In a first, scientists produced male and female cells from a single person

This is because, when people are recruited for studies, gender is only one factor that defines them. It's often unclear whether people respond differently to an illness or treatment because of their gender, genes, health background, or a range of other factors.

Now a research team led by Prof. Benjamin Reubinoff, director of the Swartz Stem Cell Research Center at the Goldyne Savad Institute of gene therapy, created male and female cells that are genetically identical except for their sex chromosomes.

This allows researchers to compare and contrast how these cells respond to medication or use them to model illness in a way that is free from the influences of other genetic or environmental factors.

A genetically identical model of male and female cells

To create the model, researchers obtained cells from the repositories of the Coriell Institute for Medical Research, where people donate samples for use in a wide range of biomedical research projects. The cells came from a donor with Klinefelter syndrome, which is characterized by the presence of an extra X chromosome in their cells.

However, in this case, the donor had a rare "mosaic" form of Klinefelter syndrome, where there is a mix of cells with different numbers of sex chromosomes. In this condition, some cells contain three sex chromosomes (XXY), some contain two X chromosomes, and some have only one X and one Y chromosome.

Rebooting cells into stem cells

Using cellular reprogramming, researchers transformed these mature white blood cells into induced pluripotent cells, also known as iPS cells. iPS cells can regenerate and differentiate into any other cell type, including neurons and muscle cells.

The team conducted experiments to confirm and replicate findings from previous studies using other models. For example, they found that certain genes were more active in XX or XY cells. They also used their stem cells to create immature versions of neurons and observed sex-based differences in their early development.

"It was reassuring to see that the model really shows differences between the sexes that were reported from other systems," said Prof. Benjamin Reubinoff.

Gender-based approach to illnesses and treatments

It is essential to explore the differences in how men and women respond to illnesses and drugs. For example, some conditions, such as heart disease and osteoporosis, are more common in one sex than the other, while others, such as autoimmune diseases, affect males and females differently.

Understanding these differences can help researchers and healthcare providers to develop gender medicines for males and females. It can also help to improve patient outcomes by allowing healthcare providers to tailor treatment plans to the specific needs of their patients.

The study was published in Stem Cell Reports.

Abstract:

Biological sex is a fundamental trait influencing development, reproduction, pathogenesis, and medical treatment outcomes. Modeling sex differences is challenging because of the masking effect of genetic variability and the hurdle of differentiating chromosomal versus hormonal effects. In this work we developed a cellular model to study sex differences in humans. Somatic cells from a mosaic Klinefelter syndrome patient were reprogrammed to generate isogenic induced pluripotent stem cell (iPSC) lines with different sex chromosome complements: 47,XXY/46,XX/46,XY/45,X0. Transcriptional analysis of the hiPSCs revealed novel and known genes and pathways that are sexually dimorphic in the pluripotent state and during early neural development. Female hiPSCs more closely resembled the naive pluripotent state than their male counterparts. Moreover, the system enabled differentiation between the contributions of X versus Y chromosome to these differences. Taken together, isogenic hiPSCs present a novel platform for studying sex differences in humans and bear potential to promote gender-specific medicine in the future.