Adult neural stem cells (NSCs) have great potential for treating damage or disease of the nervous system. However, these cells are rare and difficult to maintain in culture because they quickly lose their multi-potency after being removed from their native environment. In vivo, NSCs reside adjacent to a vascular niche, suggesting that it may be possible to maintain these cells ex vivo if critical functional features of the vascular niche are recreated in the culture environment.
The hypothesis of the proposed studies is that formation of a perfused, functional vasculature within 3-D extracellular matrix promotes self-renewal of the surrounding NSCs. To test this hypothesis, the following specific aims will be pursued: 1) Create a neurovascular unit that contains perfused vasculature and NSCs within 3-D matrix using a novel cell printing technology. 2) Establish the maturation process and functionalities of the synthesized structures with regard to matrix properties and culture parameters. 3) Examine the NSC behavior and cell fate using the engineered neurovascular unit; and determine critical factors that influence NSC fate and its relationship to the functional status of the vasculature.
Intellectual Merit: The proposed research will build a 3-D perfused vascular niche to study NSCs in a physiologically relevant experimental system, in which individual components and parameters can be easily manipulated. Using this system, the proposed research will define critical factors to achieve functionality of the vasculature and will elucidate underlying mechanisms of NSC self-renewal in the dynamically perfused system. Since vasculature is a key element of many adult stem cell niches, this research will have broader ramifications in studying other stem cell fields. Overall, this work will identify design principles and operating parameters for the printed structures to support the growth of the surrounding tissues in vitro, and thereby lay the foundation to fabricate tissues of appropriate thickness for biomedical applications in the future.
Broader Impacts: The proposed research has broader scientific impact in generating fundamental knowledge related to 3-D vascular tissue formation and its role in regulating NSC fate. Therefore, the proposed studies are expected to help develop methods for the ex vivo expansion of patient-specific NSCs to treat spinal cord injury and neurodegenerative diseases, which will benefit patients and the society at large. Research will be integrated with educational and outreach activities targeting K-12 education and underrepresented groups. Activities demonstrating how engineers can solve societal challenges will provide incentives to students to pursue careers in science and engineering.
