Preface xxix
1 Unraveling the Mechanisms: Insights Into Stem Cell Behavior in Disease Microenvironments 1
Pranshul Sethi, Aniruddha Sen, Sonima, Ayush Madan, Syed Mohsin Waheed and Bibhas Kumar Bhunia
1.1 Introduction 2
1.2 Stem Cell Biology and the Stem Cell Niche 4
1.3 Disease Microenvironments and Their Impact on Stem Cells 9
1.4 Molecular and Cellular Mechanisms 12
1.5 Techniques for Studying Stem Cell Behavior in Diseased States 16
1.6 Stem Cell Dynamics in Various Diseases 19
1.7 Therapeutic Implications 24
1.8 Case Studies 27
1.9 Future Directions 29
2 CRISPR-Cas9 and Beyond: Gene Editing Frontiers in Stem Cell Therapeutics 39
Pranshul Sethi, Sonali Rastogi, Kajal Sherawat, Neetu Panwar, Ayush Madan and Mojahidul Islam
2.1 Introduction 40
2.2 Significance of CRISPR-Cas9 Technology 41
2.3 Overview of Stem Cell Therapeutics 42
2.4 Fundamentals of CRISPR-Cas9 Technology 42
2.5 Ethical and Regulatory Considerations 50
2.6 Applications in Stem Cell Research 51
2.7 Stem Cells: A Therapeutic Frontier 52
2.8 CRISPR-Cas9 in Stem Cell Therapeutics 62
2.9 Beyond CRISPR-Cas9: Emerging Gene Editing Technologies 79
2.10 Ethical, Legal, and Social Implications (ELSI) 84
2.11 Future Prospects and Challenges 95
2.12 Conclusion 100
3 Future Vistas: Revolutionary Technologies and Paradigms in Stem Cell Therapeutics 107
Dattatraya M. Shinkar, Sharayu P. Rathod, Priyanka D. Dabir, Sandip R. Purkar, Deepali D. Bhandari and Sunil V. Amrutkar
3.1 Introduction 108
3.2 Characteristics of Several Stem Cell Types Employed in Therapeutic Applications 110
3.3 Recent Advancements and Applications of Stem Cell Therapy 120
3.4 Current Limitations 123
3.5 Innovative Isolation and Culture Techniques and Their Use in Research on Stem Cells 125
3.6 Future Prospects 134
4 Nanobiomaterials at the Nexus: Integrating Stem Cells and Nanotechnology for Precision Therapeutics 159
Aditya Banerjee and Deepika Arora
4.1 Introduction 160
4.2 Nanobiomaterials: Tailoring the Cellular Microenvironment 163
4.3 Stem Cells for Regenerative Medicine 171
4.4 Exosomes: Natural Nanocarriers for Intercellular Communication 179
4.5 Reprogramming Immunity for Cancer Through CAR-T Cell Therapy 189
4.6 Integrating Nanobiomaterials with Stem Cells and CAR-T Cells 194
4.7 Challenges and Future Perspectives 204
4.8 Conclusion 210
4.9 Summary 215
5 Exosomes from Stem Cells as Therapeutic Agents for Cardiovascular Regeneration 227
Maryam Taghavi Narmi, Nikoo Baghal Darbandi, Abdulwahab Teflischi Gharavi, Ali Babaeizad and Mohsen Sheykhhasan
5.1 Introduction 228
5.2 Biogenesis and Characteristics of Stem-Cell-Derived Exosomes 242
5.3 Mechanism of Cardiovascular Regeneration Mediated by Exosomes 249
5.4 Therapeutic Applications of Exosomes in Cardiovascular Diseases 269
5.5 Preclinical and Clinical Studies 272
5.6 Challenges and Future Directions 277
5.7 Conclusion 279
6 Cardiovascular Renaissance: Stem Cell Strategies for Heart Diseases 309
Apurva, Pracheta Janmeda, Divya Kumari, Narotam Sharma and Priya Chaudhary
6.1 Introduction 310
6.2 Stem Cell Types Considered for the Treatment of Heart Disease 311
6.3 Stem Cell Therapy Against Different Heart Diseases 317
6.4 Mechanism of Stem-Cell Based Therapy for Heart Disease 325
6.5 Gene-Modified Stem Cells 328
6.6 Limitations of Stem Cell Strategies for Cardiovascular Diseases 331
6.7 Strategies for Improving Stem Cell Therapy 335
6.8 Bioengineering Strategies: New Era 336
6.9 Conclusion 338
7 Neurological Disorders: Advancements in Stem-Cell-Based Treatments 351
Dheeraj Sharma and Shriyansh Srivastava
