In the first-ever genome-scale analysis of
the puberty process in humans, researchers at Huntsman Cancer Institute (HCI) at
the University of Utah (U of U) outline distinct and critical changes to stem
cells in males during adolescence. They further outline how testosterone, and
the cells that produce testosterone, impact stem cells in male reproductive
organs. The researchers believe this study adds dramatically to a foundation of
knowledge that may yield insights into critical areas of human health, including
infertility and cellular changes that lead to cancer and other diseases.
The study, published today in the journal Cell Stem
Cell, was led by Bradley Cairns, Ph.D., cancer researcher at HCI and professor
and chair of oncological sciences at the U of U, in collaboration with
colleagues Jingtao Guo, Ph.D., a postdoctoral fellow in the Cairns lab at HCI,
James Hotaling, MD, associate professor of surgery at the U of U, and Anne
Goriely, Ph.D., associate professor of human genetics at the University of Oxford.
Puberty spurs numerous developmental changes
in humans and other mammals. Hallmarks of puberty include physical
characteristics easily visible to the naked eye, like rapid growth. These
physical and hormonal changes signal the process of a maturing body preparing
for reproductive years.
In the testis, the male reproductive organ
that makes and stores sperm and produces testosterone, puberty introduces
monumental changes at a cellular and physiological level. Thanks to new genomic
technologies, researchers are able to examine the expression of thousands of
genes in each individual cell in an entire organ, providing unprecedented
insights into cellular behavior during puberty.
Several types of cells within the testis
regulate reproductive health. Like the human body that changes along the path
from infancy to adulthood, these cells undergo major changes as the body
matures. These cells include spermatogonial stem cells that ultimately generate
sperm production, and niche cells that help form parts of the testis, such as
the seminiferous tubule, a tube-like structure within which sperm is formed. In
this study, researchers characterized how, just prior to puberty,
spermatogonial stem cells first expand significantly in number. These stem
cells progress toward meiosis, a special type of cell division that splits
the number of chromosomes from the parent cell in half, and also separates the
male X and Y sex chromosomes to create cells that, after fertilization of eggs
and considerable subsequent development, will ultimately result in either male
(Y-containing) or female (X-containing) children. Late in puberty, these stem
cells commit to creating mature sperm, which includes a tail piece for
motility. The researchers showed how two of the cells that form the stem cell
niche and chaperone this process—the myoid cells and Leydig cells—derive from a
common precursor, and mature during early puberty.
A major novel insight of this study was the
first-ever genomic analysis of the testis of adult transfemales (individuals
assigned male at birth, but who self-identify as female). For these
individuals, gender confirmation surgery is preceded by hormone therapy that
induces long-term testosterone suppression, enabling the examination of testis
lacking testosterone. By using samples donated after surgery, researchers
uncovered critical insights into the role of testosterone in maintaining testis
development. Genomic analysis of the cells from the testis of transfemales
showed that stem cells and other cells revert to earlier states of development
when compared to samples from male adolescents. Thus, Cairns and his colleagues
identified that testosterone is critical to maintaining the mature state of the
testis: if testosterone is no longer present, the testis reverts to an earlier
developmental state.
The major changes that occur in humans during
puberty give rise to numerous functions in normal development, like
reproductive health and fertility. But, when these processes go awry,
confounding challenges can result. Infertility is a relatively common health
issue. About 50 percent of the time, the underlying cause is attributed to the
male reproductive functions, which often include errors that occur during
puberty. The team hopes these insights into how cells develop will help yield
insights into what happens when developmental issues during puberty cause
changes that result in infertility.
The study also informs understanding of
cancer and other diseases that arise due to errors in cellular processes.
"The majority of the time, testicular cancers arise when stem cells in the
testis are misregulated," said Cairns. "We want to understand how
these changes can cause testicular tumors; however, we need to know what should
normally happen before we can identify ways to prevent or more effectively
treat these cancers."
In juveniles, cancers and reproductive health
intersect via a medical process called oncofertility; that is, the study of how
to retain fertility in adolescent and young adult cancer patients whose
reproductive health and fertility may be impacted by their cancer, or as a
result of side effects of cancer treatment. "Some chemotherapies can
result in young men with cancer not being able to have children—the
chemotherapy can cause changes to their stem cells," said Cairns. "My
hope and expectation is that our research will provide a foundation for
creating options to support the reproductive health of young men affected by
cancer through a better understanding of how these stem cells survive, are
supported, and develop."
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