NEW YORK CITY— The promise of neurodegenerative disease treatment strategies lies in a more in-depth understanding of the basic biology of regional neural stem cells and their progeny, believes Mark F. Mehler, MD—or more accurately, better knowledge of the developmental properties of specific nerve cells and of their mature steady- state functioning and responses to environmental stressors. “We know little, even though thousands of investigators are studying the scientific reason, about the basic biology [of the cell]. The important thing to remember is that unless we understand more about the basic biology of nerve cell subtypes, it’s going to be very hard to effectively treat or even contemplate cures for these chronic, debilitating, and relentlessly progressive diseases.”

The utility of stem cells in complex diseases such as Alzheimer’s disease, Parkinson’s disease, and other degenerative dementias rests in the pro- vocative evidence suggeting that these diseases do not start with the aging brain, Dr. Mehler said, but rather during brain development—in utero. “If that turns out to be true, then our ability to understand how to treat these diseases changes dramatically and pushes back the clock to where we can intervene.” Intervention before damage is done to multiple areas of the nervous system where conventional treatments are not effective, that is. His comments were made at the Ninth Annual Comprehensive Approach to Dementia update at the New York Academy of Medicine.

While most research in this area has focused on pathological models of aging, Dr. Mehler, Alpern Professor and University Chair at the Saul R. Korey Department of Neurology, Director of the Institute for Brain Disorders and Neural Regeneration at the Albert Einstein College of Medicine, and Neurologist-in-Chief at Montefiore Medical Center, Bronx, New York, has a different approach. “We believe that the future of stem cell research is to regenerate tissue damaged by disease and to ultimately effect cures; this has to do with the ability to activate endogenous stem cells that all of us have present in the adult brain. And it’s only if we can figure out the way to unleash the potential of these cells in ways that recapitulate how they were originally developed during early life that we can effect a cure.”

HYPE, PROMISE, PERIL, AND POLITICS

Why is there “so much hype and so much promise? And so much peril and so much politics” surrounding stem cells? Because due to their unique biologic properties, stem cells, according to Dr. Mehler, are “magic cells.” Among the properties that make stem cells so valuable:

1. Stem cells exhibit self-maintenance/self-renewal. Because stem cells have the ability to divide and regenerate an exact copy, they can give rise to new stem cells that have the potential to participate in both repair and development.

2. Stem cells undergo exponential cell proliferation. Although stem cells represent less than 0.3% of the total cell population of the brain, Dr. Mehler noted, they have the ability to expand rapidly in response to environmental stimuli.

3. Stem cells give rise to more lineage-restricted intermediate progenitors. Initially, stem cells are multipotential and can give rise to every type of cell within the nervous system. Over time, however, they become progressively restrictive. The virtue of this is that “we can regulate them at these different junctures to control exactly what cells they turn into.”

5. Stem cells can generate appropriate replacement cells in response to injury.

During early development, stem cells give rise to neuronal cells, and later in development they give rise to glial cell types that support neuronal structure and function. Eventually, Dr. Mehler explained, the stem cells change properties as well as location, both very important factors when one considers how to genetically reprogram these extremely versatile cells.

SIGNAL AHEAD

Although it was once believed that stem cells in the brain were all the same, it is now recognized that they differ depending on their regional location. Prior to their deposition within paramedian generative zones through the brain and spinal cord, precursors of these regional neural stem cells are exposed to a complex array of graded signaling proteins called cytokines, growth factors, and gradient morphogens that endow them with unique cellular properties based on the three-dimensional axes of the evolving nervous system.

Although it was once believed that stem cells in the brain were all the same, it is now recognized that they differ depending on their regional location. Prior to their deposition within paramedian generative zones through the brain and spinal cord, precursors of these regional neural stem cells are exposed to a complex array of graded signaling proteins called cytokines, growth factors, and gradient morphogens that endow them with unique cellular properties based on the three-dimensional axes of the evolving nervous system.

POTENT RESERVOIRS

“The good thing is that all of us, even during adult years, have potent reservoirs of stem cells that participate in repair. And part of our challenge is to figure out why these cells are not being properly utilized in response to injury in the case of head trauma, stroke, multiple sclerosis, and neurodegenerative diseases,” Dr. Mehler said. Animal models have indicated that stem cells can be programmed in adult life to participate in repair.

