Ph.D. 1999 University of Rochester
M.D. 1990 Shanghai Medical University
Associate Professor of Orthopaedics
Primary Appointment: Department of Orthopaedics
Center Affiliation: Center for Musculoskeletal Research
Skeletal repair is a dynamic and well orchestrated process that involves complex and coordinated function of different cellular compartments and integrated molecular pathways. Understanding complex molecular interactions during skeletal healing represents a critical step toward developing effective treatment strategies for enhancing repair and reconstruction.
Research in my laboratory focuses on skeletal repair and reconstruction, which integrates a number of important research topics in musculoskeletal research. These topics include biology of bone/cartilage development, cell signaling, stem cell biology and bone tissue engineering. Using transgenic mouse models, primary culture of progenitor cells isolated from bone callus, and the-state-of-the-art imaging approaches, we are currently trying to understand how molecular and cellular signals are integrated to provide synergistic action for repair and regeneration. The long term goal of our laboratory is to be able to combine progenitor cells, molecular signals and bioscaffolds in a tissue-engineering construct to enhance bone repair and reconstruction.
Understanding the molecular controls of periosteum-mediated repair
Periosteum is a microvascularized connective tissue that covers the outer surface of cortical bone. Periosteum contains abundant stem/progenitor cells that are essential for bone repair and regeneration. While the critical role of periosteum in bone repair has been well established, the molecular pathways that control periosteum-mediated repair and regeneration remain superficially understood. We have established a segmental bone graft transplantation model that allows molecular analyses of periosteum contribution to bone repair and reconstruction. By transplanting a LacZ marked bone grafts from R26A mice into a wild type recipient mouse, we tracked periosteal cell fate during graft healing and show that the expansion and further differentiation of the progenitor cells account for about 70% of bone and cartilage formation during the initiation stage of healing. The removal of the donor periosteum results in marked impairment of bone graft healing whereas the engraftment of multipotent mesenchymal stem cells (MSCs) on acellular bone allografts markedly improves healing and graft incorporation. These studies underscore the critical role of periosteal MSCs in repair and reconstruction, providing a strong rationale for a deeper understanding of the molecular signals that control proliferation and differentiation of periosteum derived MSCs.
Understanding skeletal healing using intravital imaging analyses
Understanding stem cell interactions with their microenvironment is critically important for development of material-based approaches to control stem cell behavior for enhanced repair and regeneration. Current studies to elucidate the mechanisms of interactions of mesenchymal stem cells (MSCs) in a complex in vivo bone healing environment are limited due to the lack of technology and an appropriate animal model that permits dynamic and high-resolution analysis. To overcome this, we have recently established a chronic cranial defect window chamber model in mouse, which permits in vivo real time analyses of cellular recruitment, cell-matrix interactions and vascular ingrowth during skeletal repair. Utilizing multiphoton-laser scanning microscopy (MPLSM) as the imaging platform, we are able to obtain high resolution images to simultaneously visualize extracellular/bone matrix, bone forming cells, and vascular network in a dynamic and real-time fashion. Skeletal defect can be further reconstructed in a three-dimensional format, enabling quantitative and qualitative characterization of extracellular matrix synthesis and neovascularization at the cellular level. The establishment of a multiphoton based image modality in an in vivo cranial defect window chamber model enables high resolution assessment of the interactions of MSCs with fibrous matrix and neovascularization at cellular and subcellular level. With the possibility of using various transgenic animal models, this approach opens up various research opportunities to study detailed molecular and cellular mechanisms underlying MSC-based bone repair and regeneration, further offering an experimental testing modality for therapeutic strategies.
Engineering periosteal bone formation
Electrospun nanofiber holds great potential in tissue repair and regeneration due to its versatility in creating a scaffolding platform that allows presentation of integrated topographical and biochemical signals that are essential for stem cell manipulations. With the support from the Clinical Translational Science Institute (CTSI) at the University of Rochester, we have established a magnetic field-assisted electrospinning (MFAES) technique that allows the production of nanofibers with much improved control of diameter, uniformity, and orientation (1). These nanofibers can serve as the scaffolds for guided growth and differentiation of mesenchymal stem cells (MSCs). In collaboration with Dr. Hong Yang in the Department of Chemical Engineering, we are trying to characterize and further modify the biochemical and topographic features of these fibrous scaffolds and further utilize these fibrous structures for guided bone tissue engineering.
