Stem Cell & Regenerative Medicine


by

Herman Cheung

DOI: 10.2174/97816080500861100101
eISBN: 978-1-60805-008-6, 2010
ISBN: 978-1-60805-697-2

  
  


Indexed in: Scopus

The potential use of stem cells in transplantation for the purpose of tissue regeneration is an exciting area of research currently un...[view complete introduction]
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Table of Contents

FOREWORD , Pp. i

Joshua M. Hare

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PREFACE , Pp. ii-v (4)

Herman S. Cheung

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CONTRIBUTORS , Pp. vi-ix (4)

Herman S. Cheung

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Justice and Vulnerability in Human Embryonic Stem Cell Research , Pp. 1-8 (8)

Isaac H. Ritter, Robin N. Fiore and Kenneth W. Goodman

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Stem Cells and their Contribution to Tissue Repair , Pp. 9-22 (14)

Carmen Rios, Elisa Garbayo, Lourdes A. Gomez, Kevin Curtis, Gianluca D’Ippolito and Paul C. Schiller

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The Role of Microenvironment Stromal Cells in Regenerative Medicine , Pp. 23-28 (6)

Ian McNiece and Joshua Hare

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The Role of Mechanical Forces on Stem Cell Growth and Differentiation , Pp. 29-39 (11)

Daniel Pelaez, Jason R. Fritz and Herman S. Cheung

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Functional Cartilage Tissue Engineering with Adult Stem Cells: Current Status and Future Directions , Pp. 40-64 (25)

Alice H. Huang, Clark T. Hung and Robert L. Mauck

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Therapeutic Angiogenesis for Coronary Artery Disease: Clinical Trials of Proteins, Plasmids, Adenovirus and Stem Cells , Pp. 65-74 (10)

Keith A. Webster

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Use of Progenitor Cells in Pain Management , Pp. 75-99 (25)

M.J. Eaton, Stacey Quintero Wolfe and Eva Widerstrom-Noga

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Neural Stem Cells: New Hope for Successful Therapy , Pp. 100-119 (20)

Denis English, Akshay Anand, Rama S.Verma and Stefan Gluck

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Diabetes and Stem Cells , Pp. 120-139 (20)

Juan Dominguez-Bendala and Camillo Ricordi

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Stem Cells in Dentistry , Pp. 140-148 (9)

Li Wu Zheng and Lim Kwong Cheung

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Corneal Progenitor Cells and Regenerative Potential , Pp. 149-159 (11)

Gary Hin-Fai Yam, Sharon Ka-Wai Lee and Chi Pui Pang

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Index , Pp. 160

Herman S. Cheung

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Foreword

The last decade has witnessed an explosion of new knowledge regarding cellular homeostasis throughout life. This new information essentially requires a revision of fundamental paradigms regarding the life cycle of the higher organism. Importantly these new insights have therapeutic implications

The traditional paradigm has held that most (but importantly not all) of our crucial organ systems are terminally differentiated - in essence the cells that throughout life comprise the heart, central nervous system, islets of Langerhans, kidney are the ones that we are born with. The inevitable loss of these cells throughout life leads to permanent diminution in the function of the organ. Moreover, with widespread destruction of tissue such as due to myocardial infarction, stroke, or type I diabetes, tissue recovery does not occur.

We now know that all of our organs have greater plasticity than the initial paradigm held. The central discovery is that of adult stem cells - reservoirs of stem and precursor cells that underlie a cellular homeostatic process. In the heart, estimates range that throughout adult life there is a turnover rate that ranges between 1 and 7 percent per year. Importantly this rate declines with age. Thus, endogenous repair pathways are operative and disease processes must now be viewed within the context of a homeostatic balance between cell loss and replacement.

Not only do these cells exist, but they can be accessed and amplified ex vivo, offering a major new therapeutic avenue. The book edited by Professor Herman Cheung offers a state of the art examination of this exciting new area of biology and therapeutics. The contributions cover important areas ranging from the ethics and considerations of justice in stem cell therapeutics to evaluations of crucial areas of the biology of endogenous tissue homeostasis.

The field of adult stem cells builds upon the discovery of pluripotent stem cells - embryonic and inducible. The discovery of these cells has initiated a field based upon the idea that tissue and cell loss can be replaced by exogenous cells. Work in the area of pluripotency has lead to the exciting insight that the adult mammal possesses a greater degree of plasticity than previously appreciated. The book Stem Cell and Regenerative Medicine offers a comprehensive and state of the art review of this exciting new area of biology and medicine.

