Stem Cell Therapy for Autoimmune Disease

Richard K. Burt

• Publisher: CRC Press
• Year: 2019
• Print ISBN: 9781587060311
• eBook ISBN: 9781000724677
• Topic: Medicine
• Subtopic: Biotechnology in Medicine

Stem cell transplantation may be complicated by treatment-related mortality and like the immune system that it regenerates has equal potential to either create and preserve or destroy. The dual nature that defines stem cells is differentiation that ultimately leads to death and self-renewal, which leads to immortality. What types of stem cells are there? How are they collected? What are their attributes and characteristics? This textbook devotes many chapters to familiarize the reader with the basic science, clinical aspects, and new questions being raised in the field of stem cell biology. Blood stem cells for tolerance and tissue regeneration are a rapidly developing research and clinical field that is being applied to autoimmune diseases. In clinical trials, autologous hematopoietic (blood) stem cells are being used to reduce the cytopenic interval following intense immune suppressive transplant regimens. While as yet not delineated, some possible mechanisms and pathways leading to tolerance after hematopoietic stem cell transplantation are suggested in these chapters. Tissue regeneration from blood stem cells is also suggested by animal experiments on stem cell plasticity or metamoirosis (i.e., change in fate) as described within this textbook. Ongoing early clinical trials on tissue regeneration from blood stem cells are described in the chapter on stem cell therapy for cardiac and peripheral vascular disease. Whether autologous hematopoietic stem cells, through the process of mobilization and reinfusion, may be manipulated to contribute to tissue repair in autoimmune diseases is a future area for translational research.

CHAPTER 1

When is a Stem Cell Really a Stem Cell?

Gerald J. Spangrude

Introduction

In recent years, data from numerous experimental studies has suggested that the potential uses of stem cells in medicine may reach far beyond bone marrow transplantation. How applicable is recent research to modern medicine, and how soon might we expect to see stem cells applied to tissue engineering problems? These and other questions are explored in this introductory chapter. It is altogether fitting that a discussion of the therapeutic potentials of stem cell therapy be grounded in our field, being the first to apply stem cell therapy to the clinical management of acquired and inherited diseases. But what is a stem cell? In the context of bone marrow transplantation, we understand the answer to this question in a concrete and functional sense due to decades of research and clinical applications that grew out of the need to understand the effects of ionizing radiation on biological systems. In the years following the Second World War, a considerable amount of scientific effort was focused on the prevention and treatment of radiation sickness. From these studies came the observation that transplants of spleen or bone marrow cells contribute to cellular recovery following lethal radiation.¹ Almost 50 years after this dramatic insight, we now understand that the ability of such transplants to reconstitute hematopoiesis following radiation depends upon the presence of extremely rare stem cells found predominantly in the bone marrow but capable of mobilization into peripheral tissues via the blood vascular system.²

After many years shrouded in mystery and controversy, the characteristics of blood stem cells were gradually revealed through novel assays^{3, 4 and 5} and methods for isolation of these rare cells.^6,7 We now understand that the definition of a stem cell must include the two essential characteristics of self-renewal (cellular division maintains stem cell potential) and multipotency (differentiation into functionally distinct lineages). To complicate matters, it is clear that progenitor cells, which are multipotent but lack self-renewal potential, are often difficult to distinguish from true stem cells.⁸ Finally, at least some confusion persists in the tissue stem cell field, where unipotent precursor cells which maintain a tissue through a self-renewing process are often considered stem cells.

The general field of stem cell biology has been the subject of intense public interest in recent years for several reasons. First, the demonstration that recipients of bone marrow transplants harbor donor-derived cells in a variety of tissues has radically changed our expectations for the applications of this type of therapy,⁹ even though many questions have been raised by these interesting findings.¹⁰ Second, the derivation of totipotent human stem cells from both embryonic and fetal sources has introduced a potential new source of tissue for engineering applications. Equally important, this new technology marks the genesis of a new level of conflict between science and religion that surpasses that raised by older questions of creationism versus evolution. The potential use of stem cells derived from adult tissues introduces yet another side to this complex story. How are we to define when a stem cell is a stem cell? It is in this vein that I examine a few of the historical aspects of stem cell biology in order to better understand where we have come from at this stage in the development of the stem cell field.

