Current Neurovascular Research, Vol. 1, No. 3, 2004
Contents
From The Editor's Perspective: New Directions and New
Sources for Stem Cells Pp.193
Kenneth Maiese
Special Issue on Stem Cells: An Introduction from the
Guest Editor Pp.195-196
Feng C. Zhou
The Multiple Facets of Hematopoietic Stem Cells Pp.197-206
Rebecca J. Chan and Mervin C. Yoder
Neural Induction of Adult Bone Marrow and Umbilical Cord
Stem Cells Pp.207-213
Xilma R. Ortiz-Gonzalez, C. Dirk Keene, Catherine M.
Verfaillie and Walter C. Low
Neural Stem Cell Plasticity: Recruitment of Endogenous
Populations for Regeneration Pp.215-229
Patrizia Ferretti
Retina Repair, Stem Cells and Beyond Pp.231-239
Tracy Haynes and Katia Del Rio-Tsonis
Progenitor Cell Properties and the Engineering of Tissues
Pp.241-249
Janet Hardin-Young and Nancy L. Parenteau
Neurotransmitters and Substances of Abuse: Effects on
Adult Neurogenesis Pp.251-260
T.A. Powrozek, Y. Sari, R.P. Singh and F.C. Zhou
Regulation of Neurogenesis and Angiogenesis in Depression
Pp.261-267
Samuel S. Newton and Ronald S. Duman
Use of Human Umbilical Cord Blood (HUCB) Cells to Repair
the Damaged Brain Pp.269-281
Mary B. Newman, Dwaine F. Emerich, Cesario V. Borlongan,
Cyndy Davis Sanberg and Paul R. Sanberg
Cell-Replacement Therapy with Stem Cells in
Neurodegenerative Diseases Pp.283-289
Vincenzo Silani and Massimo Corbo
[Back to top]
From The Editor's Perspective: New Directions and New Sources for Stem Cells
Kenneth Maiese
From its initial conception, this special issue on stem cells was intended to showcase the potential therapeutic utility of stem cells as well as to initiate scientific debate concerning the ability of stem cells to lead to viable tissue regeneration as well as functional plasticity in an organism during acute or chronic injury. In general, stem cells begin as undifferentiated cells, but have the ability to yield progeny cells that may lead to self-renewal, nonrenewing progenitors, or terminally differentiated cells. Stem cells possess different capacities and are classified according to a particular cell type that they can produce, such as whether they are unipotent (one mature cell type), oligopotent (a restricted subset of cell lineages), multipotent (a broader range of a subset of cell lineages), pluripotent (embryo proper cells), or totipotent (embryonic and extra-embryonic cells).
While we examine the scientific basis and therapeutic promise of stem cells in this issue, we must also be cognizant of the present hurdles facing stem cell research. Debates concerning the use of human embryonic stem cells have recently been fueled with the recent publication that reports the derivation of a pluripotent embryonic stem cell line from a cloned human blastocyst (Hwang, WS et al., 2004). Yet, prior to the consideration of any clinical applications for stem cells in regards to human disease, significant additional studies are required on several fronts as follows: (1) to understand the cellular mechanisms that regulate the differentiation of animal and human tissues; (2) to elucidate how differentiated cells may be targeted to specific tissues for repair; and (3) to prevent the possible development of further injury in damaged tissue during stem cell applications, such as by the potential generation of neoplastic cells from undifferentiated stem cells. These challenges can be overcome with the proper support in a climate that requires continual reassurance and education to allay any fears that specific ethical concerns will not be breached. Timely additional work that reports the availability of seventeen new embryonic stem cell lines that reproducibly differentiate in vitro and in vivo into cell types from all three embryonic germ layers (Cowan, CA et al., 2004) (barred at this time from use in work funded by United States federal sources) further assists us in understanding the potential of stem cells for treating human disease.
As we move forward, it is our intention that highlighting both the accomplishments achieved as well as the obstacles to be overcome in stem cell research will bring both the scientific community and the public closer to objectively assessing the potential promise of stem cells for the treatment of clinical disease. In the series of manuscripts that follows, the role of stem cells from various sources are discussed as well as their developmental capacity for "transdifferentiation", the transition of a cell from a specific tissue lineage into a different tissue lineage. Our Guest Editor, Dr. Feng C. Zhou, has performed an exemplary job in assembling an outstanding group of contributors for this issue to provide an overview and platform for present and future considerations of the potential role of stem cells to treat human disease, especially those that involve neurodegenerative disorders.
