kidney Development
      • Future Directions
    • Chapter 13. The Origin and Regulation of the Renal Vasculature
      • Introduction
      • Anatomy of the Renal Vasculature
      • Mechanisms Underlying Renal Vascular Morphogenesis
      • Embryonic Origin of the Renal Vasculature
      • Lineage of Vascular Cells
      • Signaling Pathways and Regulatory Factors
      • Remaining Issues
  • Section II. Disease
    • Introduction
    • Chapter 14. Variation in Human Nephron Number and Association with Disease
      • Introduction
      • Estimating Nephron Number
      • Human Nephron Number: Variability Is the Rule
      • Human Nephron Number and Blood Pressure
      • Relationship between Glomerular Number and Glomerular Volume
      • Human Nephron Number and Renal Pathology
      • Conclusion
    • Chapter 15. The Effect of the In utero Environment on Nephrogenesis and Renal Function
      • Introduction
      • The Developmental Origins of Health and Disease
      • Evidence for Programming in the Human
      • Links between Impaired Kidney Development and Hypertension
      • Animal Models of Developmental Programming: Consequences for Kidney Development
      • Why Is the Kidney Susceptible to Programming?
      • Programming of Disease Is More than Just Nephron Number
      • Mechanism Contributing to the Formation of Low Nephron Endowment
      • Conclusion
    • Chapter 16. Wilms’ Tumor: A Case of Persistence of the Nephrogenic Mesenchyme
      • The History of Wilms’ Tumors
      • Identification of WT1 Gene
      • Structure of WT1
      • Molecular Studies on the Function of WT1 in the Nephrogenic Mesenchyme
      • Embryonic Expression of WT1 and Phenotypes of WT1 Mutant Mice
      • Other Tumor Suppressor Genes for Wilms’ Tumor
      • The Cell of Origin for Wilms’ Tumor
      • Other Influences on Kidney Progenitor Cell Expansion
      • Relationship of Wilms’ Tumors to Nephron Progenitor Cells
      • Conclusion
    • Chapter 17. Wnt, Notch, and Tubular Pathology
      • Wnt and Notch
      • Wnt and Notch in Acute Kidney Injury Repair
      • Wnt and Notch in Kidney Fibrosis
      • Wnt and Notch in Polycystic Kidney Disease
      • Wnt and Notch in Renal Cell Cancer
      • Conclusion
    • Chapter 18. Regulation of Ureteric Bud Outgrowth and the Consequences of Disrupted Development
      • Introduction
      • Nephric Duct Development and UB Outgrowth
      • Ureteric Budding Site Determination and GDNF-Dependent UB Outgrowth
      • GDNF–Independent Induction of UB Outgrowth
      • Common Human Disease Caused by Abnormal UB Outgrowth
      • Conclusions
    • Chapter 19. Vesicoureteral Obstruction and Vesicoureteral Reflux: Different Congenital Defects With a Common Cause
      • Introduction
      • Development of the Urinary Tract
      • Conclusion
    • Chapter 20. Polycystic Kidney Diseases and Other Hepatorenal Fibrocystic Diseases: Clinical Phenotypes, Molecular Pathobiology, and Variation between Mouse and Man
      • Introduction
      • Hepatorenal Fibrocystic Diseases: Clinical Phenotypes
      • Hepatorenal Fibrocystic Diseases: Genetic Defects and Molecular Pathobiology
      • Genetic Testing
      • Mouse Models
      • Conclusion
    • Chapter 21. Genetic Aspects of Human Congenital Anomalies of the Kidney and Urinary Tract
      • Introduction
      • Budding Hypothesis
      • HNF1β Nephropathy
      • RET, Hirschsprung Disease, and CAKUT
      • ITGA8 Mutations in Autosomal Recessive Bilateral Kidney Agenesis
      • PAX2 in Renal Coloboma Syndrome
      • EYA1, SIX1, and SIX5 in Branchiootorenal Syndrome
      • Renal Tubular Dysgenesis
      • BMP4
      • Other Genes Involved in CAKUT
      • Ureteral Anomalies
      • Bladder Anomalies with Functional Bladder Outflow Obstruction
