Researchers put sperm in reverse to form stem cells

For those of us who dream, at the low points in our lives, of shrinking backwards in time to a prenatal single-cell state: there might be hope.

The decisions you're trying to make are certainly microscopic compared with the original decision that your father's germline stem cells made when they committed themselves to becoming spermatogonia, the precursor to sperm, which eventually fertilized your mother's egg cell.

However, research done at the Hopkins School of Medicine may allow that decision to be unmade.

Researchers led by Erika Matunis, a professor in the cell biology department, have reversed the process of cell differentiation, going from sperm cells back to stem cells in the Drosophila (fruit fly) testis.

The paper that detailed this groundbreaking research was published last month in Cell Stem Cell.

"We knew from our previous work that cells destined to be sperm could revert back to being stem cells, but we didn't know how. Since dedifferentiation is an interesting phenomenon probably occurring in a lot of different stem cell populations, we wanted to know more about the process," said Matunis in a press release.

Cells that are "fated" to differentiate have been observed to reverse the process and dedifferentiate in several cases to replace stem cells in damaged or old tissues, but in this study, the researchers established a system to study spermatogonial dedifferentiation in fruit flies.

"Dedifferentiation occurs very rarely naturally in Drosophila testes," Matunis said. "Dedifferentiation does not require stem cells to be present, as they are generated from their daughter cells, so it could potentially be more of a 'last resort' to generating stem cells, as it is normally thought that only stem cells could generate stem cells."

Drosophila testes each have nine stem cells, which each divide to form two daughter cells, of which only one from the pair differentiates into an adult sperm cell, while the other remains a stem cell.

Matunis' team mutated the flies' genetic codes to cause both cells to differentiate, leaving no stem cells in the testes.But about a week later, the stem cell population in the testes had been replenished.

Scientists have long suspected the two protein system Jak-STAT (Janus kinase-signal transducer and activator of transcription) to be a major player in the dedifferentiation process observed in previous studies.

When Jak-STAT was removed from the cells, a little more than half of them were able to gain back stem cells, but when it was present, nearly every testis regained them. Jak-STAT is activated by clusters of connective tissue cells, called "hubs," which join together to create a niche in which stem cells naturally form.

However, the researchers removed these stem cells from the niche by increasing the levels of the differentiation factor bag-of-marbles (Bam), which forced them to become fully differentiated cells, or somatic cells.

After the researchers removed the Bam, which caused the pre-sperm cells to switch places with the newly-formed somatic cells and were able to enter into the niche and establish contact with the hub.

"My work implies that there is potentially a lot of movement in what was once thought of as a relatively static niche, and that cells could change positions with one another during dedifferentiation," Matunis said.

Now in the hub, these spermatogonia were acted on by Jak-STAT, causing them to dedifferentiate back into germline stem cells.

However, despite clear indications that they are major players in the process, it remains unclear exactly how Jak and STAT control dedifferentiation.

"We don't know if a cell is just reversing all of the steps to go back to being a stem cell or if it is doing something totally new and different, but we're eager to find out," Matunis said in a press release.