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Stem Cell Research And Textbook 2( Dental-derived stem cells, Induced pluripotent stem cells, hematopoietic stem cells, Embryonic, and Cancer Stem cells) For medical students, medical doctors, and researchers.
The regulatory capacities of epigenetic mechanisms including DNA methylation, histone modifications, and non-coding RNAs, have seen a rising interest in recent years. These epigenetic marks are pervasive and non-randomly distributed across the genome, raising intriguing questions on how epigenetics contributes to genomic features that define cellular identity and function. Unlike fixed genetic information that is shared between all cell types, epigenetics involve multiple layers of regulation and can vary dramatically across different cell types and genomic contexts. Thus, much more effort is required to procure a complete perspective of the manifold epigenetic landscape. The body of work in this dissertation focuses on epigenetic studies in the mammalian pluripotent stem cell model system. We utilize high-throughput technologies such as microarrays and next-generation sequencing (NGS) as well as leverage existing epigenetic maps to address a wide range of molecular questions on a comprehensive global scale. This dissertation is organized into three overarching themes: First, we employed genome-wide gene expression and DNA methylation profiling tools to determine whether different cell types display unique biomarkers that can be used to distinguish them from other cell types (Chapters 2-5). We found that human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) carry distinct features in both gene expression and DNA methylation patterns, arguing in favor of the idea that these two pluripotent cell types are different. Furthermore, we compared pluripotent stem cell derived retinal pigmented epithelium (hESC-RPE and hiPSC-RPE) with fetal and adult RPE and found that all RPE cells share a core set of signature genes that distinguishes them from all other cell types. We propose these signature genes will be useful for evaluating the quality of stem-cell derived RPE. Finally, novel corneal endothelial cells (CECs) biomarkers were identified through comparing 12 other tissue types, paving the way for future studies to evaluate properties of stem-cell derived CECs. We next examined how molecular features of pluripotent stem cells are altered during the differentiation process of stem cells (Chapters 6-8). Using the RPE differentiation paradigm, we profiled both microRNA and DNA methylation patterns in intermediate stages between pluripotent stem cells and mature RPE. These two separate studies identified subsets of dynamically regulated epigenetic marks, some of which are associated with RPE signature gene expression. Furthermore, we used a highly innovative and powerful single-cell RNA-sequencing approach to profile transcriptional changes in the early embryo beginning from mature oocyte to morula stages. This study identified a conserved genetic program describing a highly dynamic transcriptional architecture during early embryogenesis. Finally, we took a focused analysis on how DNA methyltransferases contribute to shaping the pluripotent stem cell epigenome (Chapters 9-10). Using mouse ESCs null of DNA methylation, we determined DNA methylation regulates a large set of genes through action with H3K27me3. Furthermore, we determined shared and unique genomic targets of each DNA methyltransferase, including novel de novo methylation activity for Dnmt1 in vivo. In the human model system, we generated iPSCs from ICF Syndrome patient fibroblasts which carry double heterozygous mutations in DNMT3B. We found DNMT3B is involved in a wave of de novo methylation during the reprogramming process and has unique genomic targets.
This book features the most cutting-edge work from the world’s leading laboratories in this field and provides practical methods for differentiating pluripotent stem cells into hematopoietic lineages in the blood system. Pluripotent stem cells have attracted major interest from a fast-growing and multidisciplinary community of researchers who are developing new techniques for the derivation and differentiation of these cells into specific cell lineages. These direct differentiation methods hold great promise for the translational applications of these cells. This book is an essential reference work for researchers at all levels in the fields of hematology and stem cell biology, as well as clinical practitioners in regenerative medicine.
The ability to induce pluripotency in human adult somatic cells by defined transcription factor expression is a revolutionary prospect in regenerative medicine. This discovery has the potential to both open new research avenues for diseases in tissue types that are difficult to obtain and to revolutionize medicine through the use of patient-derived replacement tissue. However, questions remain about the safety and efficacy of these induced pluripotent stem cells (iPSCs). Because iPSC generation protocols tend to be low efficiency, require derivation from adult tissue, often utilize viral transfection, force the expression of known oncogenes, and involve a large number of rapid cell divisions during reprogramming, it was thought that the iPSC genome itself might contain some genetic mutation. Additionally, the progenitor cell type used for iPSC derivation seemed to cause some differentiation pathways to be more highly favored, indicating that iPSCs might possess some sort of "epigenetic memory" of their progenitor state. Thanks to modern advances in high throughput sequencing, we were able to assess the genomic and epigenomic state of induced pluripotent stem cells, and thus determine if iPSCs could be used in either a clinical or a research context. We demonstrate that induced pluripotent stem cells contain a large number of point mutations across their genome regardless of donor age, time in culture, progenitor cell type, or reprogramming method. While a majority of these mutations arise due to rare progenitor mutations becoming fixed through clonal selection during reprogramming, approximately 43% arise either during the reprogramming step or during iPSC expansion. We additionally show that, in addition to epigenetic memory of the progenitor cell state and aberrant DNA methylation, nearly all iPSC lines carry a unique reprogramming-specific epigenetic signature that remains even after further differentiation and impacts gene expression in iPSC-derived cells. Taken together, these results demonstrate that iPSCs must still overcome major hurdles prior to their widespread clinical use. Rigorous work towards establishing clinical safety standards for genetic and epigenetic integrity in pluripotent-derived therapies will be essential before the promise of induced pluripotency can be fully realized.
