Advanced Surfaces for Stem Cell Research
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Ashutosh Tiwari is Secretary General, International Association of Advanced Materials; Chairman and Managing Director of Tekidag AB (Innotech); Associate Professor and Group Leader, Smart Materials and Biodevices at the world premier Biosensors and Bioelectronics Centre, IFM-Linköping University; Editor-in-Chief, Advanced Materials Letters; a materials chemist and docent in the Applied Physics with the specialization of Biosensors and Bioelectronics from Linköping University, Sweden. He has more than 100 peer-reviewed primary research publications in the field of materials science and nanotechnology and has edited/authored more than 35 books on advanced materials and technology
Bora Garipcan teaches at Boðaziçi University, Turkey.
Lokman Uzun is an Associate Professor at the Department of Chemistry, Biochemistry Division, Hacettepe University, Ankara, Turkey where he also received his PhD in 2008. He is the author of more than 75 articles in peer-review journals and is the Assistant Editor of Hacettepe's Journal of Biology and Chemistry. He recently took up a fellowship with the Biosensors and Bioelectronics Centre, Linköping University, Sweden. His research interest is mainly in materials science, surface modification, affinity interaction, polymer science, especially molecularly imprinted polymers and their applications in biosensors, bioseparation, food safety, and the environmental sciences.
Content
Preface xv
1 Extracellular Matrix Proteins for Stem Cell Fate 1 Betül Çelebi-Saltik
1.1 Human Stem Cells, Sources, and Niches 2
1.2 Role of Extrinsic and Intrinsic Factors 5
1.2.1 Shape 5
1.2.2 Topography Regulates Cell Fate 6
1.2.3 Stiffness and Stress 6
1.2.4 Integrins 7
1.2.5 Signaling via Integrins 9
1.3 Extracellular Matrix of the Mesenchyme: Human Bone Marrow 11
1.4 Biomimetic Peptides as Extracellular Matrix Proteins 13
References 15
2 The Superficial Mechanical and Physical Properties of Matrix Microenvironment as Stem Cell Fate Regulator 23 Mohsen Shahrousvand, Gity Mir Mohamad Sadeghi and Ali Salimi
2.1 Introduction 24
2.2 Fabrication of the Microenvironments with Different Properties in Surfaces 25
2.3 Effects of Surface Topography on Stem Cell Behaviors 28
2.4 Role of Substrate Stiffness and Elasticity of Matrix on Cell Culture 31
2.5 Stem Cell Fate Induced by Matrix Stiffness and Its Mechanism 32
2.6 Competition/Compliance between Matrix Stiffness and Other Signals and Their Effect on Stem Cells Fate 33
2.7 Effects of Matrix Stiffness on Stem Cells in Two Dimensions versus Three Dimensions 34
2.8 Effects of External Mechanical Cues on Stem Cell Fate from Surface Interactions Perspective 34
2.9 Conclusions 35
Acknowledgments 36
References 36
3 Effects of Mechanotransduction on Stem Cell Behavior 43 Bahar Bilgen and Sedat Odabas
3.1 Introduction 43
3.2 The Concept of Mechanotransduction 45
3.3 The Mechanical Cues of Cell Differentiation and Tissue Formation on the Basis of Mechanotransduction 46
3.4 Mechanotransduction via External Forces 47
3.4.1 Mechanotransduction via Bioreactors 48
3.4.2 Mechanotransduction via Particle-based Systems 51
3.4.3 Mechanotransduction via Other External Forces 53
3.5 Mechanotransduction via Bioinspired Materials 54
3.6 Future Remarks and Conclusion 54
Declaration of Interest 55
References 55
4 Modulation of Stem Cells Behavior Through Bioactive Surfaces 65 Eduardo D. Gomes, Rita C. Assunção-Silva, Nuno Sousax, Nuno A. Silva and António J. Salgado
4.1 Lithography 66
4.2 Micro and Nanopatterning 70
4.3 Microfluidics 71
4.4 Electrospinning 71
4.5 Bottom-up/Top-down Approaches 74
4.6 Substrates Chemical Modifications 75
4.6.1 Biomolecules Coatings 76
