Donor-derived male and female stem cells at Scientific First

SScientists have developed a new line of stem cells, all derived from the same person, that can be used to study sex differences without the confusion of interpersonal genetic differences.

Human-induced pluripotent stem cells (hiPSCs), which are cells taken from a person that are then reprogrammed to abandon their current functions and return to a stem cell-like state, have become tools valuable not only for therapeutic purposes but also for research into genetics. mechanisms underlying cell behavior and disease. However, findings gleaned from stem cell studies may not be broadly applicable, as the fact that all cells in a given line share the same genetic sequence makes it difficult to generalize the findings, especially when trying to investigate potential sex differences. .

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For this reason, a team of scientists led by Benjamin Reubinoff, an embryonic stem cell researcher at the Hadassah Medical Organization in Jerusalem, and MD-PhD student Ithai Waldhorn set out to create a new platform for studying genetic sex differences. As Reubinoff says The scientist, “The origin was really to generate a model to study sex differences, given the limitation of current studies that are based on larger cohorts, or comparing males with females, or using multiple cell lines. There was, he says, a need for “a simple model that can overcome the masking of genetic variability between individuals.”

To develop such a model, the team obtained cells from a cache that had been taken from someone with an unusual case of Klinefelter syndrome, a rare genetic condition that affects about 1 in 500 boys who are born with an extra copy of the X chromosome, resulting in an XXY genetic makeup. What made this person even more unusual, and ideal for Reubinoff’s vision, is that, in addition to the 47XXY cells characteristic of the condition, he also had a large number of 46XY cells, a phenomenon known as the mosaic phenotype. According to the study, published Nov. 24 in Stem Cell Reports, describes, the cell line taken from Klinefelter’s patient allowed the team to generate 46XX, 46XY, 45X0, and 47XXY hiPSCs that are otherwise genetically identical. This means that any observable differences between them (related, for example, to risk factors for disease or response to a drug) can almost definitely be attributed to genetic sex differences.

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“When you study individuals and you compare men with women and you find differences, you can’t tell if they stem from chromosomal differences or hormonal differences,” Reubinoff explains. “This model is unique because it allows you to differentiate between chromosomal effects and hormonal effects.”

Looking back, Reubinoff says he’s not sure why anyone had thought of developing multiple sexes from one person’s stem cells before, though it may have to do with the rarity of this particular form of Klinefelter. Mariana Argenziano, a stem cell biologist at Ncardia who works on generating stem cells for medical research and was not involved in the study, shares similar thoughts.

“In this case, the authors were lucky enough to find a case with a 47,XXY/46,XY/46,XX triple mosaicism, being able to isolate all the sexual antecedents of the same patients, working with naturally isogenic cells,” says Argenziano. The scientist in an email.

Argenziano adds that the study “was a very elegant and clean way to approach” the problem of studying sex differences in stem cells. “Testing for sex differences has been a problem in the stem cell field,” she says. “It’s no secret that males and females respond differently, but the barrier of different genetic backgrounds has always interfered with clean results and a real understanding of the effects of sex differences,” even when they take cells from family members. same nuclear family.

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In the study, the authors explored some potential uses of stem cells, such as tracking sex differences in the early stages of neural development, investigating whether the presence of the Y chromosome or an extra X chromosome led to changes in gene expression, and showing that the Y chromosome was linked to increased expression of genes associated with schizophrenia. Reubinoff says his lab will continue to study early development, but he hopes other researchers will broaden the platform to examine other aspects of chromosomal sex differences, especially disease progression and drug development. He says he was “very surprised and very excited” to see that his platform returned results that matched existing cohort studies, which he sees as a check on the model.

“I can see a lot of potential for these cells,” says Argenziano. “Drug testing is another major field where these cells can add a lot of value. Many pharmaceutical companies have established the use of stem cell-derived models in their compound testing, and the differences between men and women have not yet been addressed.”

Reubinoff admits that the fact that all the cells came from a single person is a limitation, but says that this could be overcome by generating similar lines from other Klinefelter mosaic samples. “I would say it would be good to have more similar lines from more genetic background,” he says, “to be able to confirm the results.”

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