Joshua M. Hare, MD
University of Miami
USA


Preface

Cellular-based therapies for regenerative medicine have evolved quite significantly in the past decades. The realization that such an endeavor requires the acquisition of an adequate stem or progenitor cell population, techniques to effectively maintain or induce the desired phenotype and efficient culturing and implantation conditions have led researchers to develop a wide variety of protocols to approach the issue. The goal of this eBook is to review the recent advances and applications of stem cells in regenerative medicine. The book content can be generally divided into 3 sections: Ethics, Basic Biology and Clinical Applications.

ETHICS:

The ability of pluripotent stem cells to generate various replacement cells and tissues presents the potential of their application in cell-based regenerative therapies. Although human embryonic stem cells are, in principle, the most versatile source of pluripotent stem cells, ethical controversies, immunogenic rejection and spontaneous tumor formation remain major concerns for their use in transplantation.

Ritter et al. focused largely on issues relating to the moral status of the embryo and suggest an ethically-optimized framework be established to help guide research in particular, the issues of social justice and the importance of both protecting vulnerable populations from bearing too great a burden for research while receiving too little of its benefits.

BASIC STEM CELL BIOLOGY

In contrast to ES cells, adult stem cells transplanted in pre-clinical animal models have shown no evidence of tumor formation and can be obtained mostly at all developmental stages and from numerous anatomical sites. Due to their broader clinical use, extensive research, and a more comprehensive understanding of their physiology, bone marrow-derived cells appear as the first choice for applications in regenerative medicine. Numerous environmental and trophic factors have been identified to play central roles in regulating the self-renewal, proliferation, migration, differentiation, senescence, and death of stem cells, their derived progeny, and the final differentiated cells that perform all tissue and organ functions. Besides direct differentiation of the stem cells to the desired mature cell type, other indirect mechanisms have been identified to play important roles in the overall repair of the injured tissue. These include production of paracrine factors, modulation of the host inflammatory response, host cell survival, and recruitment and activation of host tissue stem cells. (Rios et al.)

To deliver cellular products capable of replacing damaged tissue and/or cells, one must understand that the need for the balance between cellular proliferation and differentiation is a carefully controlled process involving a range of growth factors and cytokines produced in large part by tissue stromal cells. These stromal cells make up the tissue microenvironment and appear to be essential for normal homeostasis. McNiece and Hare hypothesize that tissue damage involves damage to the microenvironment resulting in a lack of signals through growth factor networks necessary to maintain survival and proliferation of tissue specific stem cells and progenitor cells. Therefore, optimal repair of disease tissue must account for the damage to the stromal environment. Optimal cellular therapies for regenerative medicine will require combination cellular products consisting of a stromal cell population to reconstitute the microenvironment and to support the survival, proliferation and differentiation of the tissue specific stem cells or progenitor cells.

Huang et al. try to define the functional metrics required for engineering articular cartilage, and to situate the current state of MSC-based constructs within this framework. They examine the components and function of the native tissue, and review the progress made to date using differentiated cartilage cells (chondrocytes) for cartilage tissue engineering. This discussion includes methods of formation, biochemical formulations for enhancing in vitro development, as well as progress made towards using mechanical forces to further direct maturation. They then review the origins and applications of adult multi-potential stem cells, and discuss how routes towards cartilage tissue engineering with stem cells match (or fail to match) those approaches that were successful using differentiated cells. In particular, they describe new requirements to be understood for cartilage formation with MSCs, and outline several research areas that may inform this new direction in cartilage tissue engineering

The application of biomimetic mechanical forces for stem cell differentiation is a technique that has been on the rise in recent years. The effects of these forces on stem cells are the most commonly explored combinations in functional tissue engineering. Paleaz et al. summarized the current findings in functional tissue engineering, explain the importance of engineering in medical research, and describe the ways tissue engineers are attempting to understand what biochemical changes are occurring in the stem cells during the application of mechanical stress

CLINICAL APPLICATIONS

The goal of angiogenic therapy is to activate endogenous angiogenic and arteriogenic pathways and stimulate revascularization of ischemic myocardial tissue. The feasibility of such a strategy has now been established through the results of studies over the past two decades, and clinical trials involving more than 1000 patients have been implemented. Critical evaluations reveal that neither proteins nor genes delivered by transient expression vectors provide an optimal therapy. Similarly, stem cell therapy is not achieving the level of improvement that was expected or predicted from preclinical results. The future of therapeutic angiogenesis lies in the use of permanent gene delivery vehicles expressing regulated genes and/or stem cells appropriately engineered with regulated genes (Keith A. Webster).

