Realizing the potential of exploiting human IPSCs and their derivatives in research of Down syndrome

Down syndrome (DS) is a genetic condition characterized by intellectual disability, delayed brain development, and early onset Alzheimer's disease. The use of primary neural cells and tissues is important for understanding this disease, but there are ethical and practical issues, including availability from patients and experimental manipulability. Moreover, there are significant genetic and physiological differences between animal models and humans, which limits the translation of the findings in animal studies to humans. Advancements in induced pluripotent stem cells (iPSC) technology have revolutionized DS research by providing a valuable tool for studying the cellular and molecular pathologies associated with DS. Induced pluripotent stem cells derived from cells obtained from DS patients contain the patient's entire genome including trisomy 21. Trisomic iPSCs as well as their derived cells or organoids can be useful for disease modeling, investigating the molecular mechanisms, and developing potential strategies for treating or alleviating DS. In this review, we focus on the use of iPSCs and their derivatives obtained from DS individuals and healthy humans for DS research. We summarize the findings from the past decade of DS studies using iPSCs and their derivatives. We also discuss studies using iPSC technology to investigate DS-associated genes (e.g., APP, OLIG1, OLIG2, RUNX1, and DYRK1A) and abnormal phenotypes (e.g., dysregulated mitochondria and leukemia risk). Lastly, we review the different strategies for mitigating the limitations of iPSCs and their derivatives, for alleviating the phenotypes, and for developing therapies.