[Back to top]
Special Issue on Stem Cells: An Introduction from the Guest Editor
Feng C. Zhou
The goal of replacing cells and re-engineering tissue to both repair our body and mind have come closer to reality as we are better-harnessing stem cells. Stem cells have been implicated for treatments in Parkinsonism, Alzheimer’s disease, stroke, diabetes, muscular dystrophy, spinal injury, and depression. To reach the above goal, a better understanding of stem cells with respect to their various origins, their regulating factors, and their various potentialities both in vitro and in vivo is essential. Recent progress of stem-cell research in a number of different areas has begun to tease out their diversity and commonality, the factors that contribute to their potentialities, and their potential applications. This special issue is dedicated to provide a cross-platform forum for a discussion of stem cells in these areas. In this issue, stem cells from mammalian hematopoietic, retinal, epithelial, and neural origins, and from highly regenerative amphibian are discussed together for the very import reason that stem cells from diverse origins share common features, and stem cells of common origins can turn into very diverse cell types.
When reading this special issue, it is convenient if the same definition for “stem cells” is used. A working definition for “stem cells” is a pool of undifferentiated cells preserved throughout the process of development into adulthood, and this pool still maintains their potentiality to turn into specialized cells in the body. This pool of undifferentiated cells is termed “stem cell” when they meet these two essential criteria: the ability of unlimited self-renewal and the ability to turn into specialized cells. The ontogeny of a line of stem cells is well illustrated in the hematopoietic stem cells (HSC) in vivo and in vitro by Drs. Chan and Yoder. It is further elucidated, in this review, that the multipotentiality of HSC that can differentiate not only into the blood and endothelial cells, but also into the cardiovascular system, muscle cells, liver cells, epithelial cells of the gut and lungs, and brain cells. Dr. Low and colleagues further discuss how both bone marrow and the umbilical cord contains HSC and how other stem cells not only have mesodermal, but also have neuroectodermal potentiality and upon appropriate treatments in vivo and in vitro can differentiate into neurons, astrocytes and oligodendrocytes.
The mechanisms of differentiation of stem cells into cell types beyond their origin (e.g. mesodermal versus ectodermal) and stem cells derived from existing mature cells have been the focus of an active debate throughout the reviews of this special issue. The mechanism of differentiation, transdifferentiation, cell fusion, etc. have been reviewed and discussed in mammalian HSC cells (Dr. Low and colleagues), amphibian and embryonic chick and mammalian retina stem cells (Drs. Haynes and Del Rio-Tsonis), amphibian ependymal stem cells from the spinal cord (Dr. Ferretti), and the epidermal stem cells from humans (Drs. Hardin-Young and Parenteau).
Regenerative powers in the spinal cord and retina are lost in mammalians through evolution, but are preserved in amphibians. The understanding of ependymal stem cells in the amphibian, which is privileged with a high level of plasticity of regeneration after injury (such as limb and tail amputation), provides further insight into the multipotentiality of stem cells and their abilities in differentiation (Dr. Ferretti). These lessons learned from the study of amphibians, which are discussed by Dr. Ferretti, are particularly valuable for spinal cord regeneration in mammalians. The understanding of the transdifferentiation of mature retinal pigmented epithelial cells, pigmented ciliary margin, and Muller glial cells into retina stem cells after injury provides a great insight into retinal regeneration. The understanding of the different potentialities of transdifferentiation of these cells among the adult amphibian, embryonic chick, and embryonic mammalian provides an important lesson for mammalian retina regeneration; these different potentialities are discussed by Drs. Haynes and Del Rio-Tsonis. With regard to humans, an understanding of the nature, maintenance, and immunology of stem cells in a regenerative organ can be applied to a better procurement and maintenance of stem cells from less regenerative organs. The epidermal (keratinocyte) stem cells, which are a more approachable type of human stem cell due to their greater availability, can provide better technical insight for harnessing the less approachable and less regenerative human pancreatic stem cells (Drs. Hardin-Young and Parenteau). In this issue, the experiences gained from studying the human epidermal stem cells are reviewed. Examples of these include: in vitro amplification and differential induction, as well as in vivo immunological consideration after grafting the stem cells. These experiences are applicable to other less abundant human stem cells (Drs. Hardin-Young and Parenteau).