Brain diseases can have a large impact on patients and society, and treatment is often not available. A new approach in which somatic cells are reprogrammed into induced pluripotent cells (iPS cells) is a significant breakthrough for regenerative medicine. This promises patient-specific tissue for replacement therapies, as well as disease-specific cells for developmental modeling and drug treatment screening. However, this method faces issues of low reprogramming efficiency, and poorly defined criteria for determining the conversion of one cell type to another. Cells contain epigenetic “memories” of what they were that can affect reprogramming. This book discusses the various methods to reprogram cells, the control and determination of cell identity, the epigenetic models that have emerged and the application of iPS cell therapy for brain diseases, in particular Parkinson’s disease and Vanishing White Matter (VWM).​
Stem cell science has the potential to impact human reproductive medicine significantly - cutting edge technologies allow the production and regeneration of viable gametes from human stem cells offering potential to preciously infertile patients. Written by leading experts in the field Stem Cells in Reproductive Medicine brings together chapters on the genetics and epigenetics of both the male and female gametes as well as advice on the production and regeneration of gene cells in men and women, trophoblasts and endometrium from human embryonic and adult stem cells. Although focussing mainly on the practical elements of the use of stem cells in reproductive medicine, the book also contains a section on new developments in stem cell research. The book is essential reading for reproductive medicine clinicians, gynecologists and embryologists who want to keep abreast of practical developments in this rapidly developing field.
Growing evidence suggests that epigenetic mechanisms play a central role in stem cell biology and are vital for determining gene expression during cellular differentiation and governing mammalian development. In Stem Cell Epigenetics, leading international researchers examine how chromatin regulation and bona fide epigenetic mechanisms underlie stem cell renewal and differentiation. Authors also explore how the diversity of cell types, including the extent revealed by single cell omic approaches, is achieved, and how such processes may be reversed or managed via epigenetic reprogramming. Topics discussed include chromatin in pluripotency, stem cells and DNA methylation, histone modifications in stem cells and differentiation, higher-order chromatin conformation in pluripotent cells, stem cells and cancer, epigenetics and disease modeling, brain organoids from pluripotent cells, transcriptional regulation in stem cells and differentiation, non-coding RNAs in pluripotency and early differentiation, and diseases caused by epigenetic alterations in stem cells. Additionally, the book discusses the potential implementation of stem cell epigenetics in drug discovery, regenerative medicine, and disease treatment. Stem Cell Epigenetics will provide researchers and physicians with a state-of-the-art map to orient across the frontiers of this fast-evolving field. Analyzes the role of epigenetics in embryonic stem cell regulation Indicates the epigenetic mechanisms involved in stem cell differentiation and highlights modifications and misregulations that may result in disease pathogenesis Examines the potential applications of stem cell epigenetics in therapeutic disease interventions and regenerative medicine, providing a foundation for researchers and physicians to bring this exciting and fast-evolving field into a clinical setting Features chapter contributions by leading international experts
This book provides a comprehensive review of the properties of various stem cell types, the mechanisms of their behaviors and their potential clinical application. Stem cells have a great capacity of self-renewal and differentiation. They represent new paradigms for disease treatment in the field of regenerative medicine since the day they were discovered. As stem cell research is complicated and making progress rapidly, it is important to have expertise in this field to share their views and perspectives. This book provides a wonderful platform for those who are interested in stem cells to learn from and communicate with experts. Particularly, it highlights the roles of stem cell based therapy for a variety of diseases. Furthermore, this book gives a detailed introduction to the great works related to stem cells in China. The readers could gain a profound knowledge of the state-of-art research done by scientists in the field of stem cells. Overall, this book will be a valuable reference resource for both experienced investigators pursuing stem cell research as well as those are just entering into this field. Dr. Robert Chunhua Zhao, a Cheung Kong Professor of Stem Cell Biology, is Professor of Cell Biology at the Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College (PUMC), Beijing, China. He is Director of the Center for Tissue Engineering, PUMC and Chief Scientist of the National Basic Research Program of China (“973 Program”). He also serves as Regional Editor of Stem Cells and Development.