A TISSUE-ENGINEERED ROSTRAL MIGRATORY STREAM FOR NEURONAL REDIRECITON AND REPLACEMENT FOLLOWING BRAIN INJURY & A GRADUATE CERTIFICATE PROGRAM IN COMMUNITY-ENGAGED STEM

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Degree type
Doctor of Philosophy (PhD)
Graduate group
Neuroscience
Discipline
Neuroscience and Neurobiology
Engineering
Subject
community engagement
community-engaged scholarship
neuroblast migration
rostral migratory stream
subventricular zone
tissue engineering
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01/01/2024
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Author
Purvis, Erin, Michelle
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Abstract

This dissertation contains two distinct parts. Part 1 builds upon the biological phenomenon wherein neuroblasts arising from the postnatal mammalian subventricular zone (SVZ) migrate through the rostral migratory stream (RMS) to the olfactory bulb. Following brain injury, neuroblasts can divert from the RMS and migrate toward injured brain regions, but they arrive in numbers too low to impact functional recovery without experimental intervention. To this end, our laboratory has created a neuronal replacement strategy that utilizes the first implantable, biomimetic tissue-engineered rostral migratory stream (TE-RMS) designed to leverage the brain’s natural mechanism for sustained neuronal replacement by replicating the structure and function of the native RMS to direct neuroblasts to sites of injury. The TE-RMS is also a powerful tool to investigate neuroblast migration along a replicated RMS in vitro. We demonstrate that the TE-RMS mimics the basic structure, astrocyte morphology, and protein expression of the endogenous rat RMS. We describe unique astrocyte behavior when TE-RMSs are fabricated in hydrogel microcolumns and microchannels. We also show that we can harvest neural precursor cells from the SVZ of adult rat brains and that these cells migrate in chain formation along the TE-RMS in vitro. Finally, we provide evidence that TE-RMSs – fabricated from human mesenchymal stem cell-derived astrocytes and implanted into rat brains – redirect migration of endogenous rat neuroblasts in vivo. Overall, this work substantially advances the TE-RMS as an in vitro tool that can be utilized to address basic questions regarding the underlying mechanisms of cell-cell communication and neuroblast migration and as a functional neuronal replacement strategy to mitigate neuronal loss. Importantly, maximally impactful biomedical research necessitates that researchers meaningfully engage with their local communities. To this end, Part 2 of this dissertation details the development and implementation of the Community-Engaged STEM graduate certificate program at the University of Pennsylvania, which is the first formalized program for graduate students to connect their academic research with bettering the lives of the local Philadelphia community. As discussed in Part 2, community engagement should be a more widespread component of STEM graduate education and research. This dissertation supports that goal.

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Cullen, D., Kacy
Date of degree
2024
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