Biomaterials as Stem Cell Niche

Recent developments in stem cell biology have opened new directions in cell therapy. This book provides the state-of-the-art developments in using biomaterials as artificial niches for engineering stem cells, both for the purpose of better understanding their biology under 3D biomimetic conditions as well as for developing new strategies for efficient long term maintenance and directed differentiation of stem cells into various therapeutic lineages. Animal and human stem cells of both embryonic and adult origin are discussed with applications ranging from nerve regeneration, orthopedics, cardiovascular therapy, blood cell generation and cancer therapy. Both synthetic and natural biomaterials are reviewed with emphasis on how material-stem cell interactions direct specific signaling pathways and ultimately modulate the cell fate. This book is valuable for biomaterial scientists, tissue engineers, clinicians as well as stem cell biologists involved in basic research and applications of adult and embryonic stem cells.

1;Preface;5 2;Contents;7 3;Engineering ECM Complexity into Biomaterials for Directing Cell Fate;9 3.1;Abstract;9 3.2;1. Cell--ECM Interactions;9 3.2.1;1.1 ECM Composition and Signaling;10 3.2.2;1.2 ECM Regulation;11 3.2.2.1;1.2.1 Proteolytic Processing of the ECM;11 3.2.2.2;1.2.2 Mechanochemical Translation of Cell-binding ECM Domains;13 3.3;2. ECM and the Stem Cell Niche;16 3.3.1;2.1 Integrins: A Sign of Stemness;16 3.3.2;2.2 Neural Stem Cells and Integrin/ECM Alterations;17 3.3.2.1;2.2.1 Integrin and ECM Profile During Neural Development;17 3.3.2.2;2.2.2 ECM and Integrin Profile in Adult Neural Stem Cell Niche;18 3.3.2.3;2.2.3 Functional Role of ECM/Integrin Interactions;19 3.4;3. Current Biomaterials Approaches;20 3.4.1;3.1 Biomimetic Approaches;20 3.4.2;3.2 Engineering Protein Variants;21 3.4.3;3.3 Future Directions for Biomaterials as Stem Cell Niches;22 3.5;References;23 4;Functional Biomaterials for Controlling Stem Cell Differentiation;27 4.1;Abstract;27 4.2;1. Introduction;28 4.2.1;1.1 Emergence of Stem Cell Engineering in Regenerative Medicine;28 4.2.2;1.2 Stem Cell Sources;28 4.3;2. Stem Cell Expansion and Differentiation Using Biomaterials;29 4.3.1;2.1 Roles of ECM in Stem Cell Differentiation;29 4.3.2;2.2 Mimicking ECM with Synthetic Biomaterials;30 4.3.2.1;2.2.1 Mimicking the Biophysical and Biochemical Properties of ECM;30 4.3.2.1.1;Functionalization of Synthetic Substrates with ECM Derived Ligands;31 4.3.2.2;2.2.2 Effects of the Cell--Matrix Interface;31 4.3.2.2.1;Surface Chemistry and Interfacial Energy;31 4.3.2.3;2.2.3 Mineralization of Matrix Materials;37 4.3.2.3.1;Mineralization of Polymeric Matrices;38 4.3.2.3.2;Effect of Mineralization on Cell Adhesion, Proliferation and Differentiation;38 4.3.2.4;2.2.4 Mechanical Properties;40 4.3.3;2.3 Biomaterial Based Delivery of Soluble Factors for 3D Cell Culture;40 4.3.3.1;2.3.1 Incorporation of Bioactive Agents into Matrix Materials;40 4.3.3.2;2.3.2 Effects of Controlled Delivery of Bioactive Agents on
