Current Neurovascular Research - Volume 1, Issue 3, 2004

From its initial conception, this special issue on stem cells was intended to showcase the potential therapeutic utilityof stem cells as well as to initiate scientific debate concerning the ability of stem cells to lead to viable tissueregeneration as well as functional plasticity in an organism during acute or chronic injury. In general, stem cellsbegin as undifferentiated cells, but have the ability to yield progeny cells that may lead to self-renewal, non-renewing progenitors, or terminally differentiated cells. Stem cells possess different capacities and are classifiedaccording 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 cognizantof the present hurdles facing stem cell research. Debates concerning the use of human embryonic stem cells haverecently been fueled with the recent publication that reports the derivation of a pluripotent embryonic stem cell linefrom a cloned human blastocyst (Hwang, WS et al., 2004). Yet, prior to the consideration of any clinicalapplications for stem cells in regards to human disease, significant additional studies are required on several frontsas 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 possibledevelopment of further injury in damaged tissue during stem cell applications, such as by the potential generation ofneoplastic cells from undifferentiated stem cells. These challenges can be overcome with the proper support in aclimate that requires continual reassurance and education to allay any fears that specific ethical concerns will not bebreached. Timely additional work that reports the availability of seventeen new embryonic stem cell lines thatreproducibly differentiate in vitro and in vivo into cell types from all three embryonic germ layers (Cowan, CA etal., 2004) (barred at this time from use in work funded by United States federal sources) further assists us inunderstanding 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 theobstacles to be overcome in stem cell research will bring both the scientific community and the public closer toobjectively assessing the potential promise of stem cells for the treatment of clinical disease. In the series ofmanuscripts that follows, the role of stem cells from various sources are discussed as well as their developmentalcapacity for “transdifferentiation”, the transition of a cell from a specific tissue lineage into a different tissuelineage. Our Guest Editor, Dr. Feng C. Zhou, has performed an exemplary job in assembling an outstanding groupof contributors for this issue to provide an overview and platform for present and future considerations of thepotential role of stem cells to treat human disease, especially those that involve neurodegenerative disorders.

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.

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.

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.

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 Muller glia cells.

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.

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.

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.

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.

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.