Scientists at Cincinnati Children’s Hospital have uncovered an important clue in the complex puzzle of male infertility. Their new research, published on Oct. 26, 2021, in Cell Reports, reveals how a specific gene affects the function of cells that are essential for sperm production.
The study focuses on Sertoli cells—also known as “nurse cells”—which are found inside narrow tubes in the testes called seminiferous tubules. These cells provide critical support and nutrients to developing sperm.
Led by co-first authors Anna Heinrich, BS, Bidur Bhandary, PhD, and senior author Tony De Falco, PhD, the team used mouse models to examine what happens when the gene Cdc42 is missing or not working properly. They discovered that the loss of this gene disrupts the normal orientation, or polarity, of Sertoli cells. Misaligned cells struggle to support sperm development and may die off, which ultimately reduces sperm production.
Interestingly, the gene malfunction affects sperm production only in adult testes—not in juveniles. This finding suggests that the role of the gene changes over time.
Why This Matters
Infertility affects nearly one in seven couples in the United States. Male infertility is a factor in many of these cases. Although it’s not yet clear how often Sertoli cell failure is to blame, the new findings could help in developing better diagnostic tools or future treatments.
However, directly targeting the Cdc42 gene is unlikely to be a short-term solution. That’s because this gene is important in many parts of the body. Modifying it could cause unintended effects elsewhere or even pass risks on to future generations.
“For these reasons, there must be a high bar set for regulating, testing, and validating the use of gene editing technologies in human patients,” said De Falco.
Instead, researchers believe this discovery could lead to new ways to detect Sertoli cell issues. Currently, diagnosing a problem with these cells usually requires a biopsy. In the future, non-invasive tests could help spot children at risk of developing Sertoli cell problems, opening the door to options like sperm or testicular biobanking before fertility declines.
Inspiration from Nerve Research
This breakthrough was partly inspired by research on nerve cells. Dr. Nancy Ratner’s lab at Cincinnati Children’s had previously found that Cdc42 is important for the structure of peripheral nerve cells. Since Sertoli cells are also highly organized, or polarized, the fertility team wondered if the gene had a similar role in the testes.
Using a mouse model developed by Ratner’s lab, they confirmed their suspicion: without Cdc42, Sertoli cells become disorganized and less effective.
What’s Next?
De Falco’s team now plans to study other cell types involved in sperm production. Germ cells, for example, also rely on a specific structure as they develop into sperm. Researchers want to find out if Cdc42 plays a similar role in these cells and others in the testis, such as immune, blood vessel, and hormone-producing Leydig cells.
Their ongoing work could bring new insights into the roots of male infertility—and potentially lead to better ways to prevent or treat it.
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