Stem Cell Differentiation;42 4.3.3.2.1;Delivery of Bioactive Agents to Embryonic Stem Cells;42 4.3.3.2.2;Tissue Specific Differentiation of Stem Cells Using Delivery of Bioactive Agents;44 4.3.4;2.4 In Vivo Applications;45 4.3.5;2.5 Future Perspectives;46 4.4;Acknowledgments;47 4.5;References;47 5;Integration of Biomaterials into 3D Stem Cell Microenvironments;53 5.1;Abstract;53 5.2;1. Introduction;53 5.2.1;1.1 Culture in Two or Three Dimensions;55 5.2.2;1.2 Strategies for Biomaterial Control of the 3D Microenvironment;55 5.3;2. Scaffolds;56 5.4;3. Encapsulation;59 5.5;4. Microcarriers and Microparticles;60 5.5.1;4.1 Microcarriers;61 5.5.2;4.2 Microparticles;61 5.6;5. Summary and Conclusions;63 5.7;References;63 6;Stem Cell Interaction with Topography;68 6.1;Abstract;68 6.2;1. Introduction;68 6.2.1;1.1 Extracellular Topography;69 6.2.2;1.2 Nanotopography;70 6.3;2. Nanofabrication Techniques;71 6.4;3. Stem Cells Reception to Topography;75 6.4.1;3.1 Embryonic Stem Cells;75 6.4.2;3.2 Neural Progenitor Cells/Neural Stem Cells;77 6.4.3;3.3 Mesenchymal Stem Cells;78 6.5;4. Making Sense of Physical Cues in the Extracellular Matrix: Mechanotransduction;81 6.5.1;4.1 Introduction to the ECM;81 6.5.2;4.2 Mechanotransduction: A Direct Connection?;82 6.5.3;4.3 Connecting with the ECM: Cell--Matrix Interactions;82 6.5.4;4.4 Integrins and Focal Adhesions: Inside Out and Outside In;84 6.5.5;4.5 Cytoskeleton: Force Transmission;85 6.5.5.1;4.5.1 Cell Exerting Forces on the Underlying Substrate;85 6.5.6;4.6 Filopodia: Probing the ECM;86 6.5.7;4.7 Nucleus: Gene Regulation;87 6.6;5. Conclusion;87 6.7;References;88 7;The Nanofiber Matrix as an Artificial Stem Cell Niche;95 7.1;Abstract;95 7.2;1. The Stem Cell Niche;95 7.3;2. Nanoscale Topography in the Extracellular Matrix;97 7.4;3. Methods to Generate Nanofibrous Matrices;98 7.4.1;3.1 Electrospinning;98 7.4.2;3.2 Self-assembly;100 7.4.3;3.3 Solution Phase Separation;102 7.4.4;3.4 Comparison of Nanofiber Generation Methods;104 7.5;4. Nan
ofibrous Matrices for Stem Cell Expansion;105 7.5.1;4.1 Nanofiber-mediated Expansion of Human Hematopoietic Stem Cells (HSCs);105 7.5.2;4.2 Nanofiber-mediated Expansion of Neural Stem Cells (NSCs);108 7.5.3;4.3 Nanofiber-mediated Expansion of Embryonic Stem Cells (ESCs);108 7.5.4;4.4 Nanofiber-mediated Expansion of Mesenchymal Stem Cells (MSCs);109 7.6;5. Nanofiber Matrices for Differentiation of Stem Cells;109 7.6.1;5.1 Nanofiber-mediated Stem Cell Differentiation into Neuronal Lineages;110 7.6.2;5.2 Nanofiber-mediated Stem Cell Differentiation into Chondrogenic and Osteogenic Lineages;112 7.6.3;5.3 Nanofiber-mediated Stem Cell Differentiation into Myogenic Lineage;114 7.7;6. Nanofibrous Matrices for Stem Cell Delivery;115 7.8;7. Summary;117 7.9;References;118 8;Micropatterned Hydrogels for Stem Cell Culture;125 8.1;Abstract;125 8.2;1. Introduction: Application of Biomaterial Technologies to Stem Cell Research;126 8.3;2. Stem Cells;128 8.3.1;2.1 MSC General Characteristics;128 8.3.2;2.2 MSC Differentiation and Plasticity;129 8.4;3. Hydrogels;130 8.4.1;3.1 Natural Versus Synthetic Polymers;131 8.4.2;3.2 Gelation Mechanisms;131 8.4.2.1;3.2.1 Radical Chain Polymerization;132 8.4.2.2;3.2.2 Chemical Cross-linking;132 8.4.3;3.3 Functionalization of Hydrogels;132 8.4.3.1;3.3.1 Biodegradable Hydrogels;132 8.4.3.2;3.3.2 Biomimetic hydrogels;133 8.5;4. Micropatterning;133 8.5.1;4.1 Microfabrication Technology;134 8.5.2;4.2 Applications in Hydrogel Patterning;135 8.5.2.1;4.2.1 Photolithography;135 8.5.2.2;4.2.2 Laser-scanning lithography;136 8.5.2.3;4.2.3 Stop-flow Lithography;137 8.5.2.4;4.2.4 Optofluidic Maskless Lithography;138 8.5.2.5;4.2.5 Photodegradation;139 8.5.2.6;4.2.6 Micromolding;140 8.5.2.7;4.2.7 Two-dimensional Templating;141 8.6;5. Micropatterning Hydrogels with Embedded Cells;141 8.6.1;5.1 Culture of One Cell Type;142 8.6.1.1;5.1.1 Cell Viability;142 8.6.1.2;5.1.2 Cell Migration (and Morphology);143 8.6.1.3;5.1.3 Cell Differentiation;145 8.6.2;5.2 Culture of M
