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Cord Blood: Biology, Transplantation, Banking, and Regulation
Description:
The relatively new field of cord blood (CB) is still evolving, having seen vast change since the first successful
CB transplantation over 20 years ago. This volume aims to continue advancing the clinical efficacy and
relevance of this area by providing a solid understanding of its present status. Representing a significant
expansion of previous literature on the topic, this comprehensive resource on CB incorporates the latest
developments into 39 chapters by experts in various areas of practice.
Topics:
- CB biology—hematopoiesis, stem/progenitor cells and their microenvironment.
- Engraftment—preclinical and clinical enhancements such as use of prostaglandin E2, inhibition of cell
surface protein CD26, expansion of shortterm
repopulating HSCs, use of fucosylation and intrabone transplantation.
- Regenerative medicine—induced pluripotent stem cells, endothelial progenitor cells and other cells.
- Immune cells—CB immune cell immaturity, T helper cells, T regulatory cells, neonatal immune tolerance,
natural killer cells and T-cell-dependent
immune competence.
- Clinical transplantation—leukemia in children, malignant disorders, nonmalignant disorders, adult
recipients, double CB transplants, reducedintensity
conditioning regimens, determinants of engraftment, and underutilization of CB transplantation.
- Operations—transplant center processes, CB banking development and processes, public vs private
banking, and unit searching and distribution.
- International perspectives.
- Accreditation and regulation.
Contents:
Preface xxiii
Editor xxxi
Cord Blood Biology: Hematopoiesis,
Stem/Progenitor Cells, Microenvironment
1 Brief Historical Overview of Hematology, Cord Blood, and Links between
the Nervous and Hematopoietic Systems
John M Kinzfogl and Hal E Broxmeyer, PhD
Identification of the Functional HSC
Phenotypic Identification of the Murine HSC
Phenotypic Identification of the Human HSC
Hematopoietic Progenitors
Hematogenesis, Hematopoiesis, and Umbilical Cord Blood
The HSC Niche
Relationship between Hematopoiesis and the Neuronal System
Conclusions
References
2 Developmental Hematopoiesis
Momoko Yoshimoto, MD, PhD, and Mervin C Yoder, MD
Overview of Hematopoiesis in the Mouse Embryo
Intraaortic Hematopoietic Clusters: Emergence of HSCs from the Hemogenic
Endothelium of the Dorsal Aorta
Overview of Hematopoiesis in the Human Embryo and Fetus
Summary
References
3 Hematopoietic Cytokines and Growth Factors
Monte Shaheen, MD, and Hal E Broxmeyer, PhD
Evaluating Growth Factor/Cytokine Effects on Hematopoiesis
Growth Factor Activities and Hematopoiesis
Growth Factor/Cytokine Families
Summary
References
4 Phenotypic Characterization of Hematopoietic Stem Cells
Brahmananda R Chitteti, PhD; Melissa A Kacena, PhD; and Edward F Srour, PhD
Historical Notes
Some Generalities
Phenotypic Characteristics of Umbilical Cord Blood Hematopoietic
Progenitor Cells During Fetal Development
Functional Differences Between Hematopoietic Progenitor Cells from
Cord Blood and Other Human Hematopoietic Tissues
Identification of Classes of Hematopoietic Progenitors
in Cord Blood
Peculiarities in the Phenotypic Identification of Cord Blood Hematopoietic
Progenitor Cells
Recent Advances in the Identification of Classes of Hematopoietic Progenitors
in Cord Blood
Conclusions
References
5 Immunodeficient Mouse Models for Assessing Human Hematopoiesis
Shanbao Cai, MD, PhD; Haiyan Wang, MD; and Karen E Pollok, PhD
Developmental History of Immunodeficient Mice for Engraftment of
Human Cells
Comparison of Engraftment Efficiencies in Immunodeficient Mouse Models
Use of Humanized NSG Mice
SCID-Repopulating Cell Frequency in Different Sources of Human
Hematopoietic Stem Cells
Use of Immunodeficient Mice for Testing Gene Therapy Strategies in
Human Hematopoietic Cells
Integrated Humanized Modeling Approaches
