Transitional Growth-Associated Skeletal Stem Cells

Boston Children'S Hospital, Boston MA

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Abstract

Postnatal bone formation relies on skeletal progenitor/stem cells (SSCs). Recent in vivo lineage-tracing studies indicate that SSC populations are temporally and spatially- regulated with distinct SSC populations functioning during bone growth and maintenance. In addition, it has been suggested that growth-associated SSCs are the predecessors to adult SSCs implying that a hierarchy may exist among the various progenitor/stem cell populations demonstrating a high degree of complexity within this system. Given this, it is likely that disruption in growth-associated SSC number, function or timing will translate into altered bone mass in adulthood. Telomerase (Tert) activity prevents cellular senescence and is required for maintenance of stem cells in regenerative tissues. Prior studies have shown that telomerase is necessary for SSC self-renewal and differentiation. In addition, decline of telomerase activity in humans correlates with a decrease in bone homeostasis leading to osteoporosis. Utilizing mTert-GFP and mTert-rtTA transgenic reporter mouse lines we investigated the role of mTert-expressing cells in postnatal mouse bone development. Quantitative RNA and histological analyses of long bones revealed that mTert is expressed predominantly at the time of weaning, suggesting these cells are temporally regulated and mark a discrete developmental time point between rapid bone growth and bone maintenance, which we have termed ?transitional growth.? Further analysis using in vivo lineage-tracing showed that mTert+ cells function as osteochondral progenitor cells. What physiological factors regulate the temporal pattern of mTert+ SSCs and whether their presence during this specific postnatal developmental stage is crucial for proper adult bone maintenance remains to be determined. Therefore, this proposal will 1) investigate the effect of two well-known physiological growth-regulating factors, estrogen and parathyroid hormone, on mTert+ SSCs and 2) investigate whether altering the temporal pattern, number or function of these cells translates into changes in adult bone.