One of the most profound advances in the last decade of biomedical research has been the development of human induced pluripotent stem cell (hiPSC) models for identification of disease mechanisms and drug discovery. Human iPSC technology has the capacity to revolutionize healthcare and the realization of personalized medicine, but differentiated tissues derived from stem cells come with major criticisms compared to native tissue, including variability in genetic backgrounds, a lack of functional maturity, and differences in epigenetic profiles. It is widely believed that increasing complexity will lead to improved clinical relevance, so methods are being developed that go from a single cell type to various levels of 2-D coculturing and 3-D organoids. As this inevitable trend continues, it will be essential to thoroughly understand the strengths and weaknesses of more complex models and to develop criteria for assessing biological relevance. We believe the payoff of robust, high-throughput, clinically meaningful human stem cell models could be the elimination of often inadequate animal models. To facilitate this transition, we will look at the challenges and strategies of complex model development through the lens of neurodegeneration to encapsulate where the disease-in-a-dish field currently is and where it needs to go to improve.

Keywords:
Induced pluripotent stem cells, Human stem cells, Neuron, Neurodegeneration, Alzheimer’s disease, Maturation, Epigenetics
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