Single-Cell RNA Sequencing Reveals Cellular Heterogeneity Across Distinct Anatomical Prostate Zones

Researchers at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center have identified a distinct type of prostate cell that may help solve the long-standing mystery of why benign prostatic hyperplasia (BPH) - a noncancerous enlargement of the prostate that commonly affects men as they age - develops almost exclusively in one region of the prostate.

Using single-cell RNA sequencing, a technology that allows researchers to examine which genes are active in individual cells from different regions of the human prostate, the researchers identified a previously unrecognized subtype of basal epithelial cell that was highly concentrated in the region surrounding the urethra where BPH typically develops. The region, known as the transition zone, contained cells that had high expression of a gene called WIF1, and these cells were significantly more abundant in prostate tissue from men