Department of Neurology, Harvard Medical School, Boston Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, USA.
Mol Autism. 2020 Feb 19;11(1):16. doi: 10.1186/s13229-020-0320-2.
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by epilepsy, intellectual disability, and benign tumors of the brain, heart, skin, and kidney. Animal models have contributed to our understanding of normal and abnormal human brain development, but the construction of models that accurately recapitulate a human pathology remains challenging. Recent advances in stem cell biology with the derivation of human-induced pluripotent stem cells (hiPSCs) from somatic cells from patients have opened new avenues to the study of TSC. This approach combined with gene-editing tools such as CRISPR/Cas9 offers the advantage of preserving patient-specific genetic background and the ability to generate isogenic controls by correcting a specific mutation. The patient cell line and the isogenic control can be differentiated into the cell type of interest to model various aspects of TSC. In this review, we discuss the remarkable capacity of these cells to be used as a model for TSC in two- and three-dimensional cultures, the potential variability in iPSC models, and highlight differences between findings reported to date.
结节性硬化症（TSC）是一种常染色体显性遗传疾病，其特征为癫痫、智力障碍以及脑、心脏、皮肤和肾脏的良性肿瘤。动物模型有助于我们理解正常和异常的人类大脑发育，但构建能够准确重现人类病理学的模型仍然具有挑战性。最近，干细胞生物学的进展使得能够从患者的体细胞中诱导产生多能干细胞（hiPSCs），为 TSC 的研究开辟了新途径。这种方法与基因编辑工具（如 CRISPR/Cas9）相结合，具有保留患者特异性遗传背景的优势，并且能够通过纠正特定突变来生成同基因对照，从而实现特定突变的纠正。患者细胞系和同基因对照可以分化为感兴趣的细胞类型，以模拟 TSC 的各个方面。在这篇综述中，我们讨论了这些细胞在二维和三维培养中作为 TSC 模型的卓越能力、iPSC 模型的潜在可变性，并强调了迄今为止报告的发现之间的差异。
