Central Nervous System Tissue Organogenesis via Precise Growth Factor Tethering



 DESCRIPTION (provided by applicant): Spinal cord injury (SCI) results in permanent loss of sensory input and motor function below the damaged region of the spinal cord. There is currently no available treatment for SCI to recover lost function. One exciting prospective strategy is the administration of stem cells to regenerate and functionally restore damaged spinal cord tissue. However, this approach is fraught with challenges as delivered cells lack the instructive cues necessary for successful integration and outcomes; most clinical work simply transfuses patients with stem cells which proves insufficient for treating SCI. Biomaterial-based strategies offer a solution to this challenge: rather than expecting the stem cells to integrate on their own, we can provide them with a support structure and the necessary instructive cues. We have shown that a naturally-derived hydrogel material, methacrylamide chitosan (MAC), can safely encapsulate adult neural stem cells (aNSCs) and provide a biomimetic matrix necessary for in vivo transplantation. Additionally, we can immobilize important lineage-specifying signaling proteins to this material through a unique application of protein engineering and click chemistry. Recently, we discovered that, when exposed to the subcutaneous environment, aNSCs encapsulated within a MAC-based neural guidance conduit and with a single immobilized neurogenic fusion protein will form developing neural epithelium. This is important, as neural epithelium represents an immature precursor to mature central nervous system (CNS) tissue. Thus, we hypothesize that our engineered conduit could be matured ectopically within the subcutaneous tissue and then transplanted into a damaged spinal cord, where it would develop and integrate with damaged tissue. This new SCI treatment paradigm will be approached through two aims. First, we aim to quantify and substantiate the environment that leads to the formation of nascent neural tubes in constructs implanted in subcutaneous tissue. Second, we aim to improve and implement the subcutaneous- matured construct to treat SCI. As we progress through this project, the information gained will be of use not only to treat SCI but also to help understand the complex behavior of stem cell-biomaterial interactions.