4.6.2 Peptide Grafting 77
4.7 Conclusion 78
References 79
Contents vii
5 Influence of Controlled Micro- and Nanoengineered Environments on Stem Cell Fate 85 Anna Lagunas, David Caballero and Josep Samitier
5.1 Introduction to Engineered Environments for the Control of Stem Cell Differentiation 86
5.1.1 Stem Cells Niche In Vivo: A Highly Dynamic and Complex Environment 86
5.1.2 Mimicking the Stem Cells Niche In Vitro: Engineered Biomaterials 88
5.2 Mechanoregulation of Stem Cell Fate 89
5.2.1 From In Vivo to In Vitro: Influence of the Mechanical Environment on Stem Cell Fate 89
5.2.2 Regulation of Stem Cell Fate by Surface Roughness 90
5.2.3 Control of Stem Cell Differentiation by Micro- and Nanotopographic Surfaces 92
5.2.4 Physical Gradients for Regulating Stem Cell Fate 96
5.3 Controlled Surface Immobilization of Biochemical Stimuli for Stem Cell Differentiation 100
5.3.1 Micro- and Nanopatterned Surfaces: Effect of Geometrical Constraint and Ligand Presentation at the Nanoscale 100
5.3.2 Biochemical Gradients for Stem Cell Differentiation 107
5.4 Three-dimensional Micro- and Nanoengineered Environments for Stem Cell Differentiation 112
5.4.1 Three-dimensional Mechanoregulation of Stem Cell Fate 113
5.4.2 Three-dimensional Biochemical Patterns for Stem Cell Differentiation 119
5.5 Conclusions and Future Perspectives 122
References 122
6 Recent Advances in Nanostructured Polymeric Surface: Challenges and Frontiers in Stem Cells 141 Ilaria Armentano, Samantha Mattioli, Francesco Morena, Chiara Argentati, Sabata Martino, Luigi Torre and Josè Maria Kenny
6.1 Introduction 142
6.2 Nanostructured Surface 144
6.3 Stem Cell 146
6.4 Stem Cell/Surface Interaction 147
6.5 Microscopic Techniques Used in Estimating Stem Cell/Surface 148
6.5.1 Fluorescence Microscopy 148
6.5.2 Electron Microscopy 149
6.5.3 Atomic Force Microscopy 153
6.5.3.1 Instrument 154
6.5.3.2 Cell Nanomechanical Motion 156
6.5.3.3 Mechanical Properties 156
6.6 Conclusions and Future Perspectives 158
References 158
7 Laser Surface Modification Techniques and Stem Cells Applications 165 Çagri Kaan Akkan
7.1 Introduction 166
7.2 Fundamental Laser Optics for Surface Structuring 166
7.2.1 Definitive Facts for Laser Surface Structuring 167
7.2.1.1 Absorptivity and Reflectivity of the Laser Beam by the Material Surface 167
7.2.1.2 Effect of the Incoming Laser Light Polarization 168
7.2.1.3 Operation Mode of the Laser 169
7.2.1.4 Beam Quality Factor 170
7.2.1.5 Laser Pulse Energy/Power 171
7.2.2 Ablation by Laser Pulses 172
7.2.2.1 Focusing the Laser Beam 172
7.2.2.2 Ablation Regime 173
7.3 Methods for Laser Surface Structuring 174
7.3.1 Physical Surface Modifications by Lasers 174
7.3.1.1 Direct Structuring 175
7.3.1.2 Beam Shaping Optics 177
7.3.1.3 Direct Laser Interference Patterning 180
7.3.2 Chemical Surface Modification by Lasers 181
7.3.2.1 Pulsed Laser Deposition 181
7.3.2.2 Laser Surface Alloying 184
7.3.2.3 Laser Surface Oxidation and Nitriding 186
7.4 Stem Cells and Laser-Modified Surfaces 187
7.5 Conclusions 191
References 192
8 Plasma Polymer Deposition: A Versatile Tool for Stem Cell Research 197 M. N. Macgregor-Ramiasa and K. Vasilev
8.1 Introduction 197
8.2 The Principle and Physics of Plasma Methods for Surface Modification 199
8.2.1 Plasma Sputtering, Etching an Implantation 200
8.2.2 Plasma Polymer Deposition 201
8.3 Surface Properties Influencing Stem Cell Fate 202
8.3.1 Plasma Methods for Tailored Surface Chemistry 203
8.3.1.1 Oxygen-rich Surfaces 204
8.3.1.2 Nitrogen-rich Surfaces 208
8.3.1.3 Systematic Studies and Copolymers 210
8.3.2 Plasma for Surface Topography 211
8.3.3 Plasma for Surface Stiffness 213
8.3.4 Plasma for Gradient Substrata 215
8.3.5 Plasma and 3D Scaffolds 218
8.4 New Trends and Outlook 219
8.5 Conclusions 219