      • Detection of Chromosomal Microimbalances
      • Concepts of Oligogenic Inheritance
      • MiRNAs as Potential Regulators of Renal Developmental Genes
      • Conclusions
    • Chapter 22. Inherited Kidney Disorders in the Age of Genomics
      • Introduction
      • From DNA to Genomics
      • Interpretation of NGS Data
      • Impact of NGS in the Nephrology Field
      • NGS Challenges
      • Personalized Therapeutics
      • Conclusions and Future Directions
    • Chapter 23. Fibrosis: A Failure of Normal Repair and a Common Pathway to Organ Failure
      • Fibrosis is a Characteristic Feature of Chronic Kidney Diseases
      • Injury–Repair Processes Gone Awry
      • Cellular Mechanisms of Fibrosis
      • Source of Fibrogenic Cells
      • Molecular Pathways in Fibrogenesis
      • Matrix Turnover
      • Resolution of Fibrosis
  • Section III. Repair
    • Introduction
    • Chapter 24. Postnatal Cell Turnover in the Nephron Epithelium: What Can This Tell Us?
      • Postnatal Glomerular Epithelial Cell Turnover
      • Glomerular Cell Turnover in Disease
      • Postnatal Tubular Epithelial Cell Turnover
      • Conclusion
    • Chapter 25. Plasticity within the Collecting Ducts: What Role Does This Play in Response to Injury?
      • Development of the Collecting Duct
      • Acute Kidney Injury and Response of the CD
      • CD-Specific Mechanisms of Epithelial Injury and Repair
      • Summary
    • Chapter 26. The Onset and Resolution of Renal Fibrosis: A Human Perspective
      • Introduction
      • Renin-Angiotensin System
      • Transforming Growth Factor-β
      • Connective Tissue Growth Factor
      • Epigenetic Control of Renal Fibrosis
      • Conclusions
    • Chapter 27. The Molecular Response to Renal Injury: How Does Chronic Renal Damage Suppress Normal Repair Processes?
      • The Renal Response to Chronic Kidney Disease
      • Adaptive Repair in the Kidney
      • Risk Factors and Features of Maladaptive Repair
      • Maladaptive Repair and Recurrent AKI
      • Mechanisms of Cell Cycle Control
      • Cell Cycle Control in Healthy and Diseased Kidneys
      • Senescent Cells, G2/M Arrest, and Kidney Injury
      • Epigenetic Changes after AKI
      • Pericytes and Kidney Scarring
      • Microvascular Loss and Renal Hypoxia
      • Conclusions
    • Chapter 28. Investigating the Process of Renal Epithelial Repair to Develop New Therapies
      • Introduction
      • Cellular Origins of Epithelial Cells during Repair
      • Targeting Epithelial Repair Pathways
      • Preventing Maladaptive Responses after AKI to Promote Repair
      • Conclusions
    • Chapter 29. Evidence for Renal Progenitors in the Human Kidney
      • Introduction
      • Renal Progenitors in the Human Nephron
      • Tubular-Committed Progenitors
      • Tubular Progenitors in the Pathogenesis of Kidney Disorders
      • Renal Progenitors in the Glomerulus of Adult Human Kidney
      • Glomerular Progenitors in the Pathogenesis of Kidney Disorders
      • Human Progenitor Cultures and Their Possible Application for Kidney Disease Modeling
      • Conclusion
    • Chapter 30. Label-Retaining Cells and Progenitor Cells in Renal Epithelial Homeostasis and Regeneration
      • Stem Cells in Adult Organs
      • Markers and Labels of Stem Cells
      • Label-Retaining Cells in the Kidney Papilla
      • A Genetic Label for Renal LRCs
      • Label-Retaining Cells Proliferate in a Restricted Compartment at the Top of the Papilla
      • In Vivo Demonstration of Migration of LRCs from the Papilla in Response to Ischemic Injury
      • SDF1/CXCR4 Cause Proliferation and Migration of LRCs in Response to Ischemic Injury
      • Microarray Analysis of LRCs: The Wnt Pathway
      • Controversies in Renal Stem Cells
      • Multiple Pools of Stem Cells in the Kidney?
