(648c) Do Sensory Neurons Synthesize Extracellular Matrix Molecules and Remodel Their 3D Environment?

Nerve injuries can be catastrophic as neurons are the only cell type in adult human that does not proliferate. Current repair treatments of peripheral nerve injuries use transplanted nerve grafts and are generally successful but suffer several disadvantages such as multiple surgeries, loss of function at the graft donor site, and low success rates for large injuries. A potential “off-the-shelf” alternative is the nerve guidance channel, but it is unclear how to best design these tubular synthetic devices. We hypothesize that this lack of knowledge stems from an incomplete understanding of how neurons behave in three-dimensional (3D) structures or matrices. While two-dimensional (2D) substrates such as petri plates have been incredibly valuable in revealing intricacies of cell biology, recent works have established that the response of non-neuronal cells is dramatically altered in a 3D matrix as compared to 2D culture ^[1]. Thus, our group strives to advance the understanding of how neurons respond to 3D matrices and we seek a biological basis upon which to rationally design new devices to promote nerve repair.

We have made significant progress in this direction by establishing that the cell-matrix signaling pathways responsible for sensory neuron morphology and development are altered in 3D versus 2D culture ^[2]. We have also demonstrated that 3D gel properties are dramatically altered in the presence of encapsulated neurons, as observed from increased gel stiffness, decreased swelling and slower degradation rate vs acellular gels ^[3]. This presentation will overview these findings and also poses the hypothesis that like non-neuronal cells, neurons actively sense and remodel their 3D microenvironment. Thus, the aim of our current work is to determine how neurons interact with these structures via mechanisms of matrix degradation, synthesis and remodeling. We have found that extracellular matrix synthesis is altered in a 3D microenvironment as compared to 2D substrates. These findings provide a biological basis for the design and testing of new peripheral nerve repair therapies.

References:

1. Irons H, et al., J Neural Eng 2008, 5:333. 2. Ribeiro A., et al. Substrate Three-Dimensionality Induces Elemental Morphological Transformation of Sensory Neurons on a Physiologic Timescale, submitted; Ribeiro A., et al. β1-integrin Cytoskeletal Signaling Regulates Sensory Neurons Response to Matrix Dimensionality, submitted. 3. Ribeiro A., et al. Degradable scaffolds for neural progenitor cell delivery. submitted.