Biomaterial Strategies to Bolster Neural Stem Cell-Mediated Repair of the Central Nervous System.

Stem cell therapies have the potential to not only repair, but to regenerate tissue of the central nervous system (CNS). Recent studies demonstrate that transplanted stem cells can differentiate into neurons and integrate with the intact circuitry after traumatic injury. Unfortunately, the positive findings described in rodent models have not been replicated in clinical trials, where the burden to maintain the cell viability necessary for tissue repair becomes more challenging. Low transplant survival remains the greatest barrier to stem cell-mediated repair of the CNS, often with fewer than 1-2% of the transplanted cells remaining after 1 week. Strategic transplantation parameters, such as injection location, cell concentration, and transplant timing achieve only modest improvements in stem cell transplant survival and appear inconsistent across studies. Biomaterials provide researchers with a means to significantly improve stem cell transplant survival through two mechanisms: (1) a vehicle to deliver and protect the stem cells and (2) a substrate to control the cytotoxic injury environment. These biomaterial strategies can alleviate cell death associated with delivery to the injury and can be used to limit cell death after transplantation by limiting cell exposure to cytotoxic signals. Moreover, it is likely that control of the injury environment with biomaterials will lead to a more reliable support for transplanted cell populations. This review will highlight the challenges associated with cell delivery in the CNS and the advances in biomaterial development and deployment for stem cell therapies necessary to bolster stem cell-mediated repair.

Photodynamic studies reveal rapid formation and appreciable turnover of tau inclusions.

Accumulation of the tau protein in fibrillar intracellular aggregates is a defining feature of multiple neurodegenerative diseases collectively referred to as tauopathies. Despite intensive study of tau, there is limited information on the formation and clearance dynamics of tau inclusions. Using rAAV vectors to mediate expression of Dendra2-tagged human wild-type, P301L and pro-aggregant P301L/S320F tau proteins, with and without the addition of exogenous tau fibrillar seeds, we evaluated tau inclusion dynamics in organotypic brain slice culture (BSC) models using long-term optical pulse labeling methodology. Our studies reveal that tau inclusions typically form in 12-96 h in tauopathy BSC models. Unexpectedly, we demonstrate appreciable turnover of tau within inclusions with an average half-life of ~ 1 week when inclusions are newly formed. When BSCs with inclusions are aged in culture for extended periods, tau inclusions continue to turnover, but their half-lives increase to ~ 2 weeks and ~ 3 weeks after 1 and 2 months in culture, respectively. Individual tau inclusions can be long-lived structures that can persist for months in these BSC models and for even longer in the human brain. However, our data indicate that tau inclusions, are not 'tombstones', but dynamic structures with appreciable turnover. Understanding the cellular processes mediating this inclusion turnover may lead to new therapeutic strategies that could reverse pathological tau inclusion formation.