The challenge, Dr. Mehler noted, is to figure out why the endogenous stem cells are not actively and effectively recruited to participate in repair. The stem cells are in a very dynamic steady state and participate in a spectrum of essential cellular processes, each of which may be utilized or modulated to promote tissue remodeling and regeneration. Such stem cells may also remain dormant for extended periods of time during normal adult life or following injury responses. Aside from remaining dormant, the stem cells can experience apoptosis during development, a fate that is also seen in neurodegenerative disease such as Alzheimer’s disease. Early in development these stem cells undergo a number of symmetric divisions needed to generate the exact number of precursors of the mature nerve cell subtypes needed in a specific brain region. Subsequently, progeny of these symmetric cell divisions undergo asymmetric cell division where they subsequently give rise to more lineage-restricted intermediate progenitors and then sequentially into specific neuronal and glial cell subtypes.

Stem cells also display the capacity to undergo transdifferentiation, Dr. Mehler explained. “And what that means is that these cells can change their cell fate and function—from a neural cell fate to a hematopoietic cell fate to an immunological cell fate.” What transdifferentiation tells us, he said, is that “there are ways we can manipulate genes that are involved in the process of forming nerve cells as opposed to skin cells as opposed to blood cells. And quite valiantly, part of our mission as physician-scientists is to find combinatorial profiles of factors that will allow us to manipulate genes in ways that will allow more effective future regenerative therapies.” This will likely involve intricate manipulation of epigenetic factors and mechanisms that will differentially modulate the expression of key individual genes or networks of genes simultaneously to reprogram the final fate and functions of these stem cells.

UNDIFFERENTIATED POSSIBILITIES

Stem cells can be cultured and exposed to various factors; a single stem cell can be grown into a uniform population. Dr. Mehler elaborated: When cultured, the cells initially express one or more stem cell marker proteins, but they do not express markers for neuronal or glial cell subtypes—meaning that they are undifferentiated and have the potential to give rise to a wide variety of mature cell types depending on the subsequent environmental signals that they receive. Detailed biophysical profiling has determined the unique cellular properties of undifferentiated cells based on the types of cell surface ion channels, cell adhesion molecules, growth factor receptors, gap junction proteins, and neurotransmitter and neuropeptide receptors they possess.

“We can study the detailed properties of regional neural stem cells by culturing them as single cells from specific brain regions and exposing them to specific growth factor paradigms or gene manipulation paradigms to generate pure clones of more differentiated cells with specific cellular and functional properties,” said Dr. Mehler. In the forebrain, for example, a single neural stem cell can give rise to radial glial intermediates that are precursors of excitatory neurons, which make up 80% of the cellular complement of the mature cerebral cortex. As he summarized, “So from a single stem cell you generate a pool of these regulatory glia.” Specific regions of the cerebral cortex are involved in complex higher cognitive functions, and these regional domains are thought to be organized into discrete vertical cortical columns or functional units by specific sets of cell-to-cell communications directed by specialized gap junction channel proteins that organize cells into integrated signaling units.

There are certain deep continuous paramedian brain regions from the forebrain (surrounding the lateral ventricular system) to the tip of the spinal cord (surrounding the central canal) that are the remnants of the inner lining of the early embryonic neural tube that represent stem cell regenerative zones. Specific regions of the stem cell regenerative zones are organized into functional domains that give rise to specific types of neural stem cells following the induction of patterning, and later, specification genes under the influence of complex three-dimensional spatial gradients of soluble signaling molecules, called “gradient morphogens.” The differential elaboration of region-specific profiles of cascades of effector genes is instrumental in endowing regional stem cells and their progeny with unique structural and functional properties required to form intact, versatile neural networks. Dr. Mehler believes that in neurodegenerative diseases, developmental alterations in these early and seminal signaling events result in subtle misspecification of regional neuronal cell subtypes, rendering them more vulnerable to later cellular injury, dysfunction, and eventual death in response to environmental cues that are normally nonpathogenic.

TIMING IS EVERYTHING

Echoing earlier sentiments, Dr. Mehler emphasized that development figures prominently in the genesis of neurodegenerative disease. “Part of what we believe is going awry early in life is that the spatial codes and temporal codes are not properly elaborated, and because of that you get premature expression of certain genes, premature expression of certain cell types, misexpression of cell types, and developmental dysregulation of cells.”

The timing of gene expression indicates to researchers “when and how we need to turn on and off these specific developmental genes. What we also learn by studying these genes is the associated growth factors and cytokines that are required for long-term cellular viability to allow long distance migration and maturation into specific temporally defined neuronal and glial subtypes,” he clarified. From these seminal developmental processes, investigators are able to compile “very detailed stem cell lineage maps akin to genetic pedigrees that actually give us clues to the very sophisticated types of genetic and epigenetic manipulations that we need to perform” in order to refine treatment strategies.