References 220
9 Three-dimensional Printing Approaches for the Treatment of Critical-sized Bone Defects 231 Sara Salehi, Bilal A. Naved and Warren L. Grayson
9.1 Background 232
9.1.1 Treatment Approaches for Critical-sized Bone Defects 232
9.1.2 History of the Application of 3D Printing to Medicine and Biology 233
9.2 Overview of 3D Printing Technologies 234
9.2.1 Laser-based Technologies 235
9.2.1.1 Stereolithography 235
9.2.1.2 Selective Laser Sintering 236
9.2.1.3 Selective Laser Melting 236
9.2.1.4 Electron Beam Melting 237
9.2.1.5 Two-photon Polymerization 237
9.2.2 Extrusion-based Technologies 238
9.2.2.1 Fused Deposition Modeling 238
9.2.2.2 Material Jetting 238
9.2.3 Ink-based Technologies 239
9.2.3.1 Inkjet 3D Printing 239
9.2.3.2 Aerosol Jet Printing 239
9.3 Surgical Guides and Models for Bone Reconstruction 240
9.3.1 Laser-based Surgical Guides 240
9.3.2 Extrusion-based Surgical Guides 240
9.3.3 Ink-based Surgical Guides 241
9.4 Three-dimensionally Printed Implants for Bone Substitution 242
9.4.1 Laser-based Technologies for Metallic Bone Implants 244
9.4.2 Extrusion-based Technologies for Bone Implants 245
9.4.3 Ink-based Technologies for Bone Implants 246
9.5 Scaffolds for Bone Regeneration 246
9.5.1 Laser-based Printing for Regenerative Scaffolds 247
9.5.2 Extrusion-based Printing for Regenerative Scaffolds 247
9.5.3 Ink-based Printing for Regenerative Scaffolds 249
9.5.4 Pre- and Postprocessing Techniques 250
9.5.4.1 Preprocessing 250
9.5.4.2 Postprocessing: Sintering 256
9.5.4.3 Postprocessing: Functionalization 256
9.6 Bioprinting 257
9.7 Conclusion 262
List of Abbreviation 263
References 264
10 Application of Bioreactor Concept and Modeling Techniques to Bone Regeneration and Augmentation Treatments 277 Oscar A. Deccó and Jésica I. Zuchuat
10.1 Bone Tissue Regeneration 278
10.1.1 Proinflammatory Cytokines 279
10.1.2 Transforming Growth Factor Beta 279
10.1.3 Angiogenesis in Regeneration 280
10.2 Actual Therapeutic Strategies and Concepts to
Obtain an Optimal Bone Quality and Quantity 281
10.2.1 Guided Bone Regeneration Based on Cells 282
10.2.1.1 Embryonic Stem Cells 282
10.2.1.2 Adult Stem Cells 282
10.2.1.3 Mesenchymal Stem Cells 283
10.2.2 Guided Bone Regeneration Based on PRP and Growth Factors 284
10.2.2.1 Bone Morphogenetic Proteins 287
10.2.3 Guided Bone Regeneration Based on Barrier Membranes 288
10.2.4 Guided Bone Regeneration Based on Scaffolds 290
10.3 Bioreactors Employed for Tissue Engineering in Guided Bone Regeneration 291
10.4 Bioreactor Concept in Guided Bone Regeneration and Tissue Engineering: In Vivo Application 294
10.5 New Multidisciplinary Approaches Intended to Improve and Accelerate the Treatment of Injured and/or Diseased Bone 303
10.5.1 Application of Bioreactor in Dentistry: Therapies for the Treatment of Maxillary Bone Defects 304
10.5.2 Application of Bioreactor in Cases of Osteoporosis 307
10.6 Computational Modeling: An Effective Tool to Predict Bone Ingrowth 310
References 311
11 Stem Cell-based Medicinal Products: Regulatory Perspectives 321 DenizOzdil and Halil Murat Aydin
11.1 Introduction 321
11.2 Defining Stem Cell-based Medicinal Products 323
11.3 Regional Regulatory Issues for Stem Cell Products 326
11.4 Regulatory Systems for Stem Cell-based Technologies 327
11.4.1 The US Regulatory System 328
11.5 Stem Cell Technologies: The European
Regulatory System 336
References 340
12 Substrates and Surfaces for Control of Pluripotent Stem Cell Fate and Function 341 Akshaya Srinivasan, Yi-Chin Toh, Xian Jun Loh and Wei Seong Toh
12.1 Introduction 342
12.2 Pluripotent Stem Cells 342
12.3 Substrates for Maintenance of Self-renewal and Pluripotency of PSCs 344
12.3.1 Cellular Substrates 344
12.3.2 Acellular Substrates 345