ultiple Cell Types;145 8.6.2.1;5.2.1 Microfluidics;145 8.6.2.2;5.2.2 Bioreactors;147 8.6.2.3;5.2.3 Micromolding;147 8.6.2.4;5.2.4 Stop-flow Lithography;148 8.7;6Future Outlook;148 8.8;References;149 9;Microengineering Approach for Directing Embryonic Stem Cell Differentiation;159 9.1;Abstract;159 9.2;1. Introduction;159 9.3;2. Control of the Cellular Microenvironment;161 9.3.1;2.1 Cell--cell Contacts;161 9.3.2;2.2 Cell--soluble Factor Interactions;162 9.3.3;2.3 Cell--extracellular Matrix Interactions;163 9.4;3. Microengineering the Environment;164 9.4.1;3.1 Microfluidic Platforms for Controlling Cell--soluble Factor Interactions;165 9.4.2;3.2 Controlled Microbioreactors;166 9.4.3;3.3 Surface Micropatterning for Controlling Cell--cell Contacts;167 9.4.4;3.4 High-throughput Microarrays for Screening Microenvironments;169 9.4.5;3.5 Three Dimensional Scaffolds for Culturing ESCs;170 9.4.6;3.6 Tissue Engineering Using Assembly of Microengineered Building Blocks;170 9.5;4. Conclusions;172 9.6;References;173 10;Biomaterials as Stem Cell Niche: Cardiovascular Stem Cells;178 10.1;Abstract;178 10.2;1. Introduction;179 10.3;2. Adult Cardiovascular Stem Cells and Their Niches;179 10.3.1;2.1 Cardiac Stem Cells;179 10.3.2;2.2 Endothelial Progenitor Cells;181 10.3.3;2.3 Mural Cell Progenitors/Mesenchymal Stem Cells;182 10.3.4;2.4 Adult Cardiovascular Stem Cell Niches;183 10.4;3. Biomaterials as Stem Cell Niches for 3D Cell Culture;184 10.4.1;3.1 3D Cell Culture Systems for Pluripotent Stem Cells;184 10.4.2;3.2 3D Cell Culture Systems for Adult Stem Cells;187 10.5;4. Biomaterials as Stem Cell Niches for Cardiac Cell Therapy;189 10.5.1;4.1 Cardiac Cell Therapy;189 10.5.2;4.2 Biomaterial Scaffolds for Cardiac Cell Therapy;190 10.6;5. Conclusions;192 10.7;References;193 11;The Integrated Role of Biomaterials and Stem Cells in Vascular Regeneration;199 11.1;Abstract;199 11.2;1. Introduction;200 11.3;2. Stem Cells for Vascular Regeneration;201 11.3.1;2.1 Vascular Development of ECs and
SMCs from Pluripotent Stem Cells;201 11.3.2;2.2 Stem-cell-derived Vascular Cells;203 11.3.2.1;2.2.1 Stem-cell-derived ECs;203 11.3.2.1.1;Endothelial Progenitor Cells;205 11.3.2.1.2;ECs Derived from ESC and iPSC Populations;206 11.3.2.2;2.2.2 Stem-cell-derived SMCs;207 11.4;3. Biomimetic Scaffolds for Vascular Regeneration;208 11.4.1;3.1 General Requirements for Biomimetic Scaffolds;208 11.4.2;3.2 Polymeric Biomimetic Scaffolds;209 11.4.3;3.3 Scaffold Types;213 11.4.3.1;3.3.1 Hydrogels;213 11.4.3.2;3.3.2 Electrospun Fibers;213 11.4.3.3;3.3.3 Other Scaffolds;214 11.4.4;3.4 Vascular Engineering Scaffold Properties;214 11.4.4.1;3.4.1 Degradation Properties;214 11.4.4.2;3.4.2 Substrate Topography;215 11.4.4.3;3.4.3 Mechanical Stimulation;215 11.5;4. Inclusion of Vascular Stem and Somatic Cells into Biomaterials;216 11.5.1;4.1 Biomaterials to Engineer Blood Vessels;216 11.5.2;4.2 Biomaterials to Deliver Cells to Host Vasculature;217 11.5.3;4.3 Biomaterials to Induce Differentiation;217 11.6;5. Future Perspectives;218 11.7;6Conclusion;219 11.8;References;219 12;Synthetic Niches for Stem Cell