Summary
References
6 Very Small Embryonic-Like Stem Cells from Umbilical Cord Blood
Janina Ratajczak, MD, PhD; Dong Myung Shin, PhD; Magda Kucia, PhD;
and Mariusz Z Ratajczak, MD, PhD
Development and Hierarchy of the Stem Cell Compartment
Identification of VSELs in Adult Tissues
Molecular Data that Support Pluripotency of Murine VSELs
In-Vitro and In-Vivo Data Supporting Pluripotency of VSELs
Why Do Pluripotent VSELs Not Contribute to Blastocyst Development and
Not Grow Teratomas? ‘
Identification of VSELs in Human UCB
Developing a Rapid and Efficient Protocol for Purification of
VSELs from UCB
UCB-VSELs Are Lost During Routine Volume Depletion in UCB Banking
Hematopoietic Differentiation of UCB-VSELs
Conclusions
References
7 Regulation of Hematopoiesis by the Bone Marrow Vascular Niche
John P Chute, MD
Concept of the Hematopoietic Stem Cell Niche
A Vascular Niche for HSCs: Origins in Embryogenesis
Vascular Endothelial Cell Regulation of Adult HSC Fate
Vascular Niche Regulation of Leukemia Stem Cell Fate
Ongoing Questions and Opportunities
References
8 Cellular Components and Regulation of the Hematopoietic Stem Cell Niche
Daniel Lucas, PhD, and Paul S Frenette, MD, FRCPC
Components of the Marrow Hematopoietic Stem Cell Niche
Regulation of the Marrow Hematopoietic Stem Cell Niche
Conclusions
References
9 The Dynamic and Modifiable Nature of Hematopoietic Stem Cells and
Their Niches
Alexander Kalinkovich, MD, PhD; Jonathan Canaani, MD; and
Tsvee Lapidot, PhD
Dynamic Marrow Niches Provide Maintenance of Hematopoietic Stem Cells
A Major Role for Osteoblast/Osteoclast Equilibrium in HSPC Regulation via the
Nervous System
Steady-State HSPC Egress: A Tightly and Dynamically Regulated Process
Essential for Balanced Blood Homeostasis
HSPC Mobilization: Accelerated, Stress-Induced Egress of HSPCs from
Marrow to the Circulation, Providing Enhancement in Their Number
on Demand
Homing: A Prerequisite Stage of Efficient HSPC Transplantation
Concluding Remarks and Perspectives
References
Preclinical/Clinical Means to Enhance Engraftment of
Cord Blood Stem/Progenitor Cells
10 Prostaglandin E2 and other Eicosanoid-Based Strategies to Enhance
Engraftment
Louis M Pelus, PhD; Jennifer Speth; and Jonathan Hoggatt, PhD
Enhancing the Effectiveness of UCB Transplantation
Eicosanoids
Enhancing UCB Transplantation with Eicosanoids
Summary
References
11 CD26 Inhibition to Enhance Cord Blood Engraftment
Sherif S Farag, MD, PhD, and Hal E Broxmeyer, PhD
Role of SDF-1 and Its Receptor CXCR4 in Homing of Hematopoietic Cells
to the Marrow
CD26 Cleaves SDF-1a and Modulates Its Interaction with CXCR4
Inhibition of CD26 Enhances Hematopoietic Progenitor Cell Migration in an
SDF-1 Gradient
Inhibition of CD26 by Pretreatment of Hematopoietic Progenitors Enhances
Homing and Engraftment of Limiting Numbers of Stem Cells
Systemic Inhibition of CD26 to Enhance Engraftment
Clinical Translation: CD26 Inhibition to Enhance Engraftment Following
Cord Blood Transplantation
Summary
References
12 Ex-Vivo Expansion of Cord Blood Stem and Progenitor Cells
Colleen Delaney, MD
Cytokine-Mediated Ex-Vivo Expansion
Notch-Mediated Expansion and Clinical Translation
Other Emerging Approaches to Ex-Vivo Expansion
Summary and Future Directions
References
13 Fucosylation for Improved Engraftment
Simon N Robinson, PhD; Paul J Simmons, PhD; Patrick A Zweidler-McKay,
MD, PhD; and Elizabeth J Shpall, MD
Lessons in Homing and Engraftment from Inflammatory Processes
Mechanisms Associated with the Homing of HPCs
Potential Role of Carbohydrate Modification (Fucosylation) of Selectin
Ligands in Homing
Studies with Fucosylation
Conclusions
References
14 Intrabone Transplantation of Cord Blood Cells and the Journey of
Hematopoietic Cells
Francesco Frassoni, MD; Marina Podesta, PhD; Riccardo Varaldo, MD;
Lorenzo Magrassi, MD; Francesca Gualandi, MD; Andrea Bacigalupo, MD;
Ambra Buschiazzo, MD; Francesco Fiz, MD; Antonio Uccelli, MD;