The use of progenitor/stem cells to modulate the sensory systems in chronic pain is a new field in translational research. Stem cells or progenitor approaches have been tested in cardiac myopathies, liver dysfunction, stroke, and genetic abnormalities, but almost none have applied progenitor cells to the relief of neuropathic, pain. Perhaps the best studied neural progenitor cell line NT2, has recently resulted in two NT2-derived cell lines: hNT2.17, secreting the inhibitory neurotransmitters GABA and glycine; and hNT2.19, secreting the neurotransmitter serotonin. Each of these NT2-lines has demonstrated antinociceptive potential in models of SCI-related neuropathic pain, in peripheral neuropathy, and diabetic neuropathic pain. These human progenitors may prove to be useful in the relief of chronic pain and open the way to other regenerative approaches to pain management (Eaton et al.)

Early results of therapy with neural stem cells have been attributed to factors released by infused cells and investigator bias. The stem cell progeny identified as neurons by antigen expression and by morphology has been questioned, leading to the re-interpretation of these results by investigators who first reported them. Despite the diminished expectations, regenerative cells, or structures that mimic the function regenerative cells possess, are present in germinal areas of the adult human brain, albeit in limited numbers. Evidence does suggest that damaged brain tissue does, in some patients, regenerate with recovery of lost function. These cellular entities have not been widely studied, characterized but they may be similar to structures generated in neural tissue of primitive vertebrates which have a remarkable capability to regenerate intact, functional brain. These structures can potentially be expanded using methods that differ vastly from stem cell culture methods employed to date. Successfully expanded and stored, these structures may provide an effective means to regenerate brain tissue after stroke and traumatic brain injury in humans (English et al.)

The existence of clinically successful islet transplantation for type I diabetes has stoked a keen interest in developing alternative, inexhaustible sources of insulin-producing cells. Domínguez-Bendala and Ricordi cover the state of the art regenerative therapies for the endocrine component of the pancreas, from stem cells to transdifferentiation. They review the basics of pancreatic development, whose recapitulation remains the subject of a plethora of in vitro differentiation strategies using both embryonic and adult stem cells. They also examine the leading theories about the cellular and molecular mechanisms behind the in vivo regeneration of the organ that is observed under specific circumstances, as well as the purported ability of some tissues to turn into pancreatic endocrine cells when subjected to specific interventions (transdifferentiation). They conclude with a general overview of the remaining challenges and clinical perspectives of all the above strategies, with a special emphasis on the immunological hurdles to be overcome for these approaches to find their way to standard clinical practice.

To date, several sources of dental stem cells have been isolated and being characterized as dental epithelial stem cells, dental pulp stem cells, dental follicle precursor cells, stem cells from human exfoliated deciduous teeth, stem cells from apical papilla, and periodontal ligament stem cells. Dental stem cells have been shown to have multi-potential by their ability to differentiate into neuronal, adipogenic, myogenic, chondrogenic, osteogenic and dentinogenic cells when cultured under specific conditions. These facilitated studies to address an important property of stem cells, that is, the capacity of a given stem cell population to regenerate an organized, functional tissue following transplantation in vivo. Furthermore, the ready availability of tooth tissues from redundant teeth such as third molars can provide a good supply of dental stem cells that may be utilized for regenerating other body parts or organs (Zheng and Cheung).

Yam et al. address the important questions regarding functions of cornea epithelial progenitor cells (CEPCs) and therapeutic strategies in health and diseases. The human cornea is a site of tissue-specific adult progenitor cells, residing between cornea and conjunctiva in the Palisade of Vogt of the limbus region. While specific molecular markers of CEPCs are still unknown, recent research provide new information to apply them for cell replacement in damaged tissues. Cultured CEPCs have been used for ex vivo cornea therapy with satisfactory clinical outcome. While the niche environment, i.e., the extracellular matrix, growth factors and cytokines, provide regulatory measures in the proliferation of CEPCs, the recent discovery of CEPC specific microRNAs opens a new direction of research on the biological properties of CEPC and stem cells of other resources.

Last but not the least, I like to thank Ms. Lauren L. Vernon, who spent countless hours in working with all the authors.

Herman S. Cheung, PhD
James L. Knight Professor of Biomedical Engineering
Senior Veteran Affairs Research Career Scientist
Professor of Medicine & Orthopedic Surgery
University of Miami
USA

List of Contributors

Editor(s):
Herman Cheung
Miami VA Medical Center
USA




Contributor(s):
Akshay Anand
Professor, Dept. of Neurology
Post Graduate Institute of Medical Education and Research
Chandigarh
India


Herman S. Cheung
James L. Knight Professor, Dept. of Biomedical Engineering
1251 Memorial Drive, Coral Gables, FL & Geriatrics Research, Education and Clinical Center and Research Service, Miami VA Healthcare System, 1201 NW 16 Street,
Miami
FL
USA


Kevin Curtis
Departments of Medicine and Biochemistry & Molecular Biology
University of Miami Leonard M. Miller School of Medicine and Geriatric Research Education and Clinical Center and Research Service Veterans Affairs Medical Center
Miami
FL
USA


