Contents -- Preface -- Foreword -- Part 1. System Biology Lessons for Stem Cells -- Chapter 1. Computational Modeling of Biochemical Processes and Cell Differentiation Max Floettmann, Till Scharp, and Edda Klipp -- 1.1. Introduction -- 1.1.1. Building a network structure -- 1.1.2. The core network in regulation of pluripotency -- 1.2. Graphs and Network Motifs -- 1.2.1. General properties of graphs -- 1.2.2. Network motifs -- 1.3. Dynamic Modeling Frameworks -- 1.3.1. Boolean networks -- 1.3.1.1. Asynchronous Boolean networks -- 1.3.2. Piecewise linear differential equations -- 1.3.4. Parameter estimation in ODE models -- 1.4. Stochasticity -- 1.5. Planning a Model -- Acknowledgements -- Bibliography -- Chapter 2. Heterogeneity and Flexibility of Stem Cell Fate Decisions - A Conceptual Perspective Ingmar Glauche and Ingo Roeder -- 2.1. Introduction -- 2.2. Stem Cell Fate Decisions -- 2.2.1. Models of stem cell self-renewal -- 2.2.1.1. Entity-based models -- 2.2.1.2. Symmetric and asymmetric divisions -- 2.2.1.3. Models of adaptive and self-organizing stem cell systems -- 2.2.2. Intracellular models of lineage specification -- 2.2.2.1. The concept of state space -- 2.2.2.2. Fluctuations and robustness -- 2.2.2.3. Reduction of complexity -- 2.3. Bistable Switches: Antagonistic Interactions between PU.1 and GATA-1 -- 2.4. Higher-Dimensional Decisions and Population Heterogeneity -- 2.4.1. Higher-dimensional decisions -- 2.4.2. Population behavior -- 2.5. Summary -- Acknowledgement -- Bibliography -- Chapter 3. Comparative Transcriptomics for Global Functional Profiling of Embryonic Stem Cells Yu Sun and Ming Zhan -- 3.1. Introduction -- 3.2. Comparative Transcriptomics Analysis -- 3.3. Conserved Functional Modules -- 3.3.1. Cell cycle -- 3.3.2. Genome stability -- 3.3.3. Nodal pathway -- 3.3.4. WNT pathway -- 3.3.5. BMP/TGF-β pathway.

3.3.6. NOTCH pathway -- 3.3.7. Intergrin-mediated pathway -- 3.4. Divergent Functional Modules -- 3.5. Conserved and Divergent Transcription Factors and Growth Factors -- 3.6. Functional Profiling of Embryonal Carcinoma Stem Cells -- 3.7. Summary and Future Prospects -- Bibliography -- Chapter 4. A Common Integrative Nuclear Signaling Module for Stem Cell Development Michal K. Stachowiak, Ewa K. Stachowiak, John M. Aletta, and Emmanuel S. Tzanakakis -- 4.1. How can Ontogenesis be Reproducible in the Stochastic Environment? -- 4.2. The Curious Evolution of Fibroblast Growth Factors Family: Extracellular Cell-Cell and Intracellular Cytoplasmic Nuclear Messengers -- 4.2.1. The discovery of the nuclear FGF receptor-1 -- 4.2.2. What is the source of nuclear FGFR1? -- 4.3. FGFR1 as a Direct Global Gene Regulator -- 4.3.1. Transduction by nuclear FGFR1 involves the transcription co-activator, CREB Binding Protein (CBP) -- 4.3.2. Transcription-gating function of CBP is regulated by nuclear FGFR1 -- 4.3.3. Dynamic, stochastic model of INFS gene regulation -- 4.4. INFS Mediates the Differentiation of Multipotent Neural Stem Cells and Pluripotent Embryonic Stem Cells -- 4.4.1. Studies in human brain neural progenitor cells -- 4.4.2. Neuronal development of pluripotent mouse (m)ESC is also directed by INFS -- 4.4.3. In vivo studies of INFS/FGFR1 function -- 4.5. Activation of INFS in Cancer Cells -- 4.6. Conclusions -- Acknowledgements -- Bibliography -- Part 2. From Mechanisms to Enabling Technologies for Stem Cells -- Chapter 5. Generation, Characterization and Propagation of Human-Induced Pluripotent Stem Cells Sheena Abraham, Marion J. Riggs, Ena Xiao, Khaled Alsayegh, Venkat Gadepalli, and Raj R. Rao -- 5.1. Introduction -- 5.2. Induction Approaches for Generating hiPSCs -- 5.2.1. Viral induction -- 5.2.1.1. Floxed viral vectors.

