Aging in human is associated with multiple changes to the skeletal and connective tissue architecture. For example, bone density declines and marrow fat content increases as a function of age. These changes either contribute to, or correlate with, the development of osteoporosis in aged individuals. The specialized cells responsible for fabricating bone, adipose and other mesenchmal tissues are believed to be derived from pluripotent mesenchymal stem cells (MSC's). For example, the connect9ive tissue stroma of bone marrow contains MSC's that serve as progenitors to both bone-forming osteoblasts and fat-forming adipocytes in the bone marrow microenvironments, depending on the local and systemic environmental stimuli. In addition, osteogenic and adipogenic cells have been reported to have the potential to interconvert between phenotypes. However, little is known about how these processes are affected by age. Changes in MSC number, replication potential and differentiation potential along the adipogenic pathways are potential mechanisms for how MSCs could influence the levels of marrow osteogenic and adipogenic cells. Likewise, changes in the plasticity of osteogenic and adipogenic cells, as a function of age, may also contribute to the age-associated changes in marrow bone and fat content. The experimentation in this research proposal is designed to test the hypothesis that the age-related changes in the levels of marrow-associated bone and fat tissue, results from changes in the replication and differentiation potential of marrow-derived MSCs and changes in the interconversion potential of osteogenic and adipogenic cells. Experimentation will be conducted with the Aims of: (1) quantifying and comparing the doubling potential and growth rate of MSCs isolated from young and aged populations; (2) determining the influence of age on the ability of human MSCs to differentiate into osteoblasts and adipocytes; and (3) measuring the influence of age on the ability of MSCs-derived progency to interconvert between the osteogenic and adipogenic lineage pathways. The data from the proposed experimentation will enhance our understanding of the cellular mechanisms responsible for the skeletal and connective tissue changes that take place in marrow as a function of age. These data will also serve as a platform for constructing future studies to investigate the age-related changes in marrow-associated bone and fat formation at the molecular level.
| Mackay, Danielle L; Tesar, Paul J; Liang, Li-Nuo et al. (2006) Characterizing medullary and human mesenchymal stem cell-derived adipocytes. J Cell Physiol 207:722-8 |
