We put forward that the unique embryological origins of individual mammalian calvaria impact differences in their osteogenic capacity. The cental hypothesis of this proposal is that differences in embryonic origins of calvarial osteoblasts affect their embryonic and post-natal osteogenic potential and skeletal regenerative capacity. The paired parietal frontal bones in the anterior skull are derived from the neural crest and the paired parietal bones, positioned posteriorly, are derived from the paraxial mesoderm. We have preliminarily observed the frontal bone to possess superior osteogenic potential both in vitro and in vivo compared to the parietal bone. Our proposal aims to verify this difference in osteogenic potential and elucidate the role of fibroblast growth factor (FGF) signaling underlying this disparity. Such an understanding is of central importance to overcoming current challenges with treatment of calvarial defects. The inability of humans older than one year of age to reossify calvarial defects poses a substantial burden on our healthcare system. Current use of autogenous grafts, allogeneic substances, and synthetic materials to reconstruct calvarial defects are all suboptimal. These inadequacies serve as the impetus for our application. Through the identification of calvarial bones with inherently superior osteogenic capacity, we seek to gain insight into novel strategies for robust calvarial regeneration.
In Specific Aim 1, we will determine the role of FGF signaling in mediating differences between neural crest-derived frontal and paraxial mesoderm-derived parietal bone osteoblasts. Will begin by comparing the expression profile of key FGF ligands and receptors, and the activation of their downstream mediators, between the frontal and parietal bones of the wild-type and transgenic mice described above.
In Specific Aim 2, we will determine if the reduced healing capacity of paraxial mesoderm-derived parietal bone is augmented by the addition of exogenous FGF-2, -9, and -18 after injury in wild-type mice.
In Specific Aim 3, we will determine if the robust healing capacity of neural crest-derived frontal bone is reduced or negated in transgenic mice possessing fgf-2-/-, -9-/-, and -18-/- loss of function mutations. Ultimately, the translational goal of this application is to identify key molecular mechanisms in the FGF family that promote robust bone regeneration. We assert that the identification of calvarial bones with superior osteogenic capacity will provide insight into such mechanisms.
The individual bones of the skull originate from different parts of the embryo. Our application aims to investigate whether this dissimilarity in origin translates into differences in their ability to heal skull defects. Furthermore, our application aims to elucidate the mechanisms underlying superior bone healing. This is of direct relevance to improving current treatment modalities for reconstructing skull defects. Defects in the skull represent a substantial biomedical burden on the US healthcare system. A myriad of reconstructive options are currently employed, each with their inherent inadequacies. Identification of skull bones with superior healing potential provides insight into novel strategies that can be employed to regenerate, rather than reconstruct, skull bones.
|Tevlin, R; Walmsley, G G; Marecic, O et al. (2016) Stem and progenitor cells: advancing bone tissue engineering. Drug Deliv Transl Res 6:159-73|
|Menon, Siddharth; Shailendra, Siny; Renda, Andrea et al. (2016) An Overview of Direct Somatic Reprogramming: The Ins and Outs of iPSCs. Int J Mol Sci 17:|
|Meier, Elizabeth M; Wu, Bin; Siddiqui, Aamir et al. (2016) Mechanical Stimulation Increases Knee Meniscus Gene RNA-level Expression in Adipose-derived Stromal Cells. Plast Reconstr Surg Glob Open 4:e864|
|Paik, Kevin J; Maan, Zeshaan N; Zielins, Elizabeth R et al. (2016) Short Hairpin RNA Silencing of PHD-2 Improves Neovascularization and Functional Outcomes in Diabetic Wounds and Ischemic Limbs. PLoS One 11:e0150927|
|Keeney, Michael; Chung, Michael T; Zielins, Elizabeth R et al. (2016) Scaffold-mediated BMP-2 minicircle DNA delivery accelerated bone repair in a mouse critical-size calvarial defect model. J Biomed Mater Res A 104:2099-107|
|Li, Shuli; Quarto, Natalina; Senarath-Yapa, Kshemendra et al. (2015) Enhanced Activation of Canonical Wnt Signaling Confers Mesoderm-Derived Parietal Bone with Similar Osteogenic and Skeletal Healing Capacity to Neural Crest-Derived Frontal Bone. PLoS One 10:e0138059|
|Zielins, Elizabeth R; Tevlin, Ruth; Hu, Michael S et al. (2015) Isolation and enrichment of human adipose-derived stromal cells for enhanced osteogenesis. J Vis Exp :52181|
|Quarto, Natalina; Senarath-Yapa, Kshemendra; Renda, Andrea et al. (2015) TWIST1 silencing enhances in vitro and in vivo osteogenic differentiation of human adipose-derived stem cells by triggering activation of BMP-ERK/FGF signaling and TAZ upregulation. Stem Cells 33:833-47|
|Atashroo, David A; Paik, Kevin J; Chung, Michael T et al. (2015) Assessment of viability of human fat injection into nude mice with micro-computed tomography. J Vis Exp :e52217|
|Marecic, Owen; Tevlin, Ruth; McArdle, Adrian et al. (2015) Identification and characterization of an injury-induced skeletal progenitor. Proc Natl Acad Sci U S A 112:9920-5|
Showing the most recent 10 out of 30 publications