The overall goal of the proposed research is a better understanding of the mechanism of cellular aging in vivo and in vitro. Much of the research focuses on cellular and molecular analysis of the limited in vitro proliferative capacity of normal diploid cells, but there is also strong emphasis on the correlation of the in vitro experiments with in vivo aging. Two hypotheses are proposed for testing. (1) The finite proliferative capacity (FPC) of normal fetal and adult fibroblasts in culture is a manifestation of the differentiation program of these cells and is related to the proliferative and/or differentiative state of the cells in vivo at the time they were transferred into primary culture. (2) Aging in vivo is related to altered number or response of stem or progenitor cells which is reflected in loose connective tissue (e.g. dermis) as decreased wound healing in vivo and as reduced proliferative capacity in vitro. The animal aging model used for these studies will be the golden Syrian hamster (SH) (Mesocricetus auratus). The primary criterion for the choice of this species over more established rat and mouse aging models is the similarity between the FPC of SH and human cells in vitro. Thus, the SH fibroblast system will be used as an animal model of human fibroblast senescence with the added advantage that direct in vitro/in vivo correlation can be done in this experimental system. Our approach to the study of the relationship between FPC of dermal fibroblasts and cellular differentiation (hypothesis 1) is three fold: (i) isolate mesenchymal progenitor cells present in primary cultures, (ii) characterize the differentiation of these cells with biochemical markers that reflect the in vivo function of these cells and (iii) verify that conditions which extend or shorten the FPC of mass cultures of these cells alter in a co-ordinate manner the differentiation of progenitor cells and the expression of markers. Our approach to the study of the relationship between FPC and in vivo aging (hypothesis 2) is also three fold: (i) to understand the in vivo development, differentiated function and aging of dermal fibroblasts especially with regard to the proliferative and differentiated state of these cells at the time of explant into culture, (ii) to use longitudinal studies to relate in vitro FPC with the in vivo wound healing rate and the natural life span of an individual hamster, and (iii) to analyze more critically the relationship between the FPC of fetal fibroblasts at equivalent stages of gestation from different rodent species with the in vivo life span of the species.
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