Understanding intervertebral disc growth, maintenance and aging
Deterioration of the intervertebral disc (IVD) is common in the elderly and has been shown to be one of the major causes for discogenic low back pain. While studies have shown that age-related disc degeneration is associated with enhanced apoptosis and loss of normal extracellular matrix composition in IVD, mechanisms underlying age-related degeneration of IVD remain poorly understood. Using various transgenic mouse models, we are currently trying to understand the molecular pathways that control the maintenance and aging of the intervertebral discs.
Zhang, X., Awad HA, O’Keefe RJ, Guldberg RE, Schwarz, EM. 2008. Perspective: engineering periosteum for structural bone graft healing. Clinical Orthopaedics & Related Research. 466(8):1777-87
Xie C, Xue M, Lin A, Schwarz E, Guldberg R, O'Keefe R, Zhang, X. 2008. COX-2 from the injury milieu is critical for the initiation of periosteal progenitor cell mediated bone healing. Bone. 43(6):1075-83
Yazici C, Yanoso L, Xie C, Reynolds DG, Samulski RJ, Samulski J, Yannariello-Brown J, Gertzman AA, Zhang, X., Awad HA, Schwarz EM. 2008. The effect of surface demineralization of cortical bone allograft on the properties of recombinant adeno-associated virus coatings. Biomaterials. 29(28):3882-7
Naik, A., Xie, C., Kingsley, P., Zuscik, MJ., Schwarz, EM., Awad, H., Guldberg, R., Drissi, H., Puzas, E., Boyce, B., Zhang, X., O'Keefe, RJ. 2009. Reduced COX-2 expression in aged mice is associated with impaired fracture healing. Journal of Bone & Mineral Research. 24(2):251-64.
Xie, C., Liang,B., Xue, M., Lin, ASP., Loiselle, A., Schwarz, EM., Guldberg,RE., O’Keefe, RJ., Zhang, X. 2009. Rescue of impaired fracture healing in COX-2-/- mice via activation of prostaglandin E2 receptor subtype 4. The American Journal of Pathology. 175(2):772-85
Clark, CA., Li, TF., Kim, KO, Drissi, H., Zuscik, MJ., Zhang, X., O'Keefe, RJ. 2009. Prostaglandin E2 inhibits BMP signaling and delays chondrocyte maturation. Journal of Orthopaedic Research. 27(6):785-92.
Tsutsumi, R., Xie, C., Wei, X., Zhang, X., Flick, LM., Schwarz, EM., O'Keefe RJ. PGE2 Signaling Through the EP4 Receptor on Fibroblasts Upregulates RANKL and Stimulates Osteolysis. 2009. Journal of Bone & Mineral Research. 24(10):1753-62.
Liu, Y., Zhang, X., Xia, Y and Yang H. 2010. Magnetic Field-Assisted Electrospinning of Aligned Straight and Wavy Polymeric Nanofibers. Advanced Materials. (In press)
Wang Q, Huang C, Zeng F, Xue M, Zhang X. Activation of the Hh pathway in periosteum-derived mesenchymal stem cells induces bone formation in vivo: implication for postnatal bone repair. Am J Pathol. 2010;177(6):3100-11.
Wang Q, Huang C, Xue M, Zhang X. Expression of endogenous BMP-2 in periosteal progenitor cells is essential for bone healing. Bone. 2011;48(3):524-32.
Graduate Program Affiliations
Xinping Zhang, B.M., Ph.D.
University of Rochester
601 Elmwood Ave., Box 665
Rochester, NY 14642
|Chunlan Huang, MD, PhD Postdoctoral Fellow|
|Fanjie Zeng, PhD Postdoctoral Fellow|
|Vincent Ness Under Graduate Student|