      • Conclusion
    • Chapter 31. A Reparative Role for Macrophages in Kidney Disease
      • Introduction
      • Macrophage Phenotype
      • Reparative Macrophages in Kidney Disease
      • The Potential for Macrophage Therapy in Kidney Disease
      • Frontiers of Kidney Macrophage Research
      • Conclusion
    • Chapter 32. The Use of Mesenchymal Stromal Cells for Treating Renal Injury and Promoting Allograft Survival after Renal Transplantation
      • Introduction
      • Mesenchymal Stromal Cells
      • Immunomodulatory Properties of MSCs
      • Reparative Properties of MSCs
      • Experimental Models of MSCs in Acute Kidney Injury and after Transplantation
      • Mesenchymal Stromal Cells for Clinical Therapeutic Use
      • Clinical Data of MSCs in Kidney Injury and after Renal Transplantation
      • Potential Risks
      • Conclusions
  • Section IV. Regeneration
    • Introduction
    • Chapter 33. Reprogramming to Kidney
      • Introduction
      • Reprogramming to Pluripotency
      • How Does Reprogramming to Pluripotency Occur?
      • Directed Differentiation of Pluripotent Cells
      • Direct Reprogramming: Fate Conversion from One Somatic Cell Type to Another
      • Pioneer versus Lineage-Specifying Factors
      • Evidence that Reprogramming to Nephron Progenitor is Feasible
      • Overlapping Actions for the Nephron Progenitor Reprogramming Genes Suggests Redundancy
      • Alternative Options for the Specification of CM
      • Transcription Factors Required for Reprogramming to Mature Renal Cell Types
      • Challenges to Direct Reprogramming and Cellular Therapies Using Reprogrammed Cells
      • Conclusion
    • Chapter 34. From Development to Regeneration: Kidney Reconstitution In vitro and In vivo
      • Strategies for Regenerative Medicine of the Kidney
      • Lessons from Kidney Development in Frogs and Mice
      • Nephron Progenitors in the Mouse Embryonic Kidney
      • The Newly Identified Origin of the Kidney
      • Generation of Nephron Progenitors In vitro
      • Reconstitution of 3D Kidney Structures from Nephron Progenitors
      • Generation of the Ureteric Bud In vitro
      • Challenges for Reconstitution of a Functional Kidney In vitro
      • Kidney Reconstitution In vivo
      • Conclusions
    • Chapter 35. Directing the Differentiation of Pluripotent Stem Cells to Renal End Points
      • Introduction
      • Pluripotent Stem Cells
      • Kidney Development
      • Differentiation Formats, Inducers, and Cell Lines
      • Animal Cap in Fertilized Eggs of Amphibians
      • Differentiation of Mouse ESCs and iPSCs into Kidney Lineages
      • Human ESCs and iPSCs
      • Cell Therapy, Disease Modeling, and Toxicology
      • Hurdles to Overcome
      • Conclusions
    • Chapter 36. Patient-Derived Induced Pluripotent Stem Cells to Target Kidney Disease
      • Induced Pluripotent Stem Cells
      • Induced Pluripotent Stem Cells Targeting the Kidney
      • Cell Memory and iPS Differentiation
      • Generating Specific Mature Renal Cell Types From iPS Cells
      • Potential Application of iPS Cell-Derived Kidney Podocytes
      • Applications of iPS Cells in Disease Modeling and Toxicity Screening
      • Understanding an Inherited Basis of Kidney Disease Using iPS Cells
      • Developing Novel Treatments Based on iPS Disease Modeling of Inherited Kidney Disease
      • Gene Targeting and Editing of iPS Cells
      • Cell Replacement Strategies
      • Conclusion
    • Chapter 37. Xenotransplantation in the Kidney: A Historical Perspective
      • Introduction
      • Xenotransplantation of Developed Kidneys
      • Transplantation of Developing Kidneys
      • Allotransplantation of Renal Primordia