7.1 Introduction 352
7.2 Types of Stem Cells 353
7.3 Mechanisms of Action 357
7.4 Technological Advancements in Stem Cell Research 358
7.5 Stem-Cell-Based Treatments for Specific Neurological Disorders 362
7.6 Clinical Trials and Case Studies 365
7.7 Ethical Considerations and Regulatory Challenges 367
7.8 Future Directions and Potential Innovations 370
7.9 Conclusion 372
8 Stem Cell Therapy for Metabolic Disorders: Harnessing the Power of Stem Cells to Treat Diabetes, Obesity, and Other Metabolic Disorders 381
Sindhu D. Bali, Anand Kumar Shukla, Rosaleen Sahoo, Varsha A. Mahadik and Narendra Kadoo
8.1 Introduction 382
8.2 Clinical Applications of Stem Cell Therapy for Metabolic Disorders 389
8.3 Molecular Mechanisms Underlying the Action of Stem Cells in Metabolic Disorders 391
8.4 Challenges and Limitations of Stem Cell Therapy for Metabolic Disorders 396
8.5 Future Directions for Stem Cell Therapy in Metabolic Disorders 399
8.6 Conclusions 401
9 Immunomodulation in Autoimmune Disorders: Harnessing the Power of Stem Cell 409
Neha Kamboj, Rahul Kumar and Debasis Mitra
9.1 Introduction 410
9.2 SCs: Types and Characteristics 412
9.3 Mechanisms of SC-Based Immunomodulation 414
9.4 Clinical Applications of SCs in Autoimmune Disorders 427
9.5 Challenges and Considerations in SC Therapy 442
9.6 Conclusion 453
10 The Microbiome Connection: Exploring Interactions with Stem Cell Therapies 463
Rizwan Ahamad, Asad Ali, Priya Manna, Neha Quadri, Zuber Khan, Radheshyam Pal, Mohammad Muztaba, Shakira Ghazanfar, Anas Islam, Asif Iqbal and Sumel Ashique
10.1 Introduction 464
10.2 The Function of Microbiota in Gut Health 464
10.3 The Intersection of Microbiome and Stem Cell Research 465
10.4 Microbiota Metabolites and Stem Cell Differentiation 466
10.5 Modulation of Mucosal Immunity and Intestinal Inflammation 468
10.6 Influences on Stem Cell Engraftment 471
10.7 Role in Neurological Diseases 474
10.8 Emerging Significance of Gut Microbiota in Neurogenesis 475
10.9 Clinical Trials 477
10.10 Role in Gastrointestinal Diseases 477
10.11 Microbiome Influence on Tumor Microenvironment 482
10.12 Challenges of Stem Cell Therapy 485
10.13 Microbiome Engineering and Integration of Multi-Omics for Personalized Medicine 487
11 Cellular Synchrony: Coordinated Strategies for Effective Tissue Regeneration Using Stem Cells 505
Amit Anand, Santhepete Nanjundiah Manjula and Mruthunjaya Kenganora
11.1 Introduction to Cellular Synchrony and Tissue Regeneration 506
11.2 Fundamentals of Stem Cells 509
11.3 Mechanisms of Cellular Synchrony 518
11.4 Methods of Investigating Cell Synchrony 520
11.5 Strategies for Enhancing Cellular Synchrony in Tissue Regeneration 522
11.6 Applications of Stem Cell-Based Tissue Regeneration 527
11.7 Challenges and Future Directions 530
12 Tissue Engineering Paradigms: Creating Functional Replacements with Stem Cells 541
Karan Goel, Isha Chawla, Garima, Sarita Sharma and Sumeet Gupta
12.1 Introduction to Tissue Engineering 542
12.2 Fundamentals of Stem Cells 542
12.3 Biomaterials and Components in Tissue Engineering 544
12.4 Cell-Seeding Techniques 547
12.5 Bioreactor Systems for Tissue Culture 549
12.6 Clinical Applications of Tissue Engineering 552
12.7 Regulatory and Ethical Considerations 556
12.8 Future Directions in Tissue Engineering 564
12.9 Conclusion and Future Perspectives 568
13 Personalized Medicine Frontiers: Interrelating Stem Cell Microenvironments with Stem Cell Therapies for Individual Patients 575
Sagar Mondal, Swati Priya, Jutishna Bora, Smita Lata, Ajay Kumar Mahalka and Sumira Malik
