Discovery of Molecular Signatures of Immature Neurons in The Human Brain Throughout Life Provide New Insights into Brain Plasticity and Other Functions

A team led by researchers at the Perelman School of Medicine at the University of Pennsylvania has used advanced techniques to show that, in a key memory region of the brain called the hippocampus, immature, plastic neurons are present in significant numbers throughout the human lifespan. The findings, published this month in Nature, hope to resolve a long-running controversy over the existence of “adult neurogenesis”—the production of new immature neurons in the mature human brain. The discovery also paves the way for the deeper study of adult neurogenesis and its roles in memory, mood, behavior, and brain disorders.

“Many mammals generate new neurons in their brains throughout their lifespans which play a critical role in the brain’s plasticity, or ability to change and adapt over time. This ability to repair itself is especially important when the brain is damaged, which is what happens during a stroke or brain injury,” said senior author Hongjun Song, PhD, a Perelman Professor of Neuroscience at Penn. “This plasticity is also important for understanding diseases like Alzheimer’s, which affect a patient’s memory, among other functions.”

Read more about this research in Penn Medicine News (by Kelsey Odorczyk)

A newly identified stem cell regulator enables lifelong sperm production

Unlike women, who are born with all the eggs they’ll ever have, men can continue to produce sperm throughout their adult lives. To do so, they require a constant renewal of spermatogonial stem cells, which give rise to sperm.

This reinvigoration of stem cells depends on a newly characterized stem cell self-renewal factor called DOT1L, according to research by Jeremy Wang of the University of Pennsylvania School of Veterinary Medicine and colleagues. When mice lack DOT1L, the team showed, they fail to maintain spermatogonial stem cells, and thus, lack the ability to continuously produce sperm.

Scientists have discovered only a handful of such stem cell renewal factors, so the find, published in the journal Genes & Development, adds another entity to a rarified group.

“This novel factor was only able to be identified by finding this unusual genetic phenotype: the fact that mice lacking DOT1L were not able to continue to produce sperm,” says Wang, the Ralph L. Brinster President’s Distinguished Professor at Penn Vet and a corresponding author on the paper. “Identifying this essential factor not only helps us understand the biology of adult germline stem cells, but could also allow scientists to one day reprogram somatic cells, like skin cells, to become germline stem cells. That is the next frontier for fertility treatment.”

Read more about this research in Penn Today.

Frozen testicular tissue still viable after 20 years

The rate of survival for childhood cancers has increased dramatically in the last several decades, but a serious side effect of treatment is diminished fertility later in life. A potential treatment for boys facing cancer treatment would be to harvest, freeze, and, after the cancer is cured, reimplant their testicular tissue, which contains stem cells that could give rise to sperm.

What happens to that tissue, however, when subjected to the long-term freezing that could be necessary, has remained unclear.

A new study in rats led by University of Pennsylvania School of Veterinary Medicine researchers has shown that male testis tissue that is cryopreserved can be reimplanted after more than 20 years and will go on to make viable sperm. The work, led by senior research investigator Eoin C. Whelan, was published in PLOS Biology.

While the long-frozen testicular tissue could produce sperm, the team found that the long delay did come with a cost in reduced sperm production compared to tissue that is only briefly frozen. The results may have important implications for treatment of prepubertal boys with cancer, for whom chemotherapy may be preceded by harvesting and freezing of testicular tissue for eventual reimplantation.

“The glass-half-empty way of looking at this is that stem cells do seem to be compromised in their ability to regenerate sperm after a long freezing time,” Whelan says. “But the good news is that sperm can be produced, and they seem to be transcriptionally normal when we examined their RNA.”

The study was conducted in the laboratory of Ralph L. Brinster, the Richard King Mellon Professor of Reproductive Physiology at Penn Vet, a renowned scientist of reproductive biology.

Read the full story about this study in Penn Today

Piezo1 Possible Key to Supporting Muscle Regeneration in Duchenne Muscular Dystrophy

One protein, Piezo1, is key to marshalling muscle stem cells’ unique shapes and response to injuries, but it is in low supply in those with Duchenne muscular dystrophy, according to a team at the Perelman School of Medicine at the University of Pennsylvania. However, when they re-activated Piezo1, it allowed muscle stem cells in mice to return to their normal, distinctly-shaped states so that they could repair broken down, dystrophic muscles. These findings, published in Science Advances, open the door to potential molecular-level treatments that may slow or even halt the progression of muscular dystrophy.

“We showed that muscle stem cells have a variety of extensions that are used to sense their environment to respond to injuries, all of which is controlled by the protein Piezo1,” said the study’s lead author, Foteini Mourkioti, PhD, an assistant professor of Orthopaedic Surgery. “This is in contrast to previous belief, which considered muscle stem cells to be simply round and dormant in undamaged muscles.”

Read more about this research in Penn Medicine News.