Abstract
Induced pluripotent stem cells (iPSCs) allow researchers to make customized patient-derived cell lines by reprogramming noninvasively retrieved somatic cells. These cell lines have the potential to faithfully represent an individual’s genetic background; therefore, in the absence of available human brain tissue from a living patient, these models have a significant advantage relative to other models of neurodevelopmental disease. When using human induced pluripotent stem cells (hiPSCs) to model X-linked developmental disorders or inherited conditions that undergo sex-specific modulation of penetrance (e.g., autism spectrum disorders), there are significant complexities in the course and status of X chromosome inactivation (XCI) that are crucial to consider in establishing the validity of cellular models. There are major gaps and inconsistencies in the existing literature regarding XCI status during the derivation and maintenance of hiPSCs and their differentiation into neurons. Here, we briefly describe the importance of the problem, review the findings and inconsistencies of the existing literature, delineate options for specifying XCI status in clonal populations, and develop recommendations for future studies.
Highlights
One third of autism spectrum disorder (ASD) patients have an identifiable pathogenic genetic variant, and as sequencing becomes more widespread, this percentage increases [1]
While results from Marchetto et al indicate that human induced pluripotent stem cells (hiPSCs) undergo X chromosome reactivation (XCR), Ananiev et al yielded results bolstering reports that the inactivation status of the somatic cell is maintained during reprogramming [22,23,24,25,26]
Human Induced pluripotent stem cells (iPSCs) represent an ethically acceptable, increasingly widely available resource for developing cellular models of disease. These models are important in autism research, given the relative lack of availability of the affected primary tissue for biological studies, marked heterogeneity in the genetic influences on ASD across affected individuals, the prevalence of the condition, and the availability of effective technologies for reprogramming noninvasively derived cells from individual patients [9]
Summary
One third of autism spectrum disorder (ASD) patients have an identifiable pathogenic genetic variant, and as sequencing becomes more widespread, this percentage increases [1]. This lack of consistency in results is apparent in research modeling Rett syndrome in human hiPSCs. For example, while results from Marchetto et al indicate that hiPSCs undergo X chromosome reactivation (XCR), Ananiev et al yielded results bolstering reports that the inactivation status of the somatic cell is maintained during reprogramming [22,23,24,25,26].
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