The neural stem cells intrinsic to the adult brain are generally confined to the hippocampus, the subventricular zone, and the olfactory bulb. The new cells, particularly neurons, produced in these brain regions can participate in existing local and distal circuitry and have functional significance. Thus, these neural stem cells intrinsic to the brain, if harnessed, hold a great hope for repairing and re-engineering the damaged brain. The neurogenesis and differentiation of these neural stem cells are regulated by trophic factors such as brain derived neurotrophic factor (BDNF), fibroblast growth factor (FGF), and vascular endothelial growth factor (VEGF) (Drs. Powrozek, Sari, Singh and Zhou). Many environmental factors, such as enriched environment, exercise, and stress, as well as neuroactive compounds, such as serotonin specific reuptake inhibitor (SSRI) and abusive substances such as methamphetamine, morphine, and alcohol all have effects on neurogenesis. These effectors are commonly found to regulate neurogenesis through common neurotransmitter pathways such as the following: 1) glutamate via its receptor subtypes, NMDA, AMPA, and mGluR2, 2) serotonin via its receptor subtypes 5-HT1A and 5-HT1B, and 3) morphine and Naltrexone via opioid receptors to activate the neurotrophic factors which in turn promote neurogenesis. Among the brain regions, the hippocampus thus far has been the most responsive to environmental factors. The neuroplasticity and neurogenesis of this brain region, along with amygdala and other limbic systems, may constitute memory and emotion imprinting onto neural structures. Dystrophy and cellular loss, such as during stress of these brain regions, have been associated with depression and affective disorders. Bioactive compounds, such as SSRI, which increase extracellular 5-HT levels, have been known to increase neurogenesis in the hippocampus and reverse depression (Drs. Newton and Duman; and Drs. Powrozek, Sari, Singh and Zhou). Interestingly, other anti-depressants which act through NMDA/AMPA/ mGluR receptors also increase neurogenesis in the hippocampus. The anti-depressive effect of SSRI and glutamate agonist may also involve angiogenesis (Drs.Newton and Duman).
Finally, the practical use of stem cells for treating diseases is illustrated by examples in the last two articles. The human umbilical cord blood cells (HUBC) are a valuable resource for HSC, which has been applied for transplantation to treat stroke, brain injury, amyotrophic lateral sclerosis (ALS), and enzymatic disorders (by Newman, Emerich, Borlongan, Davis, and Sanberg). Stem-cell transplant technology using HUBC is reviewed, and future considerations are discussed. The detailed application of stem cells in treating ALS is illustrated (Drs. Silani and Corbo). The mechanisms of stem-cell neurogenesis, differentiation, transdifferentiation, and regulation by trophic factors (such as BDNF, EGF, FGF), must each be considered when treating neurodegenerative diseases such as ALS and Parkinsonism.
In closing, the discovery of the potentiality of stem cells is not a panacea. The understanding, the procurement, and the harness of stem cells are only the beginning steps to a world with a greater capacity for healing.
In this special issue on stem cells, I would like to thank the contributors for their insightful reviews and visions. I am in debt to Rabindra Singh for his assistance during the editorial work. This special issue also received much help from Dr. Youssef Sari, Mr. David Agler, and Ms. Nandini Shah. I would also like to thank Dr. Kenneth Maiese, our Editor-in-Chief, for without him this special issue would not be in print.
[Back to top] The
Multiple Facets of Hematopoietic Stem Cells
Rebecca J. Chan and Mervin C. Yoder
Hematopoietic stem cells (HSCs) have long been defined as a cell with the capacity to repopulate the hematopoietic system of a lethally irradiated host. In clinical medicine, this property has been employed to reconstitute an individual’s diseased hematopoietic system following ablation with a healthy, normal-functioning hematopoietic system by performing autologous and allogeneic stem cell transplantations. However, despite the widespread utilization of these pragmatic procedures for multiple human bone marrow diseases, much about the basic biology of the HSC and related primitive cells, such as the ontogenic origin of the HSC, the identification of the putative hemangioblast, and the potential of the HSC to contribute to alternative tissues, remains elusive. Basic scientists continue to investigate actively the origin of HSCs during mammalian ontogeny, the stimuli that induce HSCs to divide and differentiate normally, the relationship of HSCs to hemangioblasts, and the potential capacity of HSCs to transdifferentiate to other tissues such as endodermderived liver cells and ectoderm-derived neurons. This article will summarize the historical salient studies that have characterized the HSC and will review the active research currently being conducted to understand and define further the biologic properties and potential faculties of HSCs. The application of these studies to improved therapies for human disease, from leukemia to myocardial infarction, will be discussed.