12.3.2.1 Biological Matrices 345
12.3.2.2 ECM Components 348
12.3.2.3 Decellularized Matrices 350
12.3.2.4 Cell Adhesion Molecules 351
12.3.2.5 Synthetic Substrates 352
12.4 Substrates for Promoting Differentiation of PSCs 355
12.4.1 Cellular Substrates 355
12.4.2 Acellular Substrates 356
12.4.2.1 Biological Matrices 356
12.4.2.2 ECM Components 358
12.4.2.3 Decellularized Matrices 362
12.4.2.4 Cell Adhesion Molecules 363
12.4.2.5 Synthetic Substrates 363
12.5 Conclusions 366
Acknowledgments 367
References 367
13 Silk as a Natural Biopolymer for Tissue Engineering 379 Ayse Ak Can and Gamze Bölükbasi Ates
13.1 Introduction 380
13.2 SF as a Biomaterial 383
13.2.1 Fibroin Hydrogels and Sponges 384
13.2.2 Fibroin Films and Membranes 386
13.2.3 Nonwoven and Woven Silk Scaffolds 386
13.2.4 Silk Fibroin as a Bioactive Molecule Delivery 386
13.3 Biomedical Applications of Silk-based Biomaterials 387
13.3.1 Bone Tissue Engineering 387
13.3.2 Cartilage Tissue Engineering 389
13.3.3 Ligament and Tendon Tissue Engineering 391
13.3.4 Cardiovascular Tissue Engineering 391
13.3.5 Skin Tissue Engineering 393
13.3.6 Other Applications of Silk Fibroin 393
13.4 Conclusion and Future Directions 393
References 394
14 Applications of Biopolymer-based, Surface-modified Devices in Transplant Medicine and Tissue Engineering 399 Ashim Malhotra, Gulnaz Javan and Shivani Soni
14.1 Introduction to Cardiovascular Disease 400
14.2 Need Assessment for Biopolymer-based Devices in Cardiovascular Therapeutics 400
14.3 Emergence of Surface Modification Applications in Cardiovascular Sciences: A Historical Perspective 401
14.4 Nitric Oxide Producing Biosurface Modification 403
14.5 Surface Modification by Extracellular Matrix Protein Adherence 404
14.6 The Role of Surface Modification in the Construction of Cardiac Prostheses 405
14.7 Biopolymer-based Surface Modification of Materials Used in Bone Reconstruction 406
14.8 The Use of Biopolymers in Nanotechnology 409
14.8.1 Protein Nanoparticles 410
14.8.1.1 Albumin-based Nanoparticles and Surface Modification 411
14.8.1.2 Collagen-based Nanoparticles and Surface Modification 412
14.8.1.3 Gelatin-based Nanoparticle Systems 413
14.8.2 Polysaccharide-based Nanoparticle Systems 413
14.8.2.1 The Use of Alginate for Surface Modifications 413
14.8.2.2 The Use of Chitosan-based Nanoparticles and Chitosan-based Surface Modification 414
14.8.2.3 The Use of Chitin-based Nanoparticles and Chitin-based Surface Modification 416
14.8.2.4 The Use of Cellulose-based Nanoparticles and Cellulose-based Surface Modification 417
References 418
15 Stem Cell Behavior on Microenvironment Mimicked Surfaces 423 M. Özgen Öztürk Öncel and Bora Garipcan
15.1 Introduction 424
15.2 Stem Cells 425
15.2.1 Definition and Types 425
15.2.1.1 Embryonic Stem Cells 426
15.2.1.2 Adult Stem Cells 426
15.2.1.3 Reprogramming and Induced Pluripotent Stem Cells 427
15.2.2 Stem Cell Niche 427
15.3 Stem Cells: Microenvironment Interactions 428
15.3.1 Extracellular Matrix 429
15.3.2 Signaling Factors 429
15.3.3 Physicochemical Composition 430
15.3.4 Mechanical Properties 430
15.3.5 Cell-Cell Interactions 431
15.4 Biomaterials as Stem Cell Microenvironments 431
15.4.1 Surface Chemistry 431
15.4.2 Surface Hydrophilicity and Hydrophobicity 434
15.4.3 Substrate Stiffness 435
15.4.4 Surface Topography 435
15.5 Biomimicked and Bioinspired Approaches 436
15.5.1 Bone Tissue Regeneration 439
15.5.2 Cartilage Tissue Regeneration 440
15.5.3 Cardiac Tissue Regeneration 441
15.6 Conclusion 442
References 442
Chapter 1
Extracellular Matrix Proteins for Stem Cell Fate
Betül Çelebi-Saltik
Graduate School of Health Sciences, Department of Stem Cell Sciences, Hacettepe University, Ankara, Turkey
Center for Stem Cell Research and Development, Hacettepe University, Ankara, Turkey
