Journal
DEVELOPMENTAL DYNAMICS
Volume 249, Issue 1, Pages 46-55Publisher
WILEY
DOI: 10.1002/dvdy.60
Keywords
astrocytes; brain organoids; cortical tuber; CRISPR; Cas9; disease modeling; human pluripotent stem cells; mTOR; neurons; TSC1; TSC2; tuberous sclerosis complex
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Funding
- CIHR Funding Source: Medline
- NINDS NIH HHS [R01 NS097823] Funding Source: Medline
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Recent advances in human stem cell and genome engineering have enabled the generation of genetically defined human cellular models for brain disorders. These models can be established from a patient's own cells and can be genetically engineered to generate isogenic, controlled systems for mechanistic studies. Given the challenges of obtaining and working with primary human brain tissue, these models fill a critical gap in our understanding of normal and abnormal human brain development and provide an important complement to animal models. Recently, there has been major progress in modeling the neuropathophysiology of the canonical mTORopathy tuberous sclerosis complex (TSC) with such approaches. Studies using two- and three-dimensional cultures of human neurons and glia have provided new insights into how mutations in the TSC1 and TSC2 genes impact human neural development and function. Here we discuss recent progress in human stem cell-based modeling of TSC and highlight challenges and opportunities for further efforts in this area.
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