Nicoletta Sacchi, PhD; Cecilia Marini, MD; Michele Piana; and
Gianmario Sambuceti, MD
Background Considerations in Hematopoietic Transplantation
Different Approaches to Cord Blood Transplantation
The Problem of Seeding Efficiency and the Puzzle of the Best Hematopoietic
Stem Cell Source
The Seeding Efficiency and Migratory Capacity of Hematopoietic Stem Cells
The Origin of Intrabone Transplantation
Clinical Intrabone Transplantation
Intrabone Transplantation Offers a Chance for Salvage Therapy to 90% of
Individuals with Malignant Hematopoietic Diseases
How Intrabone Injection Changes the Kinetics of Transplanted Cells
Conclusion
References
Generation or Presence of Non-Hematopoietic and Hematopoietic Cells
in Cord Blood, for Possible Future Use in Regenerative Medicine
15 Human Induced Pluripotent Stem Cells from Cord and Adult Blood
Mononuclear Cells
Zhaohui Ye, PhD; Bin-Kuan Chou; and Linzhao Cheng, PhD
Pluripotency and a Brief History of Cellular Reprogramming
Human iPSCs Derived from Blood Cells
Future Perspectives
References
16 Cord Blood-Derived Induced Pluripotent Stem Cells and Their Potential for
Clinical Therapy
Man Ryul Lee, PhD; Charlie Mantel, BS; and Hal E Broxmeyer, PhD
From Embryonic Stem Cells to Induced Pluripotent Stem Cells
Generation of iPSCs from Human Cord Blood
In-Vitro Generation of Patient-Specific Hematopoietic Lineage from hPSCs
The Future of iPSCs
References
17 Cord-Blood-Derived Endothelial Progenitor Cells
Mervin C Yoder, MD
Introduction
Methods to Define Human EPCs
Isolation of EPCs from Human Cord Blood: Early Studies
Subsequent Isolation of Early EPCs from Human Cord Blood
Subsequent Isolation of Late EPCs (ECFCs) from Cord Blood
Cryopreservation of Cord Blood EPCs
Summary
References
18 Putative Repair, Regenerative, and Antitumor Properties of Cord Blood:
Evidence, Limitations, and Challenges
Angelo A Cardoso, MD, PhD, and Nadia Carlesso, MD, PhD
Cord Blood and Epithelial Tissue Regeneration
Cord Blood and Repair of Neuronal Injuries
Cord Blood and Modulation of Cancer Development
Conclusion and Future Perspectives
References
19 The Potential of Umbilical Cord Blood Stem and Progenitor Cells to Facilitate
Tissue Repair and Regeneration in Genetic and Acquired Brain Injuries
Jessica M Sun, MD, and Joanne Kurtzberg, MD
In Search of More Effective Treatments for Brain Injuries
Umbilical Cord Blood Is a Promising Source of Stem Cells for Neurologic
Applications
Possible Mechanisms of Action and Approaches to Therapy
Unrelated-Donor Umbilical Cord Blood Transplantation for Genetic Brain
Diseases in Children
Ischemic Injuries
Neurodegenerative Diseases
Challenges
Conclusions
References
Immune Cells in Cord Blood and Their Recovery
after Cord Blood Transplantation
20 Immaturity of Cord Blood Immune Cells: Dysregulation of Gene Expression
and Protein Production
Michele Levin, MD; Carmella van de Ven, MA; and Mitchell S Cairo, MD
Dysregulation of Cord Blood Hematopoiesis and Phagocytic Immunity
Dysregulation of Cord Blood Immune Cells
Dysregulation of Gene Expression in Cord Blood T and B Lymphocytes
Dysregulation of Gene Expression in Cord Blood Immunoregulatory Cytokines
Ex-Vivo Expansion and Activation of Cord Blood Mononuclear
Cells with IL-2, IL-7, IL-12, IL-15, and IL-18 353 Dysregulation of Gene
Expression of Cord Blood CD4+/CD25+ T Regulatory Cells
Reduced CTLA-4 Expression in Cord Blood T Lymphocytes
Dysregulation of Gene Expression of Cord Blood Natural Killer Cells
Summary
References
21 Differentiation and Trafficking Potential of Cord Blood T Helper Cells
Chang H Kim, PhD, and Jee H Lee, MS
Origin of CB T Cells
CB T-Helper-Cell Subsets and Trafficking Potential
CB T-Cell Differentiation into Effector T Cells
CB T-Cell Differentiation into T Regulatory Cells
Factors Affecting CB T-Cell Development
Implications of the CB T-Cell Differentiation Potential in Development
of Immunity in Newborns and Immune Responses Following
CB Transplantation
Summary
References