13.1 Introduction 576
13.2 Stem Cells and their Microenvironments as Personalized Medicine 578
13.3 The Disease Microenvironment: A Complex Ecosystem 580
13.4 Stem Cell Plasticity and Adaptation 585
13.5 Stem Cell Dysfunction in Disease 588
13.6 Stem Cell Therapy for Human Diseases 594
13.7 Conclusion 595
14 Stem Cell Therapy for Cancer Treatment: Current Advances and Future Directions 599
Anand Kumar Shukla, Sindhu D. Bali, Varsha A. Mahadik, Rosaleen Sahoo and Narendra Kadoo
14.1 Introduction 599
14.2 Current Clinical Applications of Stem Cell Therapy for Cancer 608
14.3 Molecular Mechanisms Underlying the Action of Stem Cells 611
14.4 Challenges and Limitations of Stem Cell Therapy for Cancer 615
14.5 Future Directions for Stem Cell Therapy in Cancer Treatment 617
14.6 Summary and Conclusions 621
15 Challenges and Breakthroughs: Lessons from Stem-Cell-Based Cancer Therapies 629
Priya Chaudhary, Ayush Madan, Divya Kumari, Apurva and Pracheta Janmeda
15.1 Introduction 630
15.2 Current Hurdles in Stem-Cell-Based Treatment for Cancer 631
15.3 Stem Cell Classification and their Properties 634
15.4 Mechanism Underlying the Action of Stem Cells in Cancer 636
15.5 Potential Application of Stem Cell Therapy in Cancer Treatment 638
15.6 Other Applications of Stem-Cell-Based Cancer Therapy 643
15.7 Factors Influencing Stem Cell Therapy 645
15.8 Diapause and Hibernation Mechanism in Cancer Stem Cells 647
15.9 Cancer Stem Cell Models 648
15.10 Biomarkers Associated with Cancer 650
15.11 Side Effects Related with Stem Cell Therapy 652
15.12 Challenges to Stem Cell Therapy 655
15.13 Strategies to Improve the Anticancer Efficacy of Stem-Cell-Based Therapy 657
15.14 Conclusion 659
16 Clinical Trials and Triumphs: Navigating the Path from Bench to Bedside 673
Abdelmonem Siddiq, Al-Hassan Soliman Wadan, Abdalla Ali, Shubham Shrestha and Ejaz Ahmad Khan
16.1 Introduction 674
16.2 Current and Ongoing Clinical Trials 676
16.3 Approved Stem Cell Therapies 687
16.4 Challenges in Clinical Trials 693
16.5 Conclusion 695
17 Beyond Borders: Global Perspectives on Stem Cell Therapeutics 705
N.L. Swathi, Praveen Mallari, Mihir Dabhi and Shweta Shrivastava
17.1 Introduction 706
17.2 Global Advances in Stem Cell Research 707
17.3 Regional Regulatory Frameworks 717
17.4 Ethical Considerations and Public Perception 719
17.5 Challenges and Barriers 724
17.6 Future Directions 729
17.7 Conclusion 733
18 Ethical Considerations in Stem Cell Therapeutics: Striking a Balance 739
Rahul Kumar, Ayush Madan, Debasis Mitra and Jyotsana Singh Chandravanshi
18.1 Introduction 740
18.2 Properties of Stem Cells 741
18.3 Sources of Stem Cell 742
18.4 Research on Stem Cells 744
18.5 Source and Ethical Concerns of Deriving Stem Cells 744
18.6 Research Ethics Concerns and Process 747
18.7 Ethical Concerns Throughout the Clinical Phase and After 748
18.8 Fundamental Methods of Stem Cell Research in Different Nations 750
References 753
Index 757
1
Unraveling the Mechanisms: Insights Into Stem Cell Behavior in Disease Microenvironments
Pranshul Sethi1,2, Aniruddha Sen3, Sonima4, Ayush Madan5,6, Syed Mohsin Waheed7 and Bibhas Kumar Bhunia8*
1Chitkara College of Pharmacy, Chitkara University, Punjab, India
2College of Pharmacy, Shri Venkateshwara University, Gajraula, Uttar-Pradesh, India
3Department of Biochemistry, All India Institute of Medical Sciences, Gorakhpur, Uttar Pradesh, India
4Department of Pharmacology, University Institute of Pharma Science and Research, Chandigarh University Gharuan, Punjab, India
