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    • Another interesting finding of this study is

    2018-10-24

    Another interesting finding of this study is that bone formation in calvarial defects implanted with scaffolds laden with BMSCs pretreated with bone marrow extract is noticeably less than that in defects implanted with scaffolds laden with BMSCs pretreated with or without LCN2 and PRL. However, the in vitro results of osteogenesis in culture have shown that bone marrow extract-pretreated BMSCs produce significantly more calcium deposits in scaffolds than the vasopressin receptor pretreated with or without LCN2 and PRL. The discrepancy in the results may be due to differences in BMSC behavior between the in vitro and in vivo microenvironments, given that BMSCs are exposed to a number of cytokines and inflammatory molecules in the calvarial defect. We also hypothesized that BMSCs pretreated with bone marrow extract are more migratory and increasingly promoted to migrate out of an implanted scaffold, thus resulting in decreased bone formation in a calvarial defect relative to the cell pretreated with or without LCN2 and PRL. Our cell migration assay with transwell culture has confirmed this hypothesis. We have also found that the treatment of bone marrow extract can significantly increase the mRNA expression of CXCR4 in BMSCs to upregulate cell migration, as activation of the CXCR4/CXCL12 pathway plays a key role in mediating the homing of BMSCs (Cheng et al., 2008; Shi et al., 2007). It is unclear which percentage of bone marrow extract-treated BMSCs in our implanted scaffold is involved in cell migration and where the migrated cells end up in mice. While it would be of interest to investigate migration of bone marrow extract-treated BMSCs after implantation in future studies, our results have undoubtedly demonstrated that LCN2- and PRL-treated BMSCs can enhance repair of a critical-size bone defect without causing the concern of low cell retention within an implanted scaffold. A limitation of the current study is that bone marrow used in this study is harvested from femoral heads of donors with osteoarthritis. It is unclear how the disease may affect bone marrow compositions and properties and whether bone marrow from an osteoarthritic donor is different from that from a non-osteoarthritis donor. Future studies to confirm our findings using non-osteoarthritic donors\' cells may be helpful. Nonetheless, harvesting bone marrow from osteoarthritic donors has been used by several groups, including ours (Narcisi et al., 2015; Tsai et al., 2015) to obtain the tissue for BMSC isolation.
    Experimental Procedures
    Acknowledgments Research reported in this publication was partially supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH under Award Number R01 AR064803. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We would like to thank Huihua Yuan for the technical support in scaffold fabrication, Dr. Ellen Leiferman for her assistance in animal surgery, and Justin Jeffery for his assistance in micro-CT imaging conducted in the facility supported by the University of Wisconsin-Madison Carbone Cancer Center grant P30 CA014520.
    Introduction Kidney development begins with outgrowth of the ureteric bud (UB) at the caudal end of the nephric duct into the surrounding metanephric mesenchyme (MM). After invasion into MM, the UB forms tip and stalk regions and starts branching morphogenesis to form the collecting system (Dressler, 2009; Costantini and Kopan, 2010; Nagalakshmi and Yu, 2015). UB tip cells have higher proliferation rates and act as progenitor cells to produce UB stalks, and further differentiate into collecting ducts (Costantini and Kopan, 2010; Michael and Davies, 2004; Shakya et al., 2005). Through canonical WNT9B signaling, UB cells play two opposing roles for MM cells, i.e., maintaining stemness of MM cells while inducing their differentiation to form the remaining nephron structures (Carroll et al., 2005; Karner et al., 2011). In turn, MM cells release glial cell-derived neurotrophic factor (GDNF), which regulates UB tip cell proliferation and branching morphogenesis through RET tyrosine kinase receptor and GFRA1 co-receptor (Vega et al., 1996; Takahashi, 2001).