Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA.
Mol Autism. 2020 Mar 23;11(1):21. doi: 10.1186/s13229-020-00322-9.
Advances in human pluripotent stem cell (hPSC) biology coupled with protocols to generate diverse brain cell types in vitro have provided neuroscientists with opportunities to dissect basic and disease mechanisms in increasingly relevant cellular substrates. At the same time, large data collections and analyses have facilitated unprecedented insights into autism genetics, normal human genetic variation, and the molecular landscape of the developing human brain. While such insights have enabled the investigation of key mechanistic questions in autism, they also highlight important limitations associated with the use of existing hPSC models. In this review, we discuss four such issues which influence the efficacy of hPSC models for studying autism, including (i) sources of variance, (ii) scale and format of study design, (iii) divergence from the human brain in vivo, and (iv) regulatory policies and compliance governing the use of hPSCs. Moreover, we advocate for a set of immediate and long-term priorities to address these issues and to accelerate the generation and reproducibility of data in order to facilitate future fundamental as well as therapeutic discoveries.
人类多能干细胞（hPSC）生物学的进展，加上体外生成多种脑细胞类型的方案，为神经科学家提供了在日益相关的细胞基质中剖析基本和疾病机制的机会。与此同时，大量的数据收集和分析促进了对自闭症遗传学、正常人类遗传变异以及人类大脑发育的分子景观的前所未有的深入了解。尽管这些见解使人们能够研究自闭症中的关键机制问题，但它们也突出了与使用现有 hPSC 模型相关的重要局限性。在这篇综述中，我们讨论了影响 hPSC 模型研究自闭症功效的四个问题，包括（i）方差来源，（ii）研究设计的规模和格式，（iii）与体内人类大脑的差异，以及（iv）监管政策和合规性，以规范 hPSC 的使用。此外，我们提倡一系列立即和长期的优先事项，以解决这些问题，并加速数据的生成和可重复性，以促进未来的基础和治疗发现。