Differentiation into T cells;228 12.1;Abstract;228 12.2;1. Introduction;229 12.3;2. The T Cell Niche;230 12.3.1;2.1 T Cell Receptor Gene Rearrangement;232 12.3.2;2.2 T Cell Microenvironment;232 12.4;3. T Cell Differentiation Through Co-culture;234 12.5;4. T Cell Differentiation Through Immobilization of Notch Ligands;237 12.5.1;4.1 T Cell Differentiation Through Plate Immobilization;238 12.5.2;4.2 T Cell Differentiation Through Notch--Ligand Presenting Microbeads;240 12.6;5. Generation of Antigen-specific T Cells from Stem Cells;240 12.6.1;5.1 Retroviral Transduction of T Cell Receptors;241 12.6.2;5.2 T Cell Differentiation in a Three-dimensional Matrix;243 12.7;Acknowledgments;245 12.8;References;246 13;Understanding Hypoxic Environments: Biomaterials Approaches to Neural Stabilization and Regeneration after Ischemia;249 13.1;Abstract;249 13.2;1. Ischemic Brain Damage in Adult and Neo
natal Humans;250 13.3;2. Response of NSPCs to Ischemic Brain Damage;250 13.4;3. NSPC Implants to Treat Ischemic Brain Damage;252 13.5;4. NSPC Isolation and Culture: State-of-the-Art;253 13.6;5. Biomaterials Use in NSPC Applications: State-of-the-Art;255 13.7;6. Current Challenges in Biomaterials for NSPC Applications;258 13.8;7. Potential of Biomaterials for Reverse-engineering NSPC Microenvironments;259 13.8.1;7.1 Neurosphere Culture;259 13.8.2;7.2 The Stem Cell Niche;260 13.8.3;7.3 Physiological Hypoxia and Hypoxic/Ischemic Injury;261 13.9;8. Conclusions;264 13.10;Acknowledgments;265 13.11;References;265 14;Biomaterial Applications in the Adult Skeletal Muscle Satellite Cell Niche: Deliberate Control of Muscle Stem Cells and Muscle Regeneration in the Aged Niche;277 14.1;Abstract;277 14.2;1. Introduction;278 14.3;2. Skeletal Muscle is Regenerated and Maintained by Muscle Stem Cells;280 14.3.1;2.1 Delta/Notch Signaling Leads to Activation and Proliferation of Satellite Cells;280 14.3.2;2.2 Wnt Signaling Cues Myogenic Progenitor Cells to Differentiate;280 14.4;3. The Aged Skeletal Muscle Niche Impairs Normal Regeneration: TGF- beta 1 Signaling Maintains Satellite Cell Quiescence and Leads to Scar Tissue Formation;282 14.5;4. Toolbox to Combat TGF- beta 1-induced Aging of Satellite Cell Niche;285 14.6;5. Biomaterials to the Rescue: Proposed Strategies for Adult Skeletal Muscle Regeneration;287 14.6.1;5.1 Engineering an In Vitro Niche for Robust Skeletal Muscle Regeneration;287 14.6.1.1;5.1.1 Alignment of In Vitro Skeletal Muscle Fibers;289 14.6.1.2;5.1.2 Effects of Synthetic Niche Stiffness on Skeletal Muscle Regeneration;290 14.6.1.3;5.1.3 Electrical Stimulation of Tissue-engineered Skeletal Muscle;290 14.6.1.4;5.1.4 Vascularization of Tissue-engineered Skeletal Muscle;291 14.6.1.5;5.1.5 Natural Skeletal Muscle Niches: Mimicking the In Vivo Environment;292 14.6.2;5.2 Biomaterial Strategies to Combat Aging of the Muscle Stem Cell Niche;294 14.6.2.1;5.2.1 Gene and Dru
g Delivery Methods to Promote Skeletal Muscle Regeneration;294 14.6.2.2;5.2.2 Novel Targeting Strategies for TGF- beta 1 Inhibition;295 14.6.2.2.1;A biomaterial platform for regulating TGF- beta 1 levels to young levels in the aged niche;295 14.6.3;5.3 Satellite Cells and Muscle Stem Cells: Biomaterials to Help Determine Who is Who;297 14.6.4;5.4 Use of Biomaterials in Tissue Engineering Applications;299 14.7;6. Conclusion;299 14.8;Acknowledgments;299 14.9;References;299 15;Author Index;311