5Department of Biotechnology, School of Research and Technology, People's University, Bhanpur, Bhopal, Madhya Pradesh, India
6Institute of Tropical Aquaculture and Fisheries, Universiti Malaysia Terengganu, Kuala Nerus, Terengganu, Malaysia
7Divacc Research Laboratories Pvt. Ltd. AIC-JNUFI, Jawaharlal Nehru University, New Delhi, India
8Department of Life Sciences, Parul Institute of Applied Sciences & Research and Development Cell, Parul University, Vadodara, Gujarat, India
Abstract
Stem cell research holds great promise for the development of regenerative medicine, with potential cures and treatments for a wide range of diseases. This is still a subject area of stem cells interacting with the pathological microenvironments and their behavior that remains a core point of investigation.
This chapter offers general insight into the mechanisms by which stem cell behavior is governed within these complex settings, many of which tend to be hostile. This chapter will begin focusing on the basic features of stem cell biology and how a stem cell niche is typically organized under physiological conditions. This is accompanied by changes in the microenvironment within these niches, driven by diseases, including modifications to the extracellular matrix, oxygen levels, and the presence of inflammatory signals. These are relevant since they will largely influence the fates of stem cells vis-à-vis the processes of differentiation, migration, and self-renewal. This goes deep into the critical signaling pathways and molecular interactions pivotal in determining stem cell behavior in disease contexts, such as Wnt, Notch, Hedgehog, and so on. This chapter also discusses how stem cells respond to the mechanical and biochemical cues of their altered microenvironments and the implication of such responses for disease progression and therapy.
Moreover, the chapter discusses some of the most recent methodological developments in studying stem cell-disease interactions. Advanced imaging techniques, single-cell RNA sequencing, and innovative in vitro and in vivo models are discussed in this context, the ways those are being applied to shed new light upon disease-induced dynamics of stem cells. The chapter finishes with an outlook on potential therapeutic strategies built based on understanding derived from stem cell behavior within a diseased microenvironment. Pursuing targeted molecular pathways and microenvironmental factors allows the potential for optimal stem-cell-based therapies, leading to better clinical outcomes. This chapter will not only improve our understanding of the biology of stem cells in disease but it is also set to pave the way toward targeted regenerative therapeutics.
Keywords: Stem cells, disease microenvironments, regenerative medicine, stem cell niche, therapeutic strategies, molecular signaling pathways
1.1 Introduction
Human stem cell research has substantially developed over the past few decades and is beginning to emerge as a critical pillar for regenerative medicine. Stem cells are relevant because of their self-renewal and differentiation ability into different cells; therefore, they can help study the development and mechanisms of diseases with potential therapeutic applications. This continued in full swing after the 1981 discovery of embryonic stem cells from mice. Martin Evans and Matthew Kaufman went on to show that those cells could differentiate into any cell type [1]. The process was carried even further by James Thomson, who derived human embryonic stem cells in 1998, thus making a breakthrough in biomedical research [2].