IT’S ALL IN THE GENES

Utilizing mouse models of specific neural patterning and specification genes, Dr. Mehler has discovered the combinatorial codes of genes involved in the elaboration of the different neuronal and glial cell subtypes that make up the functioning adult forebrain. These studies have revealed that each of these genes participates in a successive array of developmental functions and is regulated, in turn, by adjacent sets of genes that help to modulate the spatial and temporal expression of each gene; this allows the genes to precisely regulate the properties of evolving neural cell species and their integration into functional neural networks that contain unique memory and informational traces. These experimental observations also indicate that a glitch in the developmental process of these specialized cells may predispose the cells to undergo delayed apoptosis, something researchers suspect occurs in neurodegenerative disorders.

“We at long last have begun to unlock the code for how to turn on and off genes,” acknowledged Dr. Mehler. There are many methods by which to activate or repress genes and a range of factors involved in modulating them; it is believed that in neurodegenerative disease, genes are turned on and off in aberrant ways. Recent technology allows the regulation of gene expression by changing specific elements of stem and more lineage-restricted progenitor species. More importantly, Dr. Mehler continued, “We cannot only regulate individual genes but banks or clusters of genes at the same time or at varying time intervals.”

THE FUTURE

Central nervous system regeneration is the wave of the future, according to Dr. Mehler. Neurodegenerative diseases are among the most complex diseases of the brain in that they do not affect just one area of the brain but many, he said. Therefore, transplantation of single stem cells or even multiple stem cells is not going to be clinically efficacious. “The only way that you can actually regenerate areas of the brain that have been damaged is to activate endogenous stem cells,” Dr. Mehler stated. “Why does this process not occur normally? When we injure our hands with a cut, it heals; when we have an internal injury, it heals; when we surgically remove the majority of the liver, it heals. But in every brain injury or nervous system disease state, there is the absence of an effective, enduring, and selective response of appropriate regional neural stem cells we know are there.”

Use of endogenous stem cells in treating neurodegenerative disorders is not such a distant goal, Dr. Mehler implied. “Whenever anyone asks me to predict these things, I’m always wrong—in a conservative direction,” he related. “Because when you follow the field of biomedical research, you realize that every two years or so some extraordinary new discovery is uncovered to revolutionize the field.” He continued, “In fact, we are planning some of the first endogenous stem cell activation trials using experimental paradigms adapted from the cancer chemotherapy literature. Our previous studies have identified specific hematopoietic cytokines and growth factors that have the potential to promote targeted endogenous neural stem cell activation and lineage maturation in response to neural cell injury when administered by peripheral infusion.”

NR

—Heidi W. Moore

Suggested Reading
Abrahams JM, Gokhan S, Flamm ES, Mehler MF. De novo neurogenesis and acute stroke: are exogenous stem cells really necessary? Neurosurgery. 2004;54:150-156.
Gokhan S, Mehler MF. Basic and clinical neuroscience applications of embryonic stem cells. Anat Rec. 2001; 265:142-156.
Mehler MF, Kessler JA. Hematolymphopoietic growth factors. In: Aminoff M, Daroff R, eds. Encyclopedia of the Neurological Sciences. Vol. 2. San Diego, Calif: Academic Press; 2003:534-538.
Mehler MF. Regional forebrain patterning and neural subtype specification: implications for cerebral cortical functional connectivity and the pathogenesis of neurodegenerative diseases. In: Hohmann C, ed. Cortical Development: Results and Problems in Cell Differentiation. Vol. 39. Heidelberg, Germany: Springer-Verlag; 2002: 157-178.
Mehler MF. Mechanisms regulating lineage diversity during cerebral cortical neurogenesis and gliogenesis. In: Hohmann C, ed. Cortical Development: Results and Problems in Cell Differentiation. Vol. 39. Heidelberg, Germany: Springer-Verlag; 2002:27-52.
Mehler MF, Kessler JA. Cytokine effects on CNS cells: implications for the pathogenesis and prevention of stroke. In: Feuerstein G, ed. Stroke and CNS Inflammation, Progress in Inflammation Research. Basel, Switzerland: Birkhauser-Verlag; 2001:115-139.
Mehler MF, Gokhan S. Developmental mechanisms in the pathogenesis of neurodegenerative diseases. Prog Neurobiol. 2001;63:337-363.
Mehler MF, Gokhan S. Mechanisms underlying neural cell death in neurodegenerative diseases: alterations of a developmentally-mediated cellular rheostat. Trends Neurosci. 2000;23:599-605.
Van De Water T, Kojima K, Tateya I, et al. Stem cell biology of the inner ear and potential therapeutic applications. In: Turksen K, ed. Adult Stem Cells. Totowa, NJ: Humana Press; 2004:269-288.

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