Stem Cell Mutations Found to Affect Differentiation Process

For the past decade, scientists have been using induced pluripotent stem cells (iPSCs) to study various diseases. However, the differentiation process of these cells is subject to significant technical variation, and the reasons behind this variation are primarily unknown. To shed light on this issue, a team of researchers from the University of Helsinki and University College London conducted a study, published in the journal Cell Genomics, following the differentiation of over 200 iPSC lines from healthy individuals to dopaminergic neurons and compared the differentiation outcomes with the mutation profile.

The researchers discovered that mutations acquired during the generation and subsequent culture of iPSC lines can majorly affect the differentiation process, independent of any disease-specific processes. In other words, the mutations that occur during the generation and cultivation of iPSCs can make them unsuitable for disease modeling, which can have significant implications for studying different diseases.

The study also found that the mutational processes compromising neuron production in laboratory conditions share some similarities with those present during brain formation. This discovery suggests that the mutations occurring during the generation and cultivation of iPSCs may have implications for brain development in vivo.

The scientists also observed that the iPSC lines with damaging mutations in a gene called BCOR produced fewer neurons, proliferated faster in culture, and presented significant differences in gene expression. BCOR is a key regulator during normal embryonic development, and its dysfunction can lead to developmental and neuropsychiatric disorders.

The team states that their findings call for caution when interpreting differentiation-related phenotypes using iPSC models to understand disease. They recognize that more optimization in the laboratory is needed to generate good disease models and eventually use them at scale with patients, specifically in developmental and neuropsychiatric disorders.

These findings denote broad differences in cell type composition between incorrectly and successfully differentiating lines, as well as significant changes in gene expression contributing to the inhibition of neurogenesis.

Controlling differentiation variability of iPSCs is essential in achieving reliable disease models, particularly in developmental biology, where substantial efforts are underway to model the cell-level consequences of genetic findings in developmental and neuropsychiatric disorders. These findings highlight the importance of optimizing lab conditions to generate reliable and robust iPSC models that can be used to study different diseases.