Throughout life all tissues are maintained by underlying systems of stem cells that continually renew tissues through the generation of new Cells. These systems involve a series of hierarchical stages, originating with a rare population of upstream stem cells, and progressing through more numerous populations of downstream progenitor cells. Aging is associated with (and possibly defined by) changes in tissue health, appearance, and capacity for repair that are inevitably associated with underlying changes in the number of stem cells and/or their downstream kinetics (e.g. activation, self renewal, proliferation, migration, differentiation, and survival). Bone marrow is particularly relevant to aging. No tissue undergoes such profound change with age. Moreover, bone marrow is the home of multiple stem cell pools. Hematopoetic stem cells (HSCs) support the formation and maintenance of blood cells and the immune system. Mesenchymal Stem Cells (MSCs) and downstream connective tissue progenitors (CTPs), support the generation of bone, cartilage, fat, fibrous tissue, and skeletal muscle. Furthermore, even less numerous stem cell pools in bone marrow (e.g. multipotent adult progenitor cells (MAPCs), side population (SP) cells) have been shown to be capable of contributing to tissues of multiple germ layers, including liver, brain, lung and gut. This multidimensional nature places bone marrow in a position of central importance for understanding stem cell systems and the age related changes in these systems that contribute to preservation of health and functional accommodation to disease. However, conventional methods for harvest and sampling of bone marrow derived cells by aspiration is not well suited for quantitative assay of the stem cell population, due to large errors associated with sampling bias and dilution and contamination with cells from blood. Furthermore, aspiration disrupts information related to stem cell function that is provided by features of distribution and tissue level organization of stem cell and progenitor populations. This proposal will address deficiencies using an integrated cell-based modeling strategy to enable the systematic assessment of stem cell populations, and provide objective information necessary to optimally perform and interpret stem cell assays available from aspirate samples and small diameter bone core biopsies. 160 patients undergoing elective hip and knee arthroplasty (age 30 to 90), will provide the opportunity to assess bone and marrow samples from a broad age range. An integrated multidisciplinary analysis strategy will be applied to each sample, including: fluorescence activated cell sorting (FACS) and cell fraction analysis, CTP colony assay, LTClC assay, assay of telomerase and telomere length, quantitative histomorphometry of bone and marrow and pathological assessment.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZAG1-ZIJ-7 (O2))
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Dutta, Chhanda
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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Marcantonio, Nicholas A; Boehm, Cynthia A; Rozic, Richard J et al. (2009) The influence of tethered epidermal growth factor on connective tissue progenitor colony formation. Biomaterials 30:4629-38
Villarruel, Sandra M; Boehm, Cynthia A; Pennington, Mark et al. (2008) The effect of oxygen tension on the in vitro assay of human osteoblastic connective tissue progenitor cells. J Orthop Res 26:1390-7