Corresponding author: betul.celebi@hacettepe.edu.tr
Abstract
Stem cell-based regenerative medicine aims to repair and regenerate injured and/or diseased tissues by implanting a combination of cells, biomaterials, and soluble factors. Unfortunately, due to an incomplete understanding and knowledge of the interactions between biomaterials and specific stem cell types, and the inability to control the complex signaling pathways ensured by these interactions, the ability to design functional tissue and organ substitutes has been limited. The greatest challenge remains the ability to control stem cells' fate outside of the cell's natural microenvironment or "niche". Stem cell fate is known to be regulated by signals from the microenvironment, such as extracellular matrix (ECM) including glycosaminoglycans and proteoglycans to which stem cells adhere. They represent an essential player in stem cell microenvironment because they can directly or indirectly modulate the maintenance, proliferation, self-renewal, and differentiation of stem cells. The interactions between stem cells and the ECM play a critical role in living tissue development, repair, and regeneration as well. The design of artificial ECM and/or binding site is important in tissue engineering because artificial ECM and/or binding regulates cellular behaviors. Identification of binding sites and key motifs in ECM proteins that interact with cellular receptors can allow researchers to generate small peptides that can mimic the function of large ECM proteins.
Keywords: Extracellular matrix proteins, stem cells, niche, integrin, signaling
1.1 Human Stem Cells, Sources, and Niches
Stem cells have two distinct abilities: self-renewal of themselves and differentiation into tissue/organ-specific cells. Based on their differentiation potential, they can be classified as totipotent, pluripotent, multipotent, or unipotent cells. The totipotent fertilized egg exhibits the stem cell that gives rise to all embryonic and extra-embryonic structures of the developing embryo [1]. Human embryonic stem cells (hESCs) derived from the inner cell mass of the blastocyst have the ability to self-renew over a long period without undergoing senescence [1]. Consequently, cells with higher regeneration capacity and plasticity are needed which lead to use of pluripotent stem cells. Identifying suitable source of stem cells is elemental for regeneration of any tissue. Mature and differentiated multipotent stem cells are easily available but least preferred due to their limited cell division and differentiation capacity. Indeed, the number of stem cells in adults is very low, and it depletes with age. Bone marrow (BM)-derived stem cells first described by Friedenstein et al. are still the most frequently investigated cell type [2]. These cells are lineage-restricted, and in contrast to hESCs, multipotent adult stem cells undergo replicative senescence and their lifespan in culture is limited. The existence of multipotent postnatal stem cells has been reported in BM, peripheral blood, umbilical cord, umbilical cord blood (UCB), Wharton's jelly, placenta, neuronal, and adipose tissues [3-7]. Takahashi and Yamanaka developed a new technique by describing the reprogramming of human somatic fibroblasts into primitive pluripotent stem cells by over-expressing OCT4, SOX2, KLF4, and MYC [8]. These human induced pluripotent stem cells are similar to hESCs in the sense that they also express pluripotency genes, have telomerase activity, and are able to differentiate into all cell types of the three embryonic germ layers (endoderm, ectoderm, and mesoderm) (Figure 1.1).
Figure 1.1 Embryonic stem cells, adult stem cells, and induced pluripotent stem cells.
