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Precursor Cell Dysfunction as a Critical Component of Disease Pathogenesis: Precursor Cell Diseases as a Major Clinical Problem

Project Overview

While one of the central interests in the field of stem cell medicine is the use of cell transplants to repair damaged tissue, we also have been interested in the question of whether abnormalities in precursor cell function might lie at the heart of understanding many diseases. Our various studies on this problem raise the possibility that such abnormalities are likely to contribute to the pathogenesis of many developmental maladies.

The first disease of abnormal development we became interested in was hypothyroidism, which is associated with deficiencies in myelination - and studies by ourselves and others indicate that one important contributor to this myelination defect is likely to be a central importance of thyroid hormone in promoting the generation of oligodendrocytes from dividing O-2A progenitor cells. Clonal studies on O-2A progenitor cells isolated from the embryonic cortex and grown in the presence of PDGF as a basal mitogen revealed that cultures grown in the presence or absence of thyroid hormone both generated oligodendrocytes at a time in vitro that corresponded with the time that oligodendrocytes first appear in vivo (Ibarrola et al., 1996). Cultures exposed to thyroid hormone, however, contained six times as many oligodendrocytes as those grown in the absence of thyroid hormone. Studies on thyroid hormone-deficient rats showed that these animals also contained about one-sixth the number of oligodendrocytes during the earliest stages of myelination as did control animals.

Studies by the Mayer-Pröschel laboratory next discovered that precursor cell dysfunction is a potential contributor to myelination disorders caused by iron deficiency, a problem that affects very large numbers of children world-wide. Mayer-Pröschel and colleagues showed that even moderate iron deficiency during pregnancy was associated with marked iron deficiency in the fetal brain (contrary to the mythology that the mother would mobilize iron stores to protect the fetus). Understanding the cellular biological and molecular basis for the effects of iron deficiency may lead to better treatments for these abnormalities, and could thus provide benefit to large numbers of children.

Subsequent studies on the generation of O-2A progenitor cells from GRP cells revealed that the defects in this transition found by the Mayer-Pröschel laboratory in their studies on iron deficiency may also apply to a better understanding of hypothyroidism. At least in vitro, exposure to thyroid hormone plays an important role in inducing dividing GRP cells to generate O-2A progenitor cells (Gregori et al., 2002). Thus, it may be that the myelination failures associated with hypothyroidism are also due to disruption of still earlier steps in development than the generation of oligodendrocytes themselves.

It is been known for over eighty years that developmental insults frequently only have severe effects if they occur during very specific developmental periods. For example, an absence of thyroid hormone, or iron, during early development is associated with profound reductions in myelin production and with subsequent neurological impairment. In contrast, if an adult becomes hypothyroid, or iron deficient, their myelin does not go away. Moreover, it is well established that if nutritional or hormonal deficiency during development is normalized quickly enough, significant recovery occurs - yet, if normalization of nutritional or hormonal status is delayed, the damage done is irreversible.

What is the biological basis for the existence of developmental windows of vulnerability to particular physiological insults? Our research indicates the answer is likely to be that these windows correspond to very specific stages in precursor cell development and that the various agents that cause - whether by their absence or their inappropriate presence - developmental abnormalities are responsible for regulating progression through these stages. In other words, it is becoming quite clear that many developmental maladies are precursor cell diseases, an insight that has considerable implications for understanding such syndromes and developing new means of treating them. One of the cornerstones of further work on this problem is to identify the common biochemical and molecular endpoints on which these different kinds of insults converge so as to similarly alter normal development.
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Gregori, N., Proschel, C., Noble, M., and Mayer-Pröschel, M. (2002). The tripotential glial-restricted precursor (GRP) cell and glial development in the spinal cord: Generation of bipotential oligodendrocyte-type-2 astrocyte progenitor cells and dorsal-ventral differences in GRP cell function. J. Neurosci. 22, 248-256. link

Ibarrola, N., Mayer-Proschel, M., Rodriguez-Pena, A., and Noble, M. (1996). Evidence for the existence of at least two timing mechanisms that contribute to oligodendrocyte generation in vitro. Dev. Biol. 180, 1-21. link

Contact

Mark D. Noble
University of Rochester
Box 633
601 Elmwood Ave.
Rochester, NY 14642
Office: MRB 2-9625
+1-585-273-1448 mark_noble@urmc.
rochester.edu