Early research primarily focused on the fundamental properties of stem cells, such as pluripotency and multipotency. Pluripotent stem cells comprise embryonic and induced pluripotent stem (iPSC) cells. Since they can differentiate to all body cell types, this is more generalized for fundamental research as well as for clinical use [3]. Notably, this field was revolutionized by the discovery of iPS cells in 2006 (which can be derived from adult somatic cells and reprogrammed to an embryonic-like state) that avoid the ethical issues associated with embryonic stem (ES) cell lines [4]. Our knowledge of adult stem cells, i.e., hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs), has also blossomed. Symporemonic cells are so named because they are quasistepwise-insoluble virtually in whole tissues, and they abode an moment character to network retrial and helium/popper. This led to our understanding of HSCs, the cells responsible for lifelong renewal of all blood cell types and successful bone marrow transplantation (now utilized worldwide for leukemia and other blood diseases) [5]. Conversely, because of their immunomodulating and regenerative properties [6], MSCs have also become promising tools for the treatment of various diseases including inflammatory diseases or tissue injuries.
However, how stem cells function for a long term in disease microenvironments will be a key factor in developing successful stem cell therapies. When in a pathogenic setting, the way stem cells act is very different and usually more negatively impacted than under normal conditions. For example, in cancer, the unique tumor microenvironment with hypoxic conditions, inflammation, and differences in the extracellular matrix components generally may precondition stem cell fate, leading to tumorigenesis and metastasis in a more interactive way [7]. In neurodegenerative diseases such as Alzheimer's and Parkinson's, the inhibitory effects are due to the inflammatory milieu and neurotoxic factors acting on neural stem cells' regenerative capacity, which precludes them from developing their regenerative potential for repair purposes [8].
Several reasons argue for studying these interactions. It may be helpful for understanding how certain disease factors modify the function of stem cells in terms of differentiation, migration, and self-renewal. Such a knowledge would point exactly toward the optimization of the stem cell therapy procedure in a way that enhances its effectiveness and safety. For example, a comprehension of the precise signaling pathways and molecular cues (e.g., Wnt, Notch, and Hedgehog) might permit to develop measures that would alter the signals, leading to less bountiful therapeutic manifestations [9]. Understanding these mechanisms in a disease context, e.g., within endothelial stem cells, is the key to designing new targeted therapies aimed at addressing the root cause of a diseases rather than merely masking symptoms. For instance, in heart diseases, stem cell therapy is adopted to repair and regenerate the damaged heart muscle cells. How hypoxia influences the properties of stem cells has been largely elucidated, and this information can further us in developing improved approaches to enhance their therapeutic potential [10].
The aim of this chapter is to provide an insight into the possible ways that alterations in the stem cell niche within disease microenvironments can regulate the behavior of a stem cell. This chapter discusses ways in which stem cells are influenced by altered biochemical and biophysical components of the niche (e.g., ECM, oxygen, inflammatory signals) with a focus on how changes to these factors affect fate selections of stem cells. This chapter provides a synopsis of the key signaling pathways and molecular crosstalk that condition stem cell function, within the context of different diseases including Wnt, Notch, and Hedgehog signaling. In addition, the chapter reviews recent methodological advances-advanced imaging, single-cell RNA sequencing, and new in vitro and in vivo models-that are transforming research into stem cell-disease interactions. While this review is not aimed at documenting the development and utility of each, these tools have been extremely valuable in advancing our knowledge regarding stem cell biology on disease states and only deserve mention here. Lastly, we will discuss potential therapeutic interventions arising from our increasing understanding of how stem cells may behave in diseased microenvironments. We seek to provide the strategy's details concerning molecular targets and the microenvironment on how to realize enhanced effectiveness of stem cell-based therapies toward ensuring better clinical outcomes overall.
1.2 Stem Cell Biology and the Stem Cell Niche
1.2.1 Characteristics of Stem Cells
Stem cells are unique cells with two defining characteristics: self-renewal and differentiation potential. These properties are essential for their role in development, tissue repair, and regenerative medicine.
1.2.1.1 Self-Renewal
A stem cell can also replicate itself without differentiation for many divisions. This phenomenon is known as self-renewal. Self-renewal is a mechanism to ensure stem cell numbers...
