Biomaterials Strategies to Enhance the Therapeutic Potential of Human Neural Stem Cells for Neural Tissue Regeneration

Transplantation of neural stem or progenitor cells (NSCs) represents a promising strategy to reconstruct the lesion cavity and promote brain tissue regeneration following traumatic brain injury. However, ongoing inflammation at the lesion site and the lack of supportive matrix structure and vasculature within the cavity present a hostile environment that results in low cell survival and poor control over differentiation and engraftment of the transplanted cells. We optimized an in situ crosslinkable hyaluronic acid (HA) hydrogel conjugated with laminin-derived peptide as a cell delivery matrix. It generated a robust neovascular network within the hydrogel at the lesion cavity when injected at 3 days following the CCI injury in a rat TBI model, and promoted significant vasculature network formation filling the lesion site at 4 weeks to 6 months following hydrogel implantation. Using this tailored HA hydrogel, delivering hNSCs in the format of spheroids for brain regeneration was superior to single cell transplantation in promoting cell survival following implantation. The majority of the grafted cells differentiated to Tuj1+ and MAP2+ neuronal progenitors and populated the entire lesion cavity. The human NSC-derived neuronal progenitors extended large numbers of axons into the host brain tissue. Since manipulation of cell transcriptional network is a more effective approach to promote stem cell differentiation, when compared to growth factors cocktails, we optimized a poly (β-amino ester) (PBAE)-based nanoparticle system to transfect hNSCs with a key transcription factors Neurogenin-2 (Ngn2) and generated a significantly larger number of neurofilament positive (NF+) mature neurons at the lesion site of CCI at 4 weeks post transplantation when compared to non-transfected cells. This approach holds great potential in promoting neuronal maturation in a tissue repair site, thus improving therapeutic outcomes of stem cell-based therapy for brain tissue regeneration.