SALT LAKE CITY – New research from scientists at Huntsman Cancer Institute (HCI) at the University of Utah and collaborators at University of Utah Health (U of U Health) sheds light on the complex process that occurs in the development of human sperm stem cells. This is the first study to characterize the changes human sperm stem cells undergo as they mature. The results have implications for understanding male infertility as well as cancer development and were published today in the journal Cell Stem Cell.
Previous studies of sperm stem cells have been limited to model systems, including mice. But this first study of developing human sperm stem cells revealed this process was much more complex in humans than had been previously understood. Using genome analysis tools, scientists outlined the multistage process that sperm stem cells undergo during their normal development.
"This information yields new insights into how sperm stem cells function and develop under normal circumstances," says the study's lead author Bradley Cairns, PhD, senior director of basic science at HCI and professor and chair of oncological sciences at the U of U. "We have built a very important framework we can now use to help us understand what happens when things go wrong, resulting in issues like infertility and cancer in men."
In the study, scientists examined all of the genes that turn 'on' or 'off' in any given cell during normal development. Using single cell RNA sequencing analysis, the Cairns lab profiled cells individually, establishing the gene expression profile in human sperm stem cells.
Their findings outlined four distinct cellular phases of sperm stem cells maturation, revealing how the stem cells progress from a "quiescent" state, to a "proliferation" state during which stem cells divide, to a final "differentiation" state when stem cells mature to become sperm. Specifically, the data reveal distinct transitions in factors that influence the different cellular states including cell cycle regulators, transcription factors, and signaling factors.
"Working with my patients with infertility, I have seen how devastating this diagnosis can be," says co-author and reproductive urologist James Hotaling, MD, also an assistant professor of surgery at U of U Health. "This study will help us understand what causes infertility in some cases."
The results may also have implications for understanding how some cancers arise. Men with infertility are known to be at higher risk for certain cancers including testicular and prostate cancers. "Our study sheds new light on how genes normally function in sperm stem cells," says Cairns. "The next steps will be to use this knowledge to better understand what changes happen when sperm stem cells don't develop normally and instead convert into cancer cells."
The authors believe the results of the study could lead to better tools for diagnosing and treating patients with male infertility, as well as uncovering the complicated genetic changes that underlie cancers associated with male infertility.
Cairns and Hotaling collaborated with first author Jingtao Guo and co-authors Edward Grow, Chongil Yi, Patrick Murphy, Candice Wike, and Douglas Carrell. The research is titled "Transcription, Signaling and Metabolic Transitions During Human Spermatogonial Stem Cell Differentiation".
This study was funded by the National Institutes of Health/National Cancer Institute P30 CA042014, the Howard Hughes Medical Institute, the University of Utah, and the Huntsman Cancer Foundation.
Huntsman Cancer Institute (HCI) at the University of Utah is the official cancer center of Utah. The cancer campus includes a state-of-the-art cancer specialty hospital as well as two buildings dedicated to cancer research. HCI treats patients with all forms of cancer and operates several clinics that focus on patients with a family history of cancer. As the only National Cancer Institute (NCI)-Designated Comprehensive Cancer Center in the Mountain West, HCI serves the largest geographic region in the country, drawing patients from Utah, Nevada, Idaho, Wyoming, and Montana. HCI scientists have identified more genes for inherited cancers than any other cancer center in the world, including genes responsible for hereditary breast, ovarian, colon, head, and neck cancers, along with melanoma. HCI manages the Utah Population Database – the largest genetic database in the world, with information on more than 9 million people linked to genealogies, health records, and vital statistics. The institute was founded by Jon M. and Karen Huntsman. Mr. Huntsman is a Utah philanthropist, industrialist, and cancer survivor.
University of Utah Health is the state's only academic health care system, providing leading-edge and compassionate medicine for a referral area that encompasses 10% of the U.S., including Idaho, Wyoming, Montana and much of Nevada. A hub for health sciences research and education in the region, U of U Health touts a $291 million research enterprise and trains the majority of Utah's health care professionals at its Schools of Medicine and Dentistry and Colleges of Nursing, Pharmacy and Health. Staffed by more than 20,000 employees, the system includes 12 community clinics and four hospitals — University Hospital; University Neuropsychiatric Institute; Huntsman Cancer Institute and the University Orthopaedic Center. For eight straight years, U of U Health has ranked among the top 10 U.S. academic medical centers in the rigorous Vizient Quality and Accountability Study, including reaching No. 1 in 2010 and 2016.