Stem cell compartments are hierarchical in that small numbers of primitive, self-renewing cells give rise to progressively differentiating progeny. The hypothesis of this proposal is that aging compromises stem cell quality as a result of progressive differentiation of the more primitive stem cells of the hierarchy over time. Compromised stem cell quality negatively affects the repair of tissue damage or stress as well as the regenerative response to chronic diseases which would lead to a decline in general health status. To test the hypothesis, Aim #1 will characterize hematopoietic and mesenchymal stem cell compartment quality in the bone marrows of a wide age range of surgical orthopedic patients. The ratios of the more differentiated to more primitive stem/progenitor cell numbers in each compartment will be identified and those with higher ratios will be defined as having poorer quality. The quality of these compartments will then be correlated with the age of the marrow donor to provide quantitation of the stem cell compartments with aging. Because some alterations in stem cell compartments with aging may result from an altered balance of pro- and anti-inflammatory cytokines, Aim #2 will analyze blood from the same patients for interleukin 6, tumor necrosis factor, transforming growth factor beta and insulin-like growth factor one levels along with complete blood counts. These findings and the age and the general health status of the donor, assessed using standardized instruments, will be correlated with the stem cell compartment quality identified in Aim #1.
In Aim #3 the marrow donors will be stratified based on having greater versus less than average stem cell compartment quality and this information will be correlated with the surgical outcomes of the patients as well as the appearance or progression of chronic or hematopoietic disease over time. The hypothesis predicts that patients with lower quality stem cell compartments will do less well and will have more confounding problems than those with high quality stem cell compartments and that health status will decline more rapidly with aging in those with poorer quality stem cell compartments. This research will validate laboratory assays of stem cell compartment quality which can then be applied to clinical situations and may reveal blood cytokine assays with surrogate predictive value.