5.2.1.2. Adenoviral vectors -- 5.2.1.3. Episomal vectors -- 5.2.1.4. PiggyBac-ing -- 5.2.2. Methods enhancing induction -- 5.3. Characterization of Pluripotent Capabilities of hiPSCs and Comparative Studies with hESCs -- 5.3.1. Uniform standards for pluripotent stem cells -- 5.3.2. Classical assays for demonstrating pluripotency -- 5.3.3. Systems biology of pluripotency -- 5.4. Directed Differentiation Studies Involving hiPSCs -- 5.4.1. Differentiation down the ectodermal lineage -- 5.4.2. Differentiation down the mesodermal lineage -- 5.4.3. Differentiation down the endodermal lineage -- 5.5. Propagation and Culture Systems -- 5.5.1. Culture medium composition -- 5.5.2. Passaging methods -- 5.5.2.1. Mechanical technique -- 5.5.2.2. Enzymatic/Non-enzymatic technique -- 5.5.3. Culture systems -- 5.5.3.1. Feeder cell culture systems -- 5.5.3.2. Feeder-free culture systems -- 5.5.3.3. Bioreactors -- 5.6. Summary & Future Possibilities -- Acknowledgements -- Bibliography -- Chapter 6. The Importance of Physiologically Inspired Physicochemical Parameters on Hematopoietic Stem-Cell Maintenance and Lineage-Specific Differentiation in Ex Vivo Cultures Stephan Lindsey and Eleftherios T. Papoutsakis -- 6.1. Introduction -- 6.1.1. The thesis for the chapter -- 6.1.2. Hematopoietic culture applications and challenges, and the importance of the physicochemical parameters of the stem cell niche -- 6.2. Hematopoietic Background and Terminology -- 6.2.1. Hematopoiesis, stroma and in vitro colony assays -- 6.2.2. Sources of hematopoietic stem and progenitor cells (HSPCs) -- 6.2.3. Hematopoietic growth factors (HGFs) and cytokines -- 6.3. The Physiology Inspires: Bone Marrow Organization, pO2 and pH Levels, and the Impact of Flow-Induced Shear Flow in Hematopoiesis -- 6.3.1. Physiological measurements and observations.

6.3.2. Modeling to estimate pO2 and pH levels and gradients in the BM hematopoietic compartment (BMHC) -- 6.3.2.1. Oxygen -- 6.3.2.2. pH -- 6.4. The Stem-Cell Niche as Related to Low Oxygen Tension -- 6.4.1. The importance of the hypoxic endosteum as a site for stem cell renewal and maintenance -- 6.4.2. Low oxygen tension or mild hypoxia is an essential element of the stem-cell niche and not only for hematopoietic stem cells -- 6.5. Beyond the Stem Cell Compartment: Low Oxygen Tension Impacts Proliferation and Differentiation Potential of Various Hematological Lineages, and More Broadly Stem Cell Differentiation -- 6.5.1. Phenomenological studies -- 6.5.2. Reactive-oxygen species (ROS) and antioxidants -- 6.6. The Largely Underappreciated Impact of Culture pH on Hematopoietic Stem and Progenitor Expansion -- 6.7. Apoptosis, its Impact on Hematopoiesis and its Relation to pO2 and pH -- 6.8. Shear Forces in Stem Cell and Hematopoietic Differentiation -- 6.8.1. Biomechanical forces in stem-cell biology -- 6.8.2. The importance of biomechanical forces in megakaryocytic differentiation -- 6.9. Learning from Nature: Case Studies of How to Integrate the Effects of pO2, pH, Fluid-forces, and Medium Perfusion in Processes to Generate Desirable Progenitor and Mature Hematopoietic Cells -- 6.9.1. Perfusion and low pO2 levels for expanding the primitive HSPC compartment -- 6.9.2. Stirred hematopoietic bioreactors with pH and pO2 control and perfusion operation for expanding myeloid cells -- 6.9.3. A three-stage process for the production of megakaryocytic cells and platelets from human CD34+ cells, and the importance of biomechanical forces in a scaled-up process -- 6.10. Summary -- Bibliography -- Chapter 7. Stem Cell Bioprocessing for Regenerative Medicine Donghui Jing, Abhirath Parikh, and Emmanuel S. Tzanakakis -- 7.1. Introduction.

7.2. Expansion and Differentiation of Embryonic Stem Cell (ESC) in Bioreactors -- 7.2.1. Mouse ESCs expansion and differentiation -- 7.2.2. Human pluripotent stem cell expansion and differentiation -- 7.2.2.1. Aggregate culture -- 7.2.2.2. Encapsulated cell culture -- 7.2.2.3. Microcarrier culture -- 7.3. Agitation/Shear and Stem Cell Culture -- 7.4. Oxygen Tension and Stem Cell Culture -- 7.5. Challenges -- 7.5.1. Chemically defined media and substrates for stem cell culture -- 7.5.2. Modeling of stem cell populations -- 7.6. Summary -- Bibliography -- Chapter 8. Engineering Bioactive Scaffolds for Stem Cell Vascular Therapy Abigail C. Cuddy, Yu-I Shen, and Sharon Gerecht -- 8.1. Introduction -- 8.1.1. A general history of tissue engineering and regenerative medicine and the need for vascular engineering -- 8.1.1.1. Cell transplantation for TE and RM -- 8.1.1.2. Introduction to vascular RM -- 8.2. Stem Cells for TE and RM -- 8.2.1. Introduction to the use of stem cells for TE and RM -- 8.2.1.1. Human embryonic stem cells -- 8.2.1.2. Induced pluripotent stem cells -- 8.2.1.3. Human umbilical cord blood cells -- 8.2.1.4. Adult mesenchymal stem cells -- 8.2.1.5. The use of stem cells for the generation of vascular structures -- 8.2.2. Angiogenesis -- 8.2.2.2. The role of EC-to-ECM interactions -- 8.2.2.3. The Role of EC-to-EC interactions -- 8.3. Biomaterials for Tissue Engineering and Regenerative Medicine -- 8.3.1. Introduction -- 8.3.2. Design criteria -- 8.3.3. Biocompatible scaffolds for the generation of vascular structures -- 8.3.3.1. Biomaterials inspired by the ECM -- 8.3.3.2. Biomaterials from synthetic sources -- 8.3.3.3. Biomaterials designed using alternative technologies and approaches -- 8.3.4. Biomaterials modification -- 8.3.4.1. Biochemical cue modification -- 8.3.4.2. Biophysical cue incorporation -- 8.3.4.3. Release strategies.

8.4. Concluding Remarks.