Scientists at the Centre for Genomic Regulation (CRG) and other institutions have published details of a treatment that accelerates the production of female induced pluripotent stem cells (iPSCs) from mouse neural precursors, which they claim has the potential to improve disease modeling and drug testing for people with two X chromosomes. The findings were published in Science Advances in a paper titled, “The Interferon-γ Pathway Enhances Pluripotency and X-Chromosome Reactivation in iPSC Reprogramming.”
Identifying a method for producing iPSCs rapidly is important because of their value for studying disease mechanisms, developing new treatments, and their regenerative potential. The current process for reprogramming specialized adult cells like skin cells back into a pluripotent state is laborious requiring both “activation of the pluripotency network” and “erasing the epigenetic memory of the somatic state.”
But there may now be a way to get iPSCs faster using one of the body’s own proteins. According to the Science Advances paper, the researchers discovered that by adding interferon-gamma (IFN𝛾) to mouse neural precursor cell cultures, they could cut the reprogramming time by a full day. The finding is surprising because IFN𝛾 is normally used in the body’s response to things like viral infections. This study marks the first time it has been shown to work in cellular programming.
Indeed, the mechanism that IFN𝛾 uses to fight infections could explain why the protein works in the cellular programming context. “Interferon-gamma can help cells respond to viral infections by opening up DNA and rapidly activating gene expression,” said Mercedes Barrero, PhD, a researcher at the CRG and first author on the study. “One possible explanation is that, by opening up DNA like a clam, it exposes certain genes, making it easier to reprogram them and accelerating the transformation of the cell into a stem cell.”
Specifically, IFN𝛾 treatment “stimulates STAT3 signaling and the pluripotency network and leads to enhanced TET-mediated DNA demethylation, which consequently boosts X-reactivation,” according to the paper. In female iPSCs, activating both X chromosomes is a hallmark of high-quality stem cells. Female adult cells usually have one dormant X chromosome to avoid the effects of a double dose of gene products from two active X chromosomes simultaneously.
Bernhard Payer, PhD, CRG researcher and senior author of the study, explained that adding IFN𝛾 made X-chromosome reactivation “twice as efficient early in the reprogramming process in mouse cells.” He further noted that “while the resulting iPSCs were the same quality, we suspect it’s likely to be different in human stem cells, and the viral defense protein is likely to be an important player in improving the quality of human female stem cell lines.”
Studying female iPSCs is helpful for understanding genetic disorders that are linked to the X chromosome. They can be used to create more accurate models for diseases or to test the efficacy and safety of different therapies. They could even eventually be used to grow tissues and organs for transplantation. “Personalized medicine for women demands high-quality female stem cell lines” without which “experimental therapies might fail,” Payer said. “Our findings are one step forward in enabling the production of high-quality female iPSCs.”