Stem cell niche consists of stem cells, supporting cells, extracellular matrix (ECM), soluble factors, and nervous systems. All these factors have an important role in stem cell niche; however, ECM that holds stem cells in a niche and controls their cellular processes plays a critical role in the control of stem cell fate [9]. Since its first definition originally proposed in 1978 by Schofield for the hematopoietic stem cell (HSC) microenvironment, the concept of the niche has increased in complexity [10]. Niches are highly specialized for each type of stem cell, with a defined anatomical localization, and they are composed by stem cells and by supportive stromal cells (which interact each other through cell surface receptors, gap junctions and soluble factors), together with the ECM in which they are located (Figure 1.2). In addition, secreted or cell surface factors, signaling cascades and gradients, as well as physical factors such as shear stress, oxygen tension, and temperature, promote to control stem cell behavior [11].
Figure 1.2 Stem cell niche. Adapted from Jhala et al. [9].
Stem cell niche cells mesenchymal and HSCs play an important role in many regeneration processes in human body. HSCs are blood forming cells which were recognized more than 50 years ago [12]. They are produced during embryogenesis in a complex developmental process in several anatomical sites (the yolk sac, the aorta-gonad-mesonephros region, the placenta, and the fetal liver), after which HSCs colonize the BM at birth [13]. These cells are divided into two major progenitor lineages; common myeloid (CMP) and common lymphoid progenitors (CLP). CMPs give rise to megakaryocyte (MK)/erythroid and granulocyte/macrophage progenitors developing into platelet producing MKs, erythrocytes, mast cells, neutrophils, eosinophils, monocytes, and macrophages. CLPs will mature into B-lymphocytes, T-lymphocytes, and natural killer cells. They are positive to cell surface markers such as CD34, CD45, and CD117 [14]. HSCs have the ability to leave their tissue of origin, enter circulation, identify, and relocate to an available niche elsewhere during early development [15]. In the adult, they can leave the BM and return back to it through homing mechanisms [16].
Since the identification of mesenchymal stem cells (MSCs) as colony-forming unit fibroblasts (CFU-Fs) by Friedenstein et al. in 1970 and the first detailed description of the tri-lineage capacity by Pittenger et al., our understanding of these cells has taken great strides forward [17]. These plastic adherent multipotent cells are able to differentiate into bone, cartilage, and fat cells and can be isolated from many adult tissue types. They have been obtained from a wide variety of fetal and adult tissues: adipose tissue, placenta, umbilical cord, Wharton's Jelly, synovial membrane, and dental pulp [18]. Specifically, a recent study reported plastic-adherent MSC-like colonies derived from the non-mesodermal tissues such as brain, spleen, liver, kidney, lung, BM, muscle, thymus, and pancreas [19]. They are positive to cell surface markers such as CD29, CD44, CD105, CD90, and CD73 [20]. MSCs secrete cytokines, chemokines, growth factors, and ECM either spontaneously or after induction by other cytokines [21]. The mesenchymal ECM consists of various proteins such as collagens types I, III, IV, V, and VI, laminin, fibronectin, proteoglycans, such as syndecan, Pln, decorin, and the glycosaminoglycan (GAG) hyaluronan (Figure 1.3) [22]. Proteoglycans are macromolecules consisting of a core protein attached to several polysaccharides (GAGs). They are able to bind cells to the matrix and bind growth factors to GAGs, thus preventing extracellular protease degradation of growth factors [23].
Figure 1.3 The mesenchymal ECM proteins network.
The ECM is a highly dynamic structure that is constantly being remodeled, either enzymatically or non-enzymatically, and its molecular components are subjected to many post-translational modifications [24]. ECM proteins vary not only in composition but also in physical parameters including elasticity and topography. Such physical properties are known to affect the micro- to nanotopography of integrin receptors (alpha and beta subunits) and to influence a range of cellular processes through changes in cell shape and the actin cytoskeleton [25-27]. Cell adhesion to the ECM is mediated by ECM receptors, such as integrins, discoidin domain receptors, and syndecans [24]. ECM properties including stiffness, fiber orientation, and ligand presentation dimensionality provoke specific cellular behaviors [24]. It is clear that ECM-based control of the cell may also occur through multiple physical mechanisms, such as ECM geometry at the micro- and nanoscale (shape, porosity, and topography), ECM elasticity or mechanical signals (stiffness and stress) transmitted from the ECM to the stem cells that turn into biochemical response (Figure 1.4). An understanding of the interaction of these mediators with signaling pathways may provide new insights into the regulation of self-renewal and differentiation of stem cells [28].
Figure 1.4 ECM-based control of the cell.
1.2 Role of Extrinsic and Intrinsic Factors
1.2.1 Shape
The interactions between many extrinsic and intrinsic factors that govern cell shape are varied and may involve relatively long-term interactions with the...