Gianluca D'Ippolito
Assistant Professor, Geriatric Research Education and Clinical Center and Research Service
Veterans Affairs Medical Cente
Miami
FL
USA


Juan Domínguez-Bendala
Assistant Professor, Diabetes Research Institute University of Miami Leonard M. Miller School of Medicine
1450 NW 10th Avenue
Miami
FL
USA


M. J. Eaton
Associate professor, Dept. of Veterans Affairs Medical Cente
Miami
FL
USA


Denis English
Professor, Dept. of Neurosurgery
Foundation for Developmental Research University of S. Florida College of Medicine
Tampa
FL
USA


Robin N. Fiore
University of Miami Bioethics Program, University of Miami
FL
USA


Elisa Garbayo
Departments of Medicine and Biochemistry & Molecular Biology
University of Miami Leonard M. Miller School of Medicine Geriatric Research Education and Clinical Center and Research Service VA Medical Center
Miami
FL
USA


Stephan Gluck
Professor, Division of Hematology/Oncology Dept. of Medicine
Sylvester Comprehensive Cancer Center
Miami
FL
USA


Lourdes A. Gomez
Departments of Medicine and Biochemistry & Molecular Biology
University of Miami Leonard M. Miller School of Medicine Geriatric Research Education and Clinical Center and Research Service Veterans Affairs Medical Center
Miami
FL
USA


Kenneth W. Goodman
Joshua Hare Professor & Director Interdisciplinary Stem Cell Institute
Professor & Chief, University of Miami Bioethics Program, University of Miami
1120 NW 14th St
Miami
FL
USA


Josh M. Hare
Louis Lemberg Professor & Director
University of Miami Leonard M.Miller School of medicine, Interdisciplinary Stem Cell Institute
Miami
FL , 33101
USA


Alice H. Huang
Dept of Orthopaedic Surgery and Dept. of Bioengineering University of Pennsylvania
McKay Orthopaedic Research Laboratory
Philadelphia
PA
USA


Clark T. Hung
Associate Professor, Dept. of Biomedical Engineering Columbia University
Cellular Engineering Laboratory
New York
NY
USA


Lim Kwong Cheung
Professor, Oral & Maxillofacial Surgery
The Prince Philip Dental Hospital
34 Hospital Road
Hong Kong
SAR
China


Robert L. Mauck
Asistant Professsor, McKay Orthopaedic Research Laboratory Dept of Orthopaedic Surgery and Dept. of Bioengineering
University of Pennsylvania
Philadelphia
PA
USA


Ian McNiece
Professor University of Miami Leonard M. Miler School of Medicine, Interdisciplinary Stem Cell Institute
1120 NW 14th St
Miami
FL
USA


Daniel Pelaez
Ph.D. Candidate, Dept. of Biomedical Engineering
1251 Memorial Drive
Coral Gables
FL
USA


Carmen Rios
Geriatric Research Education and Clinical Center and Research Service
Veterans Affairs Medical Center
Miami
FL
USA


Camillo Ricordi
Professor#x0026; Scientific Director, University of Miami Leonard M. Miller School of Medicin, Diabetes Research Institute
1450 NW 10th Avenue
Miami
FL
USA


Isaac H. Ritter
University of Miami Bioethics Program, University of Miami
FL
USA


Paul C. Schiller
Associate Professor, Departments of Medicine and Biochemistry #x0026; Molecular Biology
University of Miami Miller School of Medicine and Geriatric Research Education and Clinical Center and Research Service VA Medical Center
Miami
FL
USA


Rama S. Verma
Stem Cell and Molecular Biology Laboratory Deptartment of Biotechnology
Institute of Technology-Madras
Chennai
India


Keith A. Webster
Professor Dept. of Molecular and Cellular Pharmacology, Leonard M. Miller School of Medicine
The Vascular Biology Institute, University of Miami
Miami
FL
USA


Eva Widerström-Noga
Associate Professor, The Miami Project to Cure Paralysis
University of Miami Leonard M. Miller School of Medicine
Miami
FL
USA


Stacey Quintero Wolfe
Dept. of Neurological Surgery
University of Miami Leonard M. Miller School of Medicine
Miami
FL
USA


Li Wu Zheng
Assistant Professor, Oral #x0026; Maxillofacial Surgery
The Prince Philip Dental Hospital
34 Hospital Road
Hong Kong
SAR
China


Gary Hin-Fai Yam
Assistant Professor, Department of Ophthalmology & Visual Sciences
The Chinese University of Hong Kong
Hong Kong



Chi Pui Pang
Professor, Department of Ophthalmology & Visual Sciences
The Chinese University of Hong Kong
Hong Kong





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