A human isogenic iPSC-derived cell line panel identifies major regulators of aberrant astrocyte proliferation in Down syndrome

Abstract Astrocytes exert adverse effects on the brains of individuals with Down syndrome (DS). Although a neurogenic-to-gliogenic shift in fate-specification step has been reported, mechanisms and key regulators underlying accelerated proliferation astrocyte precursor cells (APCs) DS remain elusive. Here, we established human isogenic cell line panel based DS-specific induced pluripotent stem cells, XIST -mediated transcriptional silencing system trisomic chromosome 21, genome/chromosome-editing technologies to eliminate phenotypic fluctuations caused by genetic variation. The responses genes observed upon induction and/or downregulation are not uniform, only small subset show characteristic expression pattern, which is consistent proliferative phenotypes APCs. Comparative analysis experimental verification using gene modification reveal dose-dependent proliferation-promoting activity DYRK1A PIGP Our collection lines provides comprehensive set cellular models for further investigations.