Stem cells and neurologic diseases: hope or hype?

Abstract

Future NeurologyVol. 2, No. 5 EditorialFree AccessStem cells and neurologic diseases: hope or hype?Emily Potter, Melissa Cardona & Douglas KerrEmily PotterJohns Hopkins University, Institute for Cellular Engineering, Neuroregeneration Program 760, Broadway Research Building, 733 N Broadway, Baltimore, MD 21287-6965, USA. Search for more papers by this authorEmail the corresponding author at epotter6@jhmi.edu, Melissa CardonaJohns Hopkins University, Institute for Cellular Engineering, Neuroregeneration Program 760, Broadway Research Building, 733 N Broadway, Baltimore, MD 21287-6965, USASearch for more papers by this author & Douglas Kerr† Author for correspondenceJohns Hopkins University, Department of Neurology, Pathology 627C, 600 North Wolfe Street, Baltimore, MD 21287-6965, USA. Search for more papers by this authorEmail the corresponding author at dkerr@jhmi.eduPublished Online:23 Aug 2007https://doi.org/10.2217/14796708.2.5.471AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Are stem cells the therapy of the future for virtually all neurologic diseases from Alzheimer’s disease to Zellweger syndrome? Or are they the hype of overzealous scientists overinterpreting data from animal models that only vaguely mimic human disease? The answer is neither. Stem cells will likely be a powerful part of the therapeutic armamentarium of neurologists in years and decades to come. In some cases they will slow disease progression. In others, stem cells, combined with other therapies, may modestly increase function. And rarely, stem cells may markedly reduce disability or cure disease. Conversely, in some diseases stem cells are likely to never be effective, and the journey from animal model success to clinical therapy will be longer than many expect. This editorial will assess the likely future role of stem cells in combating neurologic diseases 5–10 years in the future. We will discuss the biological foundation and current applications of stem cells, focusing on two specific areas: endogenous neural stem cells and their capacity to repair injury, and myelinating precursors and their application to demyelinating disorders.Promise of stem cellsThe promise of stem cells is an appealing one that has captured the attention of the lay public. Everybody knows individuals who have suffered greatly owing to to injury or disease and it is powerful and emotionally appealing to think that their suffering and disability could be reduced or eliminated. It is a regular occurrence that some medical advance is discussed in the media. But it is rare that the advance promises to reduce suffering. Rather, most promise more effective treatments for diseases or better diagnoses. Since advocates of stem cells promise more, they have garnered public attention probably in excess of their scientific advances. Many feel that stem cells have the potential to treat, cure and restore function to patients suffering from almost any disease. And for some, the model of how stem cells will work is the ‘gas-station’ model: come in to the hospital or clinic, get your stem cells and go home with the disease ameliorated or eliminated.The reality will be much more sobering on several fronts. Some diseases will be intractable to recovery or even slowing of disease by virtue of the mechanism or extent of neural injury. At their best, stem cell therapies will need to be combined with prolonged rehabilitation therapies to ‘retrain’ the nervous system, much as the prolonged rehabilitation after an organ or joint replacement. But even with those cautionary notes, there is the likelihood that we will be able to alter the course of devastating neurologic diseases using stem cells in the future, and we will begin to see this potential in human patients in the next 5–10 years.Biological underpinning of stem cellsStem cells have the potential to differentiate into mature cell types by responding to developmental cues appropriate to that cell type. These developmental cues may be provided when culturing the stem cells or after transplantation, by the local microenvironment within the transplanted site.Recent advances have suggested that stem cells can be specifically and efficiently directed toward distinct cell lineages in vitro. These cells can then be utilized in biological studies of those cell types in vitro. Alternatively, they can be directed toward a mature cell type prior to transplantation to enhance the efficiency of engraftment of that cell type in vivo. However, it is also clear that in order to take advantage of this capability, scientists must understand the developmental factors required for inducing a particular cell lineage and we understand very little of this biology at present.Applications of stem cells in neurological diseasesThere are several categories of uses for stem cells in the research and treatment of neurological diseases. First, stem cells can be utilized as a