Despite broad research, stroke and other disorders of the brain and spinal cord continue to be the leading cause of disability nationwide. No treatment exists to rebuild neural tissue destroyed by a stroke and the subsequent inflammatory reaction. This proposal will utilize a new protein-based biomaterial to 1) direct mouse neural stem cell (NSC) growth, 2) tailor drug delivery, and 3) deliver NSCs to a stroke lesion site in a mouse model. The three specific aims will provide data critical to advancing neural stem cell culture in the laboratory and improve their utility for clinical medicine. The end goal of this proposed research is to decrease stroke- induced brain damage. This type of therapy may eventually produce an improvement in physical function of mice after a stroke. In order to accomplish this, specific goals are to direct transplanted neural stem cell differentiation, maintain transplanted cell viability, and keep cells localized to the target site.
The specific aims are: 1: Direct neural stem cell proliferation and differentiation in three-dimensional culture as a function of material stiffness. The three-dimensional culture is made of a newly-developed matrix that forms a hydrogel upon simple mixing of two component proteins. NSC growth and behavior can be controlled by their interactions with biomaterials in which they grow. Therefore this novel material will be used to control NSC differentiation, primarily to generate a large number of neurons useful for transplantation. 2: Optimize delivery of neuroprotective peptides from three-dimensional matrices to improve neural survival in response to oxidative stress. In order to protect transplanted NSCs from toxic free radicals, protective molecules must be delivered at the target location over a period of time. Using traditional delivery methods, these useful drugs are quickly inactivated. By incorporating these molecules into a protein hydrogel, they will be localized to only the wound site and their effectiveness will be maintained. The rate of delivery will be tailored by using multiple different mechanisms. These mechanisms will be studied and optimized for efficiency at protecting NSCs from a model of free radical-driven toxicity. 3: Improve NSC survival upon transplantation in a rodent stroke model. Typically, NSCs do not survive transplantation into a wound site within the brain. This proposal will investigate the use of a protein hydrogel to protect cells from physical injury sustained during injection and from the toxic inflammation found at the wound site. This hydrogel has the unique ability to flow as a liquid during injection, but gels to form a scaffold for cell growth once inside the brain. Once injected, animals will be monitored using state of the art technology for indications of transplant survival, decreases in the size of dead brain tissue at the stroke site, and recovery of brain function.

Public Health Relevance

This research seeks to advance the understanding of neural stem cell growth, an area of increasing interest for clinical treatment of brain and spinal cord disorders. Proposed work will study a mechanism by which neural stem cells can be protected from toxic molecules in the body and will utilize new materials to transplant cells in order to improve stroke outcomes.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F01-L (20))
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Bosetti, Francesca
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Stanford University
Engineering (All Types)
Schools of Engineering
United States
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Romano, Nicole H; Lampe, Kyle J; Xu, Hui et al. (2015) Microfluidic gradients reveal enhanced neurite outgrowth but impaired guidance within 3D matrices with high integrin ligand densities. Small 11:722-30
Lampe, Kyle J; Antaris, Alexander L; Heilshorn, Sarah C (2013) Design of three-dimensional engineered protein hydrogels for tailored control of neurite growth. Acta Biomater 9:5590-9
Lampe, Kyle J; Heilshorn, Sarah C (2012) Building stem cell niches from the molecule up through engineered peptide materials. Neurosci Lett 519:138-46
Chung, Cindy; Lampe, Kyle J; Heilshorn, Sarah C (2012) Tetrakis(hydroxymethyl) phosphonium chloride as a covalent cross-linking agent for cell encapsulation within protein-based hydrogels. Biomacromolecules 13:3912-6