Cheng, Du, 2011-2012

Du Cheng
Du
Cheng

Host research mentor: Jill Helms, D.D.S., Ph.D.
Stanford University

When skeletal injury occurs, osteogenic stem cells, residing in the bone marrow, are responsible for the regeneration of new bone. Aging negatively impacts this process. As we get older, bone reabsorption predominates and commonly manifests as osteoporosis or a non-healing fracture. Based on the fact the Wnts signals are critical regulators of bone formation, we hypothesize that promoting Wnt signaling in aged patients will stimulate bone healing. A novel method of packaging Wnt protein into liposomes (L-Wnt3a) has been developed recently to allow the direct test of this hypothesis.

In this study we used a mouse critical size calvarial defect to evaluate the bone forming ability of bone grafts harvested from aged and young donors. First, we found that young bone marrow makes about three-times more new bone in the defect site than does aged bone marrow. Second, we found the endogenous expression of Wnt genes and Wnt targets were lower in bone marrow from aged vs from young mice. Third, we found that aged grafts that are supplied with L-Wnt3a regenerate the same amount of new bone as did grafts from young mice. Last, we showed that the bone forming ability of young bone marrow grafts depends upon its ability to respond to an endogenous Wnt signal. In order to study the mechanism of how L-Wnt3a improves the bone forming ability of a graft we examined cell proliferation and cell death of the bone marrow. No significant differences in cell proliferation were observed between the control treated and L-Wnt3a treated bone marrow sample. However, we found that L-Wnt3a significantly prevented cell death in the graft compare to control treatment. We also found L-Wnt3a treatment stimulates the activation of the Wnt pathway 24 hours post treatment and suppresses adipogenesis factor (PPAR gamma) expression. Collectively, the data suggest that, L-Wnt3a treatment is a promising therapeutic for improving bone marrow transplants and engraftment.