Engineering Neural Tissue Patterning from Human Induced Pluripotent Stem Cells for Modeling Alzherimer's Disease

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders and causes cognitive impairment and memory deficits of the patients. The mechanism of AD is not well known, due to the lack of study materials, e.g., human brain tissues. Human pluripotent stem cells (PSCs) show the capacity to proliferate indefinitely and potent differentiation abilities, therefore, can be used to offer unlimited neural cell source for studying AD pathology and subsequent therapeutic purpose. Recently, the novel neural tissue patterning technology called organoid has been applied to generate mini-brain tissues, e.g., cerebral organoids, for modeling human brain development and neurological diseases. We hypothesize that this neural tissue patterning could also be utilized for AD-related pathogenesis research and partially reflect the disease hallmarks. To better understand the patterning method, we investigated the factors that influence the neural patterning, developed the patterning method for cortical organoids generation, and then applied it in establishment of AD models. First, we focused on the specific patterning factor-extracellular matrix (ECM) that regulate stem cell behavior, by cultivating PSCs on acellular ECM scaffolds and artificial ECM scaffolds, the auxetic polyurethane foams. Our data showed that Wnt/β-catenin signaling and Poisson's ratio played important roles in PSCs expansion and neural specifications. Then we developed the neural patterning method to generate cortical neural subtypes and cortical tissues, called cortical organoids, by tuning the sonic hedgehog signaling. Lastly, we used this cortical patterning method to model AD using patient specific PSCs cell line, and observed some AD-associated features, including an accumulated Aβ42 level and hyperphosphorylated tau. Our studies demonstrate the capacity of PSCs for modeling AD using neural patterning technology and provide a potential approach for AD therapy and drug screening.