22 Role of T Regulatory Cells in Allogeneic Hematopoietic Stem Cell
Transplantation
Young-June Kim, PhD, and Hal E Broxmeyer, PhD
Classification of T Regulatory Cells
Phenotypic Characterization of Tregs
Factors That Affect Treg Function
Functional Aspects of Tregs
Graft-vs-Host Disease
Isolation of Human Tregs
In-Vivo Induction of Tregs
Human Umbilical Cord Blood Tregs
Obstacles in Using Human Tregs for Clinical Trials
Future Directions
Summary
References
23 Umbilical Cord Blood Graft Lymphocytes: Unique Biology of Relevance to
Neonatal Immune Tolerance
R Patrick Weitzel, PhD, and Mary J Laughlin, MD
Clinical Reports: Banked Allogeneic Unrelated-Donor UCB Transplantation
Incidence and Severity of Acute and Chronic Graft-vs-Host Disease
Micro-RNA Regulation of NFAT1 Translation in UCB Graft T Lymphocytes
BACH2 Regulation of Interleukin-2 in UCB Graft T Lymphocytes
NFAT1, FoxP3, and BACH2 Regulation and Treg Maturation
Summary
References
24 T-Cell-Dependent Immune Competence after Cord Blood Transplantation
Paul Szabolcs, MD
Opportunistic Infections and Survival after Cord Blood Transplantation
General Principles of Immune Recovery after Hematopoietic Cell Transplantation
Unique Functional Features of Fetal Lymphocytes and Dendritic Cells
The Kinetics of Cellular Immune Recovery after Cord Blood Transplantation
The Prognostic Value of Monitoring Immune Recovery for Clinical Outcomes
Antigen-Specific and Antiviral Immunity
Adoptive T-Cell Immunotherapy after Cord Blood Transplantation
In-Vitro Priming of Ex-Vivo-Expanded, CD3/CD28-Costimulated Cord Blood
T Cells Against Lymphoid and Myeloid Leukemia
Conclusions
References
25 Umbilical Cord Blood Natural Killer Cells
Yong-Oon Ahn, PhD, and Michael R Verneris, MD
Role in Adaptive Immune Responses
NK-Cell Subsets in Peripheral Blood and Umbilical Cord Blood
Cytotoxic Capacity of Cord Blood NK Cells
Cytokine Production of Cord Blood NK Cells
NK-Cell-Inhibitory and -Activating Receptors
Cord Blood Contains Large Numbers of NK Progenitors
NK-Cell Development from Hematopoietic Stem Cells
Terminal NK-Cell Maturation and Acquisition of NK-Cell Cytotoxicity
NK22 Cells
NK Cells and Transplantation: Role in Hematopoietic Stem Cell Engraftment
Cord Blood NK-Cell Recovery and Function after Transplantation
Use of Cord Blood NK Cells for Adoptive Immune Therapy
References
Clinical Cord Blood Transplantation: Single and
Double Cord Blood Units—Myeloablative and
Reduced-Intensity Conditioning
26 Cord Blood Transplantation for Leukemia in Children
Mary Eapen, MD, MS
Indications for Transplantation
Transplantation of Umbilical Cord Blood
References
27 Umbilical Cord Blood Transplantation for Treatment of Nonmalignant
Disorders
Mitchell E Horwitz, MD, and Nelson Chao, MD, MBA
Use of Umbilical Cord Blood Stem Cells for Allogeneic Transplantation:
Historical Perspective
Umbilical Cord Blood Transplantation for Inherited Congenital
Immunodeficiency Disorders
Umbilical Cord Blood Transplantation for Hemoglobinopathies
Umbilical Cord Blood Transplantation for Marrow Failure Disorders
Conclusion
References
28 Extending the Use of Cord Blood Cells to Adults
Eliane Gluckman, MD, FRCP; Annalisa Ruggeri, MD; and
Vanderson Rocha, MD, PhD
Logistic and Biologic Comparison of Stem Cell Sources
Current Results of Unrelated Cord Blood Transplantation in Adult Patients
with Hematologic Malignancies
Comparison of Single-Unit Unrelated-Donor Cord Blood and Matched
Unrelated-Donor Marrow or Peripheral Blood Transplantation
Comparison of Double Unrelated Cord Blood Transplantation with HLA-Matched
Sibling and HLA-Matched and -Mismatched Unrelated Hematopoietic
Stem Cell Transplantation
Comparison of Unrelated Cord Blood Transplantation and Family
Haploidentical Hematopoietic Stem Cell Transplantation
How to Improve Outcomes
Summary
References
29 Double Umbilical Cord Blood Transplantation for Malignant Disorders
Claudio G Brunstein, MD, PhD, and John E Wagner, MD