Embryonic Stem Cells: A Timeline

Lewis¹¹ has correctly identified the origins of the stem cell biology field in the work of Leroy Stevens, a developmental biologist who identified frequent testicular tumors arising spontaneously in strain 129 mice at the Jackson Laboratories. This work was published to little fanfare beginning in 1958.¹² However, the curiosity of Mintz and Illmensee led to a startling observation. When malignant teratocarcinoma cells were mixed into developing mouse embryos, the environment of the embryo harnessed the unregulated growth of the tumor and directed these cells to proper channels of proliferation and differentiation.¹³ The result was chimeric mice in which a significant portion of the body mass was derived from the teratocarcinoma. This startling discovery was viewed at the time as evidence for environmental regulation of malignant growth, but the potential of these cells was certainly not overlooked by developmental biologists. Embryonic stem cell lines were derived from the inner cell mass of mouse blastocysts in 1981,^14,15 as shown in Figure 1. These cells were adapted for growth in culture without differentiation, but could differentiate into mesoderm, endoderm, and ectoderm in vitro and in vivo. The derivation of embryonic stem cell lines was rapidly exploited to give birth to the field of targeted mutagenesis,^16,17 an entirely new approach to the investigation of complex mammalian biological systems. Today, it is difficult for scientists to imagine a world in which the genome could not be mutated in a specific manner. The true power of stem cell biology was revealed to the world at large with the announcement that the transfer of nuclei derived from adult somatic cells into enucleated oocytes produced, at a low frequency, viable offspring clonally derived from the donor of the nuclei.¹⁸

Adapted with permission from Bone Marrow Transplantation, Vol. 32, Supplement 1, Aug 2003.

Stem Cell Therapy for Autoimmune Disease, edited by Richard K. Burt and Alberto M. Marmont. ©2004 Landes Bioscience/Eurekah.com.

Figure 1. From the initial descriptions of the ability of testicular carcinoma cells to produce pluripotent embryonic stem cells, these cells have since been derived from blastocysts as well as the primordial germ cells in the developing genital ridge in both mouse and man. Figure courtesy of Terese Winslow, used with permission of the artist.

Mouse to Man

The successful application of targeted mutagenesis in the mouse was not the only useful application of embryonic stem cell lines. A variety of investigators utilized these cell lines to model the development of the early embryo in culture systems, and successfully recapitulated several aspects of embryogenesis. When the application of in vitro fertilization to the clinical problem of infertility resulted in the birth of the first test-tube baby in 1978, the stage was set for the eventual derivation of human embryonic stem cells from embryos fertilized in vitro but not implanted into a womb.¹⁹ Since these early embryos are frozen in quantities that exceed clinical need, large banks of fertilized embryos destined for destruction now exist around the world as a consequence of the widespread application of in vitro fertilization. Some of these embryos have been cultured to derive embryonic stem cell lines, however the derivation of cell lines in addition to those already in existence has been deemed unnecessary and will not be supported by federal funding agencies in the United States.

A second approach to the application of stem cell technology in humans utilizes tissue derived from the genital ridge of aborted first trimester fetuses (Fig. 1).²⁰ These cells, which normally develop into mature gametes, can be cultured under specific conditions to produce cell lines with all known characteristics of blastocyst-derived embryonic stem cells but lacking apparent tumorigenic potential. This combination of multipotential differentiation in the absence of tumor formation has lead to the proposed use of these cells in clinical trials to treat spinal cord injury, Parkinson’s disease, and other cell-based therapies. With the specter of the cloning of human beings looming before us, the National Academy of Sciences initiated a comprehensive analysis of this brave new world.²¹ The current state of federal funding will support the utilization of fetal-derived embryonic germ cells in clinical applications, most likely because the derivation and use of these cells avoids some of the concerns raised by the concept of frozen embryos as sources of embryonic stem cells. Embryonic germ cells are unable to be implanted into a surrogate mother to produce a genetically normal human, unlike the embryos formed during in vitro fertalization. As such, the only embryos that might be formed by embryonic germ cells would be genetic mosaics of the germ cell and a blastocyst in which such cells might be introduced, or would be the product of somatic cell nuclear transfer. Since the latter process can be performed using a wide variety of cell types, the embryonic germ cell provides no special advantage in this sense.

Adult Stem Cells

Undifferentiated cells that are found in a differentiated adult tissue are considered adult stem cells, particularly when these cells contribute to ongoing tissue maintenance or repair. These cells may be capable of self-renewal, but do not replicate indefinitely in culture. Adult stem cells may differentiate to produce progenitor, precursor, and mature cells, but these activities are usually limited to the cells contained in the tissue of origin. Adult stem cells usually comprise a small minority of the total tissue mass, and as such are usually quite difficult to identify and isolate. Adult stem cells have been described in regenerating tissues such as the liver, epithelium and muscle, as well as in tissues like the brain, which previously was thought not to possess extensive regenerative properties. By far, the most well-characterized example of adult stem cells is that of the hematopoietic system.

