Ph.D. 1999 University of Rochester
M.D. 1990 Shanghai Medical University
Associate Professor of Orthopaedics
Primary Appointment: Department of Orthopaedics
Center Affiliations: Center for Musculoskeletal Research and
UR Stem Cell and Regenerative Medicine Institute
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 in repair and reconstruction. Our current project centers on a number of integrated molecular signaling pathways that are critical for periosteum-initiated bone repair. By understanding these signals, our goal is to be able to establish targeted-therapeutic approaches to enhancing repair and reconstruction.
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 of Vascularized Biomimetic Periosteum for Bone Graft Repair and Reconstruction
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 University of Rochester Clinical and Translational Sciences Institute (UR CTSI), we have established a magnetic field-assisted electrospinning (MFAES) technique that allows the production of nanofibers with improved control of diameter, uniformity, and orientation. In view of the essential role of periosteum in bone tissue repair and regeneration, our current project proposes to combine nano- and microfiber technologies to create a multi-modular, prevascularized bone tissue graft, with growth factor releasing property, simulating the highly organized and functional periosteum for reconstruction of large bone defects. The completion of the project will establish a novel strategy to enhance vascularization of engineered bone constructs; further offering a tissue engineering solution and a translational therapeutic strategy to enhance bone defect repair and reconstruction.
- Tiyapatanaputi P, Rubery PT, Carmouche J, Schwarz EM, O’Keefe RJ. *Zhang, X. (2004) A novel murine segmental femoral graft model. Journal of Othopaedic Research. 22(6):1254-60
- *Zhang X, Xie C, Lin AS, Ito H, Awad H, Lieberman JR, Rubery PT, Schwarz EM, O'Keefe RJ, Guldberg RE. (2005) Periosteal progenitor cell fate in segmental cortical bone graft transplantations: implications for functional tissue engineering. Journal of Bone and Mineral Research. 20:2124-2137
- Koefoed M, Ito H, Gromov K, Reynolds DG, Awad HA, Rubery PT, Ulrich-Vinther M, Soballe K, Guldberg RE, Lin AS, Zhang X, Schwarz EM. (2005) Biological effects of rAAV-caAlk2 coating on structural allograft healing. Molecular Therapy. 12:212-21
- Robertson G, Xie C, Chen D, Awad H, Schwarz EM, O’Keefe RJ, Guldberg RE, *Zhang X. (2006) Alteration of femoral bone morphology and density in cox-2-/- mice. Bone. 39(4):767-72
- Xie C, Reynolds D, Awad H, Rubery PT, Pelled G, Gazit D, Guldberg RE, Schwarz EM, O’Keefe RJ, *Zhang X. (2006) Structural bone allograft combined with genetically engineered mesenchymal stem cells as a novel platform for bone tissue engineering. Tissue Engineering. 13(3):435-45
- Xie C, Xue M, Wang Q, Schwarz EM, O’Keefe RJ, *Zhang X. (2008) Tamoxifen inducible CreER mediated gene targeting in periosteum via bone graft transplantation Journal of Bone and Joint Surgery. 90 (Suppl 1):9-13
- *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
- 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
- Liu Y, Zhang X, Xia, Y and Yang H. (2010) Magnetic field-assisted electrospinning of aligned straight and wavy polymeric nanofibers. Advanced Materials. 22(22):2454-7. PMC2941969
- Wang Q, Huang C, Zeng F, Xue M, *Zhang X. (2010) Activation of the Hedgehog pathway in periosteum-derived mesenchymal stem cells induces bone formation in vivo: implication for postnatal bone repair. The American Journal of Pathology. 177(6):3100-11.
- Wang Q, Huang C, Xue M, *Zhang X. (2011) Expression of endogenous BMP-2 in periosteal progenitor cells is essential for bone healing. Bone. 48(3):524-32.
- Colnot C, Zhang X, Knothe Tate ML. (2012) Current insights on the regenerative potential of the periosteum: molecular, cellular & endogenous engineering approaches. Journal of Orthopaedic Research. 30(12):1869-78.
- Lyu S, Huang C, Yang H, *Zhang X. (2013) Electrospun fibers as a scaffolding platform for bone tissue repair. Journal of Orthopaedic Research. 31(9):1382-9.
- Hoffman MD, Xie C, Zhang X, Benoit DS. (2013) The effect of mesenchymal stem cells delivered via hydrogel-based tissue engineered periosteum on bone allograft healing. Biomaterials. 34(35):8887-98.
- Huang C, Tang M, Yehling E, *Zhang X. (2014) Overexpressing sonic hedgehog peptide restores periosteal bone formation in a murine bone allograft transplantation model. Molecular Therapy. 22(2):430-9.
- Huang H, Xue M, Chen H, Jiao J, Herschman HR, O’Keefe RJ, *Zhang X. (2014) The spatiotemporal role of COX-2 in osteogenic and chondrogenic differentiation of periosteum-derived mesenchymal progenitors in fracture repair. Plos One. 9(7): e100079
- Huang C, Ness VP, Yang C, Chen H, Luo J, Brown EB, *Zhang X. (2015) Spatiotemporal Analyses of Osteogenesis and Angiogenesis via Intravital Imaging in Cranial Bone Defect Repair. Journal of Bone and Mineral Research. 30(7):1217-30.
- Yuan X, Cao J, Liu T, Li Y-P, Scannapieco F, He X, Oursler MJ, Zhang X, Vacher J, Li C, Olson D and Yang S (2015). Regulators of G protein signaling 12 promotes osteoclastogenesis in bone remodeling and pathological bone loss. Cell Death and Differentiation. [Epub ahead of print]
- Zhang L, Wang T, Chang M, Kaiser C, Kim JD, Wu T, Cao X, Zhang X, Schwarz EM. (2017). Teriparatide Treatment Improves Bone Defect Healing Via Anabolic Effects on New Bone Formation and Non-Anabolic Effects on Inhibition of Mast Cells in a Murine Cranial Window Model J Bone Miner Res. 32(9):1870-1883.
- Wang T, Zhang X, Bikle DD (2017). Osteogenic Differentiation of Periosteal Cells during Fracture Healing. The Journal of Cellular Physiology. J Cell Physiol. 2017 May; 232(5):913-921. PMID: 27731505 PMCID: PMC5247290
- Wang T, Zhai Y, Nuzzo M, Yang X, Yang Y, Zhang X (2018). Layer-by-layer nanofiber-enabled engineering of biomimetic periosteum for bone repair and reconstruction. Biomaterials. 182:279-88.
- *Zhang, X. (2018) Intravital Imaging to Understand Spatiotemporal Regulation of Osteogenesis and Angiogenesis in Cranial Defect Repair and Regeneration. Methods Mol Biol. 1842, 229-239.
- Schilling K, El Khatib M, Plunkett S, Xue J, Xia Y, Vinogradov SA, Brown E, *Zhang X. (2019) Electrospun Fiber Mesh for High-Resolution Measurements of Oxygen Tension in Cranial Bone Defect Repair. ACS applied materials & interfaces. 11 (37), 33548-33558.
Graduate Program Affiliations