This application responds to PA-06-137 """"""""Testing stem cell therapy in mouse models of premature aging"""""""";this project explores in the R21 format the potential use of stem cell therapy in basic aging research. Two models of aging stem cells, one mouse and one human;will be used as donor cells for evaluation of their relative roles in bone wound healing. The SAMP6 mouse is known to be osteopenic and have fewer osteoblast progenitors in marrow compared with control SAMR1 mice. Marrow stromal cells (MSCs, a.k.a. mesenchymal stem cells), which contain osteoblast progenitors, will be prepared from male SAMP6 and SAMR1 mice and from marrow discarded from young and older men during orthopedic surgery. It is known that in vitro osteoblast differentiation of human MSCs declines with age of the subject. These murine and human MSCs will be engrafted into immunoprivileged female NOD/SCID recipient mice with a validated technique that results in greater engraftment of stromal cells because of the clearing of the recipient marrow niche with high dose irradiation only to the hindlimb. Following irradiation and before injection of MSCs, standardized unicortical tibial wounds will be made. Thus the hindlimb will contain donor stromal cells from young or old male mice or humans, allowing for tracking of their relative functional contribution to bone wound healing. In addition, we shall test the efficacy of a novel mitochondria-targeted antioxidant, JP4-039, to increase the functional contribution of the engrafted MSCs to bone wound healing. Methods include isolation of MSCs from male SAMP6 and SAMR1 mice and from young and older men undergoing orthopedic surgery, production of chimeric mice, measuring kinetics of tibial wound healing by weekly radiographs and

Public Health Relevance

New tools are needed to assess the effects of age on stem cells, in the contexts of normal aging and of potential stem cell therapy. This project is designed to reveal the effect of aging on marrow stromal cells'contribution to bone healing and the efficacy of a novel antioxidant on this process.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Williams, John
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Brigham and Women's Hospital
United States
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Glowacki, Julie; Mizuno, Shuichi; Kung, Jason et al. (2014) Effects of mouse genotype on bone wound healing and irradiation-induced delay of healing. In Vivo 28:189-96
O'Sullivan, Regina P; Greenberger, Joel S; Goff, Julie et al. (2012) Dysregulated in vitro hematopoiesis, radiosensitivity, proliferation, and osteoblastogenesis with marrow from SAMP6 mice. Exp Hematol 40:499-509
Zhou, Shuanhu (2011) TGF-? regulates ?-catenin signaling and osteoblast differentiation in human mesenchymal stem cells. J Cell Biochem 112:1651-60