Regulatory Mechanisms in Load-Induced Osteogenesis
Funding: Department of Veterans Affairs
The mechanisms by which stem cells are activated and recruited to bone forming surfaces in response to biophysical signals are incompletely understood. We are studying the role of paracrine factors and cell-cell signaling in mesenchymal stem cell proliferation, recruitment, and differentiation using mechanically-driven osteogenesis, genetically modified in vivo systems, stem cell transplantation, drug-delivery assays, lineage tracing studies, and engineered microfluidic devices. The goal of this project is to systematically decipher the role of mesoderm-derived tissues in supporting load-induced guided cellular migration and tissue-specific specialization in young and aged skeletal systems.
Mechanical Regulation of Skeletal Repair & Regeneration
Funding: AO Foundation, Switzerland
Successful reconstruction of bone defects resulting from traumatic fracture, oncological tumor resection, and revision surgery remains challenging. Up to 10% of routine fractures and up to 80% of significant volumetric defects result in non-union. Mechanical stimulation is a known regulator of bone repair, and early weight-bearing is an important factor in post-surgical care, though how mechanical signals are sensed and integrated to regulate the underlying biology of bone regeneration is not completely understood. We are studying the relationship between mechanical signals and underlying cell and molecular mechanisms regulating bone healing using a novel in vivo tibial defect loading model, lineage-tracing studies, and computational models. The goal of this project is to determine the effects of mechanical stimulation on bone repair and biomechanical integrity.
Angiogenesis During Skeletal Homeostasis and Regeneration
Angiogenesis is a process by which new blood vessels emerge from existing vessels through endothelial cell sprouting, migration, proliferation, and tubule formation. Angiogenesis during skeletal growth, homeostasis and repair is a critical yet complex and incompletely understood process. The goal of this project is to elucidate the molecular mechanisms regulating angiogenesis in the context of skeletal mechanoadaptation and repair. See 3D image dataset here.
Mechanobiological Guidance of Stem Cell Fate Decisions in the Aged Skeleton
Bone adapts to its mechanical environment by optimizing its size and shape to meet mechanical demands, and mechanical stimulation in the form of weight bearing exercise has long been a strategy to maintain bone mass and to mitigate age-related bone loss. As the skeleton ages there is a reduction in mechanoresponsiveness, rendering exercise less effective in building bone mass in the aging skeleton. This project is aimed at understanding fundamental changes in skeletal stem cells in adult and aged bone with the goal of identifying targetable molecular mechanisms that may prevent or reverse the effects of aging.