[Back
to top] Neural Induction of Adult Bone Marrow and
Umbilical Cord Stem Cells
Xilma R. Ortiz-Gonzalez, C. Dirk Keene, Catherine M.
Verfaillie and Walter C. Low
Recent reports of neural differentiation of postnatally derived bone marrow and umbilical cord cells have transformed our understanding of the biology of cell lineages, differentiation, and plasticity. While much controversy remains, it is clear that adult tissues, and bone marrow in particular, are composed in part of cells with much more diverse lineage capacity than previously thought. Traditionally, cell-based therapies for the CNS have been derived from fetal or embryonic origin. By harnessing the neural potential of readily-available and accessible adult bone marrow and umbilical cord blood stem cells, substantial ethical and technical dilemmas may be circumvented. This review will focus on the potential of adult bone marrow derived cells and umbilical cord blood stem cells for cell replacement and repair therapies of the central nervous system. The various isolation protocols, phenotypic properties, and methods for in vivo and in vitro neural differentiation of mesenchymal stem cells/marrow stromal cells (MSC), hematopoietic stem cells (HSC), multipotent adult progenitor cells (MAPCs), and umbilical cord blood stem cells (UCBSC) will be discussed. Current progress regarding transplant paradigms in various disease models as well as in our understanding of transdifferentiation mechanisms will be presented.
[Back to top]
Neural Stem Cell Plasticity: Recruitment of Endogenous Populations for
Regeneration
Lower vertebrates, such as fish and urodele amphibians can regenerate complex body structures including significant portions of their central nervous system by recruiting progenitor cells to repair the damage. Significant ability to regenerate the nervous system is observed also during development in higher vertebrates, for example in the chick spinal cord, though it is not yet clear whether this involves de novo neurogenesis, in addition to axonal re-growth, also at the latest stages of development permissive for regeneration. The mechanisms underlying recruitment of progenitor cells in response to injury, particularly within the nervous system, are still poorly understood. Although it has been suggested that some neurogenesis can be induced even in regions of the adult mammalian brain, this potential is largely lost with evolution and development. Following tail amputation in urodeles, an ependymal tube, resembling a developing neural tube, forms from ependymal cells that migrate from the cord stump towards the terminal vesicle, and elongates by cell proliferation. The new cord might originate from stem cells, with possibly only a subset of ependymal cells displaying such properties, or via a process of dedifferentiation / transdifferentiation of these cells. Data currently available are more supportive of the latter hypothesis. Whereas dedifferentiation is a well demonstrated phenomenon in a broad range of urodele tissues, transdifferentiation seems to occur less widely and in extreme circumstances, and may contribute significantly to regeneration only in a few cases. In higher vertebrates it is even less clear how common and relevant to repair transdifferentiation is, as much work both in favour and against it has recently been published. However, the existence of multipotent neural progenitors in adult mammalian CNS and of a much higher neural cell plasticity, at least in vitro, than previously believed, encourages the view that if we were to better understand progenitor cell recruitment and plasticity in species where it does occur spontaneously, we might then find the way to make it happen effectively in mammals.
[Back to top] Retina
Repair, Stem Cells and Beyond
Tracy Haynes and Katia Del Rio-Tsonis
In this review, we will explore several studies where stem cells from neural, non-neural and even embryonic cells have been used as potential sources to repair the damage retina. In addition, we will also discuss the possibility of inducing retina regeneration by transdifferentiation of cells present in existing eye tissues, such as, the Retinal Pigmented Epithelium (RPE), the Pigmented Ciliary Margin (PCM) and Müller glia cells.
[Back to top] Progenitor
Cell Properties and the Engineering of Tissues
Janet Hardin-Young and Nancy L. Parenteau
The need for human tissue to aid in organ repair or provide a curative therapy is well known. In this review, we discuss the properties of the epidermal keratinocyte progenitor cell and the biology that underlies the methods that have helped deliver cell therapies to the clinic using this cell type. In addition, we review what the keratinocyte and the dermal fibroblast have taught us about the potential immunogenicity of allogeneic cells. The many observations made using the keratinocyte have broader biological implications and we discuss how this body of work parallels neural stem cell culture and might help us interpret cell behavior in the pancreas.
