DOI
https://doi.org/10.25772/V20N-E037
Author ORCID Identifier
https://orcid.org/0000-0003-4363-3302
Defense Date
2021
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Biomedical Engineering
First Advisor
Rene Olivares-Navarrete, DDS, PhD
Abstract
Osseous healing is regulated by various classes of cells and signaling mechanisms. Of these, Wnt signaling has long been known to be critically important in directing the differentiation of mesenchymal stem cells (MSCs) into osteoblasts during bone healing. However, the source of these Wnt ligands is not known. Recently, a body of literature has arisen finding both beneficial and detrimental effects of macrophage-derived Wnt ligands on the regeneration of other tissues (liver, kidney, heart, and intestine), often by regulating inflammatory activation and stem cell behavior. As macrophages have been well-characterized as orchestrators of healing, their use of Wnt signaling to regulate tissue regeneration is unsurprising. However, no studies have yet identified the contribution of macrophages to Wnt signaling during osseous healing. Interestingly, recent work suggests that macrophages represent a major source of Wnt ligands during bone healing and underscore the importance of macrophages in driving this process. In the work described here, the expression of Wnt ligands by macrophages will first be measured, as well as the cells targeted by Wnt ligands, during osseous healing. Then, Wls, the gene encoding a necessary Wnt ligand trafficking protein, will be deleted in Csf1r- expressing cells (monocytes and macrophages), inhibiting the secretion of all Wnt ligands by these cells after induction of Cre recombinase with tamoxifen. Following deletion of macrophage Wls, the consequences of loss of macrophage-derived Wnt ligands will be characterized during the inflammatory and proliferative phases of osseointegration. Appropriate transition through these phases will be evaluated using qPCR, ELISA, and flow cytometry. Finally, the mechanism of Wnt regulation in response to pro-healing material surface cues—namely, through integrin signaling—will be evaluated. The studies defined in this proposal will elucidate the importance of macrophage Wnt ligands on bone healing and potentially identify Wnt signaling as a targetable pathway to enhance successful osseous healing.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-25-2021
Included in
Biomaterials Commons, Cell Biology Commons, Molecular, Cellular, and Tissue Engineering Commons, Musculoskeletal Diseases Commons, Other Immunology and Infectious Disease Commons