      • Xenotransplantation of Renal Primordia
      • Xenotransplantation of Pig Renal Primordia
      • Use of Non-renal Precursor Cells Integrated into Renal Primordia or Xenobiotic Nephrogenesis
      • Challenges in the Application of Embryonic Kidney Transplantation
      • Recapitulation of Filtration, Reabsorption, and Secretion
      • Conclusions
    • Chapter 38. Use of the Nephrogenic Niche in Xeno-Embryos for Kidney Regeneration
      • Introduction
      • Niche in the Blastocyst
      • Niche in the Growing Embryo
      • Niche in the Adult Organ
      • Conclusions
    • Chapter 39. Human Fetal Kidney for Regenerative Medicine: From Embryonic Rudiments to Renal Stem/Progenitor Cells
      • Introduction
      • Pre- and Post-Mesenchymal-to-Epithelial Transition Stages of Nephrogenesis
      • Human Embryonic Kidney Rudiments
      • Biomarking the hFK and Wilms’ Tumor as a Step for Progenitor Cell Identification
      • Isolation of Expandable Human Nephric Progenitor Cells From Fetal Kidney
      • Identification of WT Stem Cells
      • Clinical Relevance and Concluding Remarks
    • Chapter 40. Renal Replacement Approaches Using Deceased Donor Cell Sources
      • Introduction
      • Section I
      • Section II
      • Section III
      • Conclusions
    • Chapter 41. Tissue Engineering through Additive Manufacturing: Hope for a Bioengineered Kidney?
      • Additive Manufacturing Meets Tissue Engineering
      • Strategies for Building Kidney Tissue through Additive Manufacturing
      • Renal Tissue Design Considerations for Regenerative Applications
      • Considerations for Tissue Maturation
      • Summary
    • Chapter 42. Decellularized Whole Organ Scaffolds for the Regeneration of Kidneys
      • Introduction
      • Tissue Engineering Strategy
      • Extracellular Matrix
      • Whole Organ Decellularization
      • Re-endothelialization
      • Renal Recellularization
      • In vivo Functionality
      • Conclusions
  • Index


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About the Editor

Melissa Little

Melissa Little

Professor Melissa Little is an NHMRC Senior Principal Research Fellow at the Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne and is a Professor in the Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Australia. An alumnus of The University of Queensland, Australia, she worked for more than 20 years at the Institute for Molecular Bioscience, where her research has focused on the molecular basis of kidney development, renal disease, and repair. She is internationally recognized both for her work on the systems biology of kidney development and also for her pioneering studies into potential regenerative therapies in the kidney. Her research now focuses on the generation of mini-kidneys from patient stem cells for use in drug screening and disease modelling. Professor Little is a recipient of the GlaxoSmithKline Award for Research Excellence (2005), Gottschalk Medal (2004), Eisenhower Fellowship (2006) and a Boorhaave Professorship (2015). From 2007-2008, she served as the Chief Scientific Officer at the Australian Stem Cell Centre and is currently the Vice President of the Australasian Society for Stem Cell Research. Professor Little is also on the editorial board of the Journal of the American Society for Nephrology, Kidney International, Development and Developmental Biology. Her appreciation for the wonder of developmental biology also stems from her role as the mother of two beautiful children.

Affiliations and Expertise

Professor, Group Leader, Kidney Research Laboratory, Murdoch Children’s Research Institute and University of Melbourne, Victoria, Australia