Engraftment after Double Umbilical Cord Blood Transplantation
Mechanism of UCB Unit Predominance
Graft-vs-Host Disease after dUCBT
Treatment-Related Mortality after dUCBT
Long-Term Outcomes after dUCBT
Double UCB Platform as a Research Model
UCB Unit Selection Algorithm
Summary
References
30 Determinants of Engraftment after Double-Unit Cord Blood Transplantation
Doris M Ponce, MD, and Juliet N Barker, MBBS, FRACP
Early Experience with Double-Unit Transplantation
Determinants of Unit Dominance
Determinants of the Speed and Success of Neutrophil Engraftment
Practical Implications for Unit Selection
Conclusions
References
31 Reduced-Intensity Conditioning and Double Umbilical Cord Blood
Transplantation
Yi-Bin Chen, MD; Corey Cutler, MD, MPH; and Karen Ballen, MD
Clinical Results
Transplant-Related Mortality and Comparison to Myeloablative Regimens
Engraftment Requirements
Comparison to Other Stem Cell Sources
Future Directions
References
32 The Underutilization of Cord Blood Transplantation: Extent of the Problem,
Causes, and Methods of Improvement
Lawrence D Petz, MD; Stephen R Spellman, MBS; and Loren Gragert
The Extent of Underutilization of Hematopoietic Cell Transplantation
Causes of Underutilization of HSCT
Proposals for Improvement
Barriers to Increasing the Number of HSCTs to Optimal Levels
References
Logistics of Cord Blood Transplantation, and Public and Private Cord Blood
Banking, and US Regulation by the Food and Drug Administration
33 Management of Umbilical Cord Blood at the Transplant Center
Jeffrey McCullough, MD, and David McKenna, MD
General Steps or Activities at the Transplant Center
Advance Communication between Cord Blood Bank and Transplant Center
Receipt and Inspection of the Unit
Storage of the Unit
Preparation before Transplantation
Thawing and Processing the Cord Blood Unit
Quality Control of the Process and Critical Values
Infusion of the Cord Blood Unit and Nursing Care of the Patient
Adverse Events and Reporting
Summary and Conclusions
References
34 Public and Private Cord Blood Banking
Edward S Guindi, MD; Thomas F Moss; and Michael T Ernst, MBA
Public Cord Blood Banking
Private Cord Blood Banking
The Parents’ Choice
Conclusion
References
35 Cord Blood Banking: The Development and Application of Cord Blood
Banking Processes, Standards, and Regulations
Donna M Regan, MT(ASCP)SBB
Background
Concept and Start-Up
Financing
Facility
Equipment
Personnel
Collection
Donor Eligibility
Donor Testing
Processing
Product Characterization and Testing
Storage
Bioinformatics
Distribution
Quality Management
Accreditation
FDA Regulation
Conclusion
References
36 Cord Blood Banking in Developing Countries
Irena Sniecinski, MD
Poland
Mexico
Brazil
China
Thailand
Egypt
South Africa
India
Summary
References
37 Accreditation and Regulation of Cord Blood Banking
Michael Boo, JD; Kathleen Welte; and Dennis Confer, MD
Overview
Accreditation
Regulation
Conclusion
References
38 Worldwide Searching and Distribution of Cord Blood Units
Kathleen Welte; Michael Boo, JD; and Dennis Confer, MD
Development of Cord Blood Unit Searches
Development of International Cord Blood Unit Searches
Issues in Providing Access to Cord Blood Units
Standardizing Responsiveness of the Search Facilitation Service
Ordering and Shipping a Cord Blood Unit
Providing Recipient Data to Cord Blood Banks
Complying with International Regulations
Projects to Improve Rapid International Exchange of Search Results and Unit
Information
Future Search Enhancements
Conclusion
References
39 US FDA Regulation of Placental/Umbilical Cord Blood
Ellen F Lazarus, MD, CAPT, USPHS
Implementation of the Regulatory Approach to HCT/Ps and Applicability to
Cord Blood
Phased-In Implementation of IND and BLA Requirements for Minimally
Manipulated Unrelated Allogeneic Placental/Umbilical Cord Blood
Procedure for Submitting a Biologics License Application for Unrelated HPC-C
References
Index
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