[Back to top] Neurotransmitters
and Substances of Abuse: Effects on Adult Neurogenesis
T.A. Powrozek, Y. Sari, R.P. Singh and F.C. Zhou
Neurogenesis in the adult brain is now a well-recognized
phenomenon. The compelling subject of interest now is that besides the intrinsic,
what are the environmental factors which affect neural stem cells ability to
maintain themselves and enter the pool of the adult brain. While the molecular
and cellular mechanisms that regulate this process remain to be elucidated,
substantial data implicate common pathways involving action of
neurotransmitters through neurotrophic factors to regulate the neural stem
cells. This transmitter-mediated neurotrophic factor pathway could be altered
by extrinsic environmental factors including enriched environment, exercise,
stress, and drug abuse (i.e. alcohol, opioid, methamphetamine). Our special
attention focuses on the role of neurotransmitters; among them are serotonin
(5- HT), glutamate and gamma-amino-butyric acid (GABA). Substances of abuse including
alcohol, which may interact through these neurotransmitters and neurotrophic
factors to affect neurogenesis, are also reviewed.
[Back to top] Regulation of
Neurogenesis and Angiogenesis in Depression
Samuel
S. Newton and Ronald S. Duman
The characterization of depression as a treatable disease has led to very significant research aimed at understanding disease mechanisms and treatments. Antidepressant therapy, employing chemical and non-chemical antidepressants are quite successful in treatment of the disorder although their mechanism of action is not well understood. Basic research with rodent models is providing vital evidence concerning the molecules and mechanisms involved in antidepressant action. The regulation of neurotrophic and growth factors observed after antidepressant administration is seen as playing an important role in modulating the therapeutic effects of antidepressants. Recently, adult neurogenesis or the birth of new neurons has emerged as a physiological phenomenon necessary for the behavioral response of antidepressant treatment. Equally interesting are correlative associations between neurogenesis and angiogenesis or the birth of new vasculature. Growth factors such as brain derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) play vital roles in both these phenomena making the interplay of neurogenesis and angiogenesis an exciting avenue of brain research. This review will focus on the research that has led us to this current understanding of antidepressant action in context with the pathophysiology of depression using examples from basic, preclinical and clinical investigations.
[Back to top] Use of Human
Umbilical Cord Blood (HUCB) Cells to Repair the Damaged Brain
Mary B. Newman, Dwaine F. Emerich, Cesario V. Borlongan,
Cyndy Davis Sanberg and Paul R. Sanberg
Neurodegenerative diseases as well as acute center nervous system (CNS) injuries remains a problematic and frustrating area of medicine in terms of treatments and cures, which is mostly due to the complex circuitry of the CNS along with our limited knowledge. Therapeutically, the last two and a half decades have offered new hope for those suffering from neurodegenerative diseases or injuries with advent of new drug discoveries and cellular therapies. Cell transplantation is a compelling and potential treatment for certain neurological and neurodegenerative diseases as well as for acute injuries to the spinal cord and brain. The hematopoietic system offers an alternative source of cells that is easily obtainable, abundant, and reliable when compared to cells obtained from fetal or embryonic origins. Human umbilical cord blood (HUCB) cells have been used clinically for over ten years to treat both malignant and non-malignant diseases. With in the last five years these cells have been used pre-clinically in animal models of brain and spinal cord injuries, in which functional recovery have been shown. This paper reviews the advantages, utilization, and progress of HUCB cells in the field of cellular transplantation and repair.
[Back to top] Cell-Replacement
Therapy with Stem Cells in Neurodegenerative Diseases
Vincenzo Silani and Massimo Corbo
In the past few years, research on stem cells has expanded greatly as a tool to develop potential therapies to treat incurable neurodegenerative diseases. Stem cell transplantation has been effective in several animal models, but the underlying restorative mechanisms are still unknown. Several mechanisms such as cell fusion, neurotrophic factor release, endogenous stem cell proliferation, and transdifferentiation may explain positive therapeutic results, in addition to replacement of lost cells. The biological issue needs to be clarified in order to maximize the potential for effective therapies. The absence of any effective pharmacological treatment and preliminary data both in experimental and clinical settings has recently identified Amyotrophic Lateral Sclerosis (ALS) as an ideal candidate disease for the development of stem cell therapy in humans. Preliminary stem transplantation trials have already been performed in patients. The review discusses relevant topics regarding the application of stem cell research to ALS but in general to other neurodegenerative diseases debating in particular the issue of transdifferentiation, endogenous neural stem cell, and factors influencing the stem cell fate.