Plastic Surgery Research Council
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PSRC 60th Annual Meeting

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Identification of Cell-Intrinsic Mechanisms and Differentially Regulated Genetic Pathways Responsible for the Age-Related Functional Decline in Aged Skeletal Stem Cells.
Adrian McArdle, MB, BCh, BAO, MRCSI, Charles Chan, PhD, Jun Seita, MD, PhD, Kshemendra Senarath-Yapa, MBBChir, MA, MRCS, Michael Hu, MD, MPH, Graham G. Walmsley, BS, Elizabeth Zielins, MD, David Atashroo, MD, Ruth Tevlin, MB, BCh, BAO, MRCSI, Irving Weissman, MD, Michael T. Longaker, MD, MBA, FACS.
Stanford University, Stanford, CA, USA.

PURPOSE:
Aging is associated with a gradual loss of homeostatic mechanisms that maintain the structure and function of adult tissues. Most adult tissues contain resident stem cells, which proliferate to compensate for tissue loss throughout the life of the organism. It is believed that both chronological aging and replicative aging of adult stem cells negatively affects their functional capacity for tissue regeneration. Natural aging has a profound effect on skeletal healing, evidenced by the reduced healing ability with advancing age, and an increased incidence of osteoporosis. In mice, we have identified a resident stem-cell pool in skeletal tissue. We can successfully isolate a highly-purified population of skeletal stem cells that have the ability of forming bone, cartilage, stroma and a functioning bone marrow cavity at the clonal level. This study examines the cell-intrinsic mechanisms, and the role of the extrinsic stem cell niche on influencing skeletal stem cell aging. The aim of this study is to identify potential pathways that could be manipulated to reverse the effects of skeletal stem cell aging.
METHODS:
Highly-purified populations of skeletal stem cells were prospectively isolated by fluorescence-activated cell sorting (FACS) using a novel panel of cell surface markers. Microarray analysis was performed to identify genetic pathways that are differentially regulated with aging. Cell intrinsic function was assayed using isochronic and heterochronic transplantations beneath the kidney capsule to assess their bone-forming ability at an ectopic location. To determine if exposure of aged bone to a young, healthy circulation would improve bone health, we surgically paired mice, creating isochronic and heterochronic parabiosis to determine if it is possible to manipulate the niche and rescue an age-related functional decline in stem cell function.
RESULTS:
The ability of skeletal stem cells to form colonies in vitro declined significantly with age (*p<0.05). Isochronic and heterochronic ectopic skeletal stem cell transplantation assays demonstrated a functional decline in the ability of aged skeletal stem cells to form bone beneath the renal capsule.
Aged mice demonstrated a significant reduction in bone mineral density using microCT analysis (*p<0.05). Fracture healing was also delayed in this group, as measured by the callus index. The ability of a young, systemic microenvironment to rejuvenate aged stem cells remains to be seen.
Microarray data analysis of skeletal stem cell populations comparing early post-natal to aged mice, has identified differentially regulated genes that may be responsible for the functional decline in the ability of aged skeletal stem cells to form bone.
CONCLUSION:
Aging is associated with changes in cell-intrinsic mechanisms that underlie the functional decline in the ability of skeletal stem cells to form bone. Microarray analysis has identified differentially regulated genes that may be responsible for this functional decline. Manipulation of these pathways may allow us to reverse the effects of skeletal stem cell aging and improve bone healing in vivo.


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