Hematopoietic Stem Cells: Paradigms for Stem Cell Biology

The limited life-span of most blood cells demands that a continual source of these cells be assured throughout life. It is like...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Dedication Page
• Table of Contents
• Editors
• Contributor
• Frontispiece
• Preface
• 1. When is a Stem Cell Really a Stem Cell?
• 2. Embryonic Stem Cells: Unique Potential to Treat Autoimmune Diseases
• 3. Neural Stem Cells and Oligodendrocyte Progenitors in the Central Nervous System
• 4. Turning Blood into Liver
• 5. Adipose Tissue-Derived Adult Stem Cells: Potential for Cell Therapy
• 6. Hematopoietic Stem Cell Biology: Relevance to Autoimmunity
• 7. Properties and Therapeutic Potentials of Adult Stem Cells from Bone Marrow Stroma (MSCs)
• 8. Regeneration of Cardiomyocytes from Bone Marrow Stem Cells and Application to Cell Transplantation Therapy
• 9. Clinical Trials of Hematopoietic Stem Cells for Cardiac and Peripheral Vascular Diseases
• 10. The Stem Cell Continuum: A Plastic Plasticity
• 11. Adult Stem Cell Plasticity
• 12. Collection and Expansion of Stem Cells
• 13. The Extracellular Matrix as a Substrate for Stem Cell Growth and Development and Tissue Repair
• 14. Gene Transfer into Human Hematopoietic Stem Cells: Problems and Perspectives
• 15. The Etiopathogenesis of Autoimmunity
• 16. Overview of Immune Tolerance Strategies
• 17. Death Receptor-Mediated Apoptosis and Lymphocyte Homeostasis
• 18. Shifting Paradigms in Peripheral Tolerance
• 19. Dendritic Cells Control the Balance between Tolerance and Autoimmunity
• 20. CD4+ Τ Regulatory Cells and Modulation of Undesired Immune Responses
• 21. Major Histocompatibility Complex and Autoimmune Disease
• 22. Analyzing Complex Polygenic Traits: The Role of Non-HLA Genes in the Susceptibility to Autoimmune Disorders
• 23. Drug-Induced Autoimmunity
• 24. Evidence for a Role of Infections in the Activation of Autoreactive Τ Cells and the Pathogenesis of Autoimmunity
• 25. Molecular Analysis of Immunity
• 26. Immune Reconstitution after Hematopoietic Stem Cell Transplantation
• 27. Historical Perspective and Rationale of HSCT for Autoimmune Diseases
• 28. High-Dose Immune Suppression without Hematopoietic Stem Cells for Autoimmune Diseases
• 29. Autologous Stem Cell Transplantation in Animal Models of Autoimmune Diseases
• 30. Allogeneic Hemopoietic Stem Cell Transplantation in Animal Models of Autoimmune Disease
• 31. Mobilization and Conditioning Regimens in Stem Cell Transplant for Autoimmune Diseases
• 32. Infection in the Hematopoeitic Stem Cell Transplant Recipient with Autoimmune Disease
• 33. Immunological Aspects of Multiple Sclerosis with Emphasis on the Potential Use of Autologous Hemopoietic Stem Cell Transplantation
• 34. Axonal Injury and Disease Progression in Multiple Sclerosis
• 35. Monitoring Disease Activity in Multiple Sclerosis
• 36. Intense Immunosuppression Followed by Autologous Stem Cell Transplantation in Severe Multiple Sclerosis Cases: MRI and Clinical Data
• 37. Hematopoietic Stem Cell Transplantation for Multiple Sclerosis: Finding Equipoise
• 38. Molecular and Cellular Pathogenesis of Systemic Lupus Erythematosus
• 39. Definition, Classification, Activity and Damage Indices in Systemic Lupus Erythematosus
• 40. Lupus Nephritis
• 41. Hematopoietic Stem Cell Transplantation for Systemic Lupus Erythematosus
• 42. Treatment of Rheumatoid Arthritis
• 43. Haemopoietic Stem Cell Transplantation for Rheumatoid Arthritis—World Experience and Future Trials
• 44. Autologous Stem Cell Transplantation for Refractory Juvenile Idiopathic Arthritis (JIA)
• 45. Immunology of Scleroderma
• 46. Hematopoietic Stem Cell Transplantation for Systemic Sclerosis
• 47. High-Dose Immunosuppressive Chemotherapy with Autologous Stem Cell Support for Chronic Autoimmune Thrombocytopenia
• 48. High-Dose Chemotherapy with Haematopoietic Stem Cell Transplantation in Primary Systemic Vasculitis, Behcet’s Disease and Sjogren’s Syndrome
• 49. Hematopoietic Stem Cell Transplantation in the Treatment of Chronic Inflammatory Demyelinating Polyradiculoneuropathy
• 50. Hematopoietic Stem Cell Therapy for Patients with Refractory Myasthenia Gravis
• 51. Hematopoietic Stem Cell Transplantation in Patients with Autoimmune Bullous Skin Disorders
• 52. Idiopathic Inflammatory Myositis
• 53. Hematopoietic Stem Cell Transplantation as Treatment for Type 1 Diabetes
• 54. Autologous Hematopoietic Stem Cell Transplantation for Crohn’s Disease
• 55. Bronchial Asthma and Idiopathic Pulmonary Fibrosis as Potential Targets for Hematopoietic Stem Cell Transplantation
• 56. Autologous Stem Cell Transplantation in Relapsing Polychondritis
• 57. Allogeneic Hematopoietic Stem Cell Transplantation for Autoimmune Diseases
• Index