There has recently been a great increase in interest in stem cells, including their significant potential for use in the treatment of a wide range of clinical conditions that involve loss of neural cells. Although proteoglycans and related extracellular matrix components with which they interact are obvious candidates for molecules that can be expected to exert a decisive influence on stem cell behavior, essentially no work has yet been directed to this area. This lack of pertinent information is particularly striking in view of recent evidence that the expression of a number of proteoglycans and extracellular matrix protein ligands that we have previously identified and studied is as much as 10-fold greater in neural progenitor cells from adult brain as compared to the cell population from which they were isolated. My laboratory has had a longstanding interest in the structures, localization, and functional roles of nervous tissue glycoconjugates. This exploratory (R21) grant proposal therefore has two complementary objectives related to these questions: a.) to obtain preliminary data concerning age-related changes in the properties of brain extracellular matrix components that would affect the interactions and differentiation of neural stem cells, and b.) to identify by immunocytochemistry any differences in the expression of these extracellular matrix components by stem cells as a function of aging. The first objective is based on our previous demonstration of changes in the glycosylation and sulfation of brain proteoglycans during development, and the reasonable possibility that other structural alterations may accompany aging. If differences are found in the response of progenitor cells to proteoglycans isolated from brains of aged as compared to young or adult rats, the structural properties of proteoglycans from aged brain can, as a later extension of this project, be examined in detail to identify potentially important structural modifications. Because it can be anticipated that methods will be developed for the "induction" of endogenous progenitor cells in aged brain, we will also begin to characterize their production of extracellular matrix components in an attempt to define possibly distinctive characteristics that would facilitate or inhibit this process. Later more detailed studies could then be devoted to aspects such as variations in glycosaminoglycan fine structure that might affect their interactions with growth factors and other ligands. These pilot experiments will provide a foundation of preliminary data on the cues provided by the brain cell microenvironment that affect stem cell survival and differentiation in the aging brain, and will facilitate the formulation of hypotheses and the design of studies aimed at examining these environmental effects in more detail in the context of a subsequent R01 proposal. [unreadable] [unreadable]
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NIH ExPorter