Engineering a Neural Tissue Model of Oligodendroglial and Matrix Remodeling after Biophysical Injury

University Of Virginia Main Campus, Charlottesville VA

Investigators

Abstract

Cells in the brain reside in a three-dimensional matrix that regulates their fate and function. These include neurons, which quickly send signals up and down their long axons, and oligodendrocytes, which deposit an insulating sheath, called myelin, on the axons. This myelin is analogous to insulation on a wire, and thus essential for proper function. Injuries to the brain from mechanical forces, like blast injury, damage brain cells and frequently lead to loss of myelin along with death of oligodendrocytes and neurons. In order to develop ways to repair this damage, it is first necessary to understand the mechanisms connected to myelin creation and destruction (myelination and demyelination, respectively). As oligodendrocytes neither simply appear in the brain nor remain there without changing, it is also important to understand how progenitor cells (earlier, undifferentiated cells) become mature oligodendrocytes. This project's primary goals are to create a tunable, 3D environment that will support oligodendrocyte progenitor cell (OPC) growth, axon growth, and production of myelin, and then to understand the degenerative process after mechanical injury to the engineered tissue. The 3D environment will include important aspects of the cell-cell and cell-matrix environment that are not present in traditional 2D culture. The outreach and education objectives planned through this project will significantly expand interest in the role of engineering in health fields to broadly diverse elementary school children and provide means for socioeconomically challenged students to pursue STEM related fields through paid college research opportunities. The PIs will continue to mentor underrepresented undergraduate students, particularly women, in their research groups. Finally, the PI will create a new opportunity to facilitate graduate student:faculty communication and career mentoring This project includes three research aims. The first is to determine the mechanism through which the mechanical properties of the culture matrix will support differentiation of precursor cells into mature oligodendrocytes, and then to optimize this system. This will take into account differentiation of neural stem cells to OPCs as well as differentiation of OPCs to mature, myelin producing oligodendrocytes. The second aim will focus on structural cues in 3D culture to support myelin production by the oligodendrocytes, which is not observed in 2D culture. Finally, the optimized system with differentiated oligodendrocytes will be exposed to pressure blast waves through a controllable blast chamber. Multiscale measurements of mechanical parameters that characterize the cell responsivity threshold as well as mechanotransduction mechanisms and phenotypic changes will be assessed. This will be done with both 2D and 3D culture to identify the effect of differences in the cellular environment on the demyelination process. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.