biological tool to understand disease. For example, the ability to isolate and propagate embryonic stem (ES) cell lines from a variety of genetically defined animal models of human disease and to efficiently direct ES cells toward particular neural lineages allows researchers to examine the abnormal cellular and molecular processes in these cells. The goal is to create a cell-culture model of human disease that could serve as a valuable tool in understanding disease and in screening potential therapies. Second, the potential of endogenous stem cells present in the mammalian nervous system can be harnessed and expanded to repair damaged tissue. It is increasingly clear that endogenous stem cells exist within multiple regions of the mammalian nervous system, that they have the potential to guide extensive neural repair and that they fail to repair the nervous system in most instances of neural injury. By gaining an understanding of the cues that guide endogenous stem cell function, researchers may be able to harness the ability of these cells to repair neural tissue. Finally, stem cells or committed progenitors derived from stem cells can be transplanted into the injured nervous system as a therapeutic strategy.Transplanted cells may serve a therapeutic role in any of a number of ways (presented in order of increasing complexity): they may provide trophic support to host cells, slow a degenerative process, facilitate axonal growth or glial function, secrete neurotransmitters deficient in the host, deliver toxic substances to CNS tumors, differentiate into oligodendrocytes and myelinate host axons, or differentiate into neurons and either form neuronal bridges across disconnected populations or replace damaged neuronal circuits.However, arguably, the application of stem cells to neurological diseases is much more complex than in other systems such as the endocrine or musculoskeletal systems. Several challenges unique to the nervous system are as follows: • The need to integrate into a sophisticated array of interconnected cells that extend over great distances;• The absence of developmental cues in adults that guided the establishment of neural networks during development, thus making regeneration more difficult;• The possibility in progressive or recurrent neurologic diseases that the transplanted cells may be attacked and injured.Endogenous neural stem cells in health & diseaseStem cells exist within the adult mammalian nervous system and these stem cells contribute to newly born, functioning neurons (termed neurogenesis) throughout the life of all mammals, including humans. Although neurogenesis only occurs in discretely defined regions of the brain under normal conditions, endogenous progenitor cells can be recruited to non-neurogenic areas following injury and may contribute to repair of the injured area. Endogenous stem cells also exist within the spinal cord, although these cells do not contribute to the generation of new neurons under normal conditions or following injury.It is interesting to note, however, that spinal cord stem cells do produce neurons when transplanted into the hippocampus, a known neurogenic region. Therefore, these spinal cord stem cells have the potential to become neurons but are prevented from doing so by the host environment. It is becoming increasingly clear that failure of endogenous neurogenesis contributes to clinical disorders such as major depression and memory impairment. Several laboratories are developing strategies to enhance the efficiency of neurogenesis and, therefore, it may ultimately be possible to utilize endogenous stem cells to modulate a broad array of neurological diseases.Stem cells & remyelination in the futureTo restore function in demyelinating diseases, such as multiple sclerosis and transverse myelitis, a stem cell must be guided from proliferating progenitor to mature, myelinating oligodendrocyte. Whether endogenous or transplanted, it has become apparent that a number of obstacles block the potential of stem cells to follow such a fate. While inflammation may provide an initial and welcome stimulus for oligodendrocyte progenitor cell (OPC) proliferation following a demyelinating insult, ultimately it appears to impede functional remyelination. In the inflamed CNS, OPCs may follow cues that induce differentiation of astrocytes rather than oligodendrocytes. Formation of an astroglial scar provides further hindrance to remyelination. Future strategies that aim to preserve axonal function through remyelination must address these inflammatory-imposed blocks.In cases where the endogenous population of OPCs may be depleted, such as following multiple demyelinating events, transplantation of exogenous stem cells may be an attractive option. However, central questions such as when (in terms of cellular maturation) and where these cells should be transplanted remain incompletely addressed.If a stem cell is transplanted too early in the differentiation process, it may fail to adopt a myelinating phenotype. Conversely, transplantation of a more committed cell may compromise migratory potential so that it fails to reach the target region of demyelination. Our ability to strike the correct balance and facilitate remyelination will be greatly aided by the ongoing studies examining OPC migratory and differention cues.Political realities in the USAIt is unclear how quickly we will see stem cells become a clinical reality for several reasons. In the USA, researchers can receive federal funding for adult stem cells and for study on a limited number of ES cell lines. Most researchers believe these ES cell lines (the federally approved ones) are biologically corrupt and dangerous to use, in part because of genomic instability. Any preclinical or clinical research on ‘nonapproved’ ES cell lines must be funded by philanthropy or private industry. Because of the complexity involved in translating stem cell biology into a therapeutic reality, the amount of money required is daunting.Hundreds of millions of dollars are required to fund a large trial. The commercialization strategy for a company is complex and in many cases it is not clear that a profit can be made from stem cell therapy for any single neurologic indication. This is where the federal government should be advancing science and advancing the care of people with disabling neurologic diseases. We, as a society, should not be driven in our advance of science by whether a profit can be made. The NIH has long advanced science because it serves its mission, which is the following: science in pursuit of fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to extend healthy life and reduce the burdens of illness and disability.Currently, the NIH has abrogated that role because of federal restrictions imposed upon it. The impact of this failure will be felt for decades to come as stem cell progress is slowed, clinical trials do not get started and other countries with greater governmental support seize the lead in this scientific arena.ConclusionSeveral conclusions can be drawn about the current and future use of stem cells in the nervous system: • Stem cells exist in the adult mammalian nervous system and the potential to augment and harness their function exists if the embryological and developmental principles that guide their differentiation can be fully understood;• The application of developmental principles leading to differentiation of stem cells into specific mature cell types is a dramatic advance and will become the most significant contribution to the application of stem cells in neurological diseases. This allows researchers to recreate differentiation and to analyze countless numbers of highly selected, mature cells in culture. The application of modern biological techniques such as high-throughput screening, proteomics and pharmacogenomic strategies to precisely define abnormalities in development may result in the development of novel therapies;• Exogenous stem cell transplantation is not the potential cure-all for neurological disease that it has been reported to be. The physiological complexities of the mature nervous system will always preclude widespread replacement following injury or damage;• It is clearly not necessary to achieve widespread replacement of the nervous system in order to enact meaningful functional recovery. The nervous system is a very plastic system and the attainment of even rudimentary remyelination or the re-establishment of simple neural networks, for example, can lead to restoration of function. The re-establishment of even a fraction of the initial complexity of a region of the nervous system may allow for augmentation and maintenance of this functional recovery using other strategies, such as trophic factor delivery and rehabilitation;• The type of stem cells that will be most beneficial will depend upon the setting in which they are used and the desired goal. It is clear that bone-marrow-derived and mesenchymal stem cells may have therapeutic benefit in neurological diseases. They may support host cells and they may halt or slow a degenerative process. However, it is clear that they are less likely than embryonic stem cells and fetal neural stem cells (NSCs) to differentiate into mature neural cells (i.e., oligodendrocytes and neurons). Thus, if the particular application requires the generation of new neurons, ES cells and fetal NSCs are more likely to be the most optimal sources;• Both biological and political hurdles remain to be overcome before stem cells can provide a therapeutic strategy in neurological diseases. However, it is a virtual certainty that stem cells will be used in neurological diseases within the next 2–5 years. It is realistic to believe that stem cells will be used clinically, not as a cure-all but as part of a therapeutic armamentarium. Some patients may get better, but as with any therapy, some patients may get worse. The key, however, will be in applying the right cell type to the right disease and conveying the right amount of expectation to the patient. Only then will stem cells become clinically relevant tools for the neurologist in the future.Future perspectiveThe near future promises several small trials using stem cells. A Phase I trial using human fetal tissue has been conducted in the USA and was found to be safe in patients with chronic spinal cord injury. Additionally, there are several planned Phase I trials of cell-based interventions for neurologic conditions. Athersys Inc. (OH, USA) plans to carry out a clinical trial using the Multistem™ platform based on the multipotent adult progenitor cell technology in Hurler’s disease, a lethal pediatric syndrome caused by enzyme deficiency. BrainStorm Cell Therapeutics (Israel) plans to carry out a trial of bone marrow-derived cells in Parkinson’s disease. Geron (CA, USA) plans to carry out a clinical trial using human ES cells in patients with acute spinal cord injury.Q Therapeutics, Inc. (UT, USA) plans a clinical trial with glial-restricted precursors in patients with the focal demyelinating disorder transverse myelitis, and Living Cell Technologies, Ltd (Australia, New Zealand, Italy and RI, USA) will study porcine choroid plexus brain cells encased in a biopolymer capsule to avoid rejection in patients with Huntington disease.Where we go after that depends on many things. First and foremost, will these trials demonstrate hints of the effectiveness of stem cells in treating neurologic disease? No trials promise to definitively demonstrate that stem cells are effective, as they involve small numbers of patients and often have an open-label design, but rather hope to be ‘suggestive’, therefore justifying larger, more complex clinical trials. Second, do these trials reveal any adverse outcomes, including patient injury or death? If such an outcome occurs, as it did in gene-therapy trials, the field of stem cell transplantation will be slowed with appropriate requirements for more preclinical studies. But if they do demonstrate the potential for benefit, it may be that large pharmaceutical companies and federal governments throughout the world extend this research forward.The field is likely to proceed in stops and starts. There will be hints of an amazing future interspersed with confusing and potentially sobering results. Ultimately, most of us in neurology practice today will be seeing patients who have received stem cell therapies. It will be a therapy that isn’t experimental anymore. It will be part of the therapeutic armamentarium available to treat patients. And we will be able to offer patients hope for not only halting or slowing their disease, but for reducing or curing it.Executive summary• Stem cells are defined as precursor cells that have the capacity to self-renew and to generate multiple mature cell types.• Embryonic stem (ES) cells are derived from the inner cell mass of cultured embryos at the blastocyst stage. These cells are pluripotent, as defined by the ability to form many mature cell types in tissue culture or by the generation of chimeric mice on injection into recipient blastocysts.• Several sources of stem cells exist, including blastocysts frozen after in vitro fertilization clinics (from which ES cells are derived), fetal and adult tissues.• Endogenous stem cells exist within the adult nervous system of higher mammals, generate functional neurons throughout the life of all mammals and can be successfully isolated and expanded from specific regions of the brain and spinal cord.• The biological underpinning of the use of stem cells in neurodegenerative disorders is that stem cells have the potential to differentiate into mature cell types by responding to developmental cues appropriate to that cell type.• Researchers have recently begun to develop strategies to specifically direct the differentiation of stem cells toward particular mature cell lineages in vitro. This is a critical advance in stem cell biology since it allows researchers to generate a potentially inexhaustible supply of relatively pure, committed or fully-differentiated mature cell types. These cells can then be utilized in biological studies of diseases in vitro or can be transplanted to treat disease.• Clinical trials with stem cells will begin in the next few years, but the full potential of stem cells will take decades to realize.Financial disclosureThe authors have no relevant financial interests including employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties related to this manuscript.FiguresReferencesRelatedDetails Vol. 2, No. 5 Follow us on social media for the latest updates Metrics History Published online 23 August 2007 Published in print September 2007 Information© Future Medicine LtdFinancial disclosureThe authors have no relevant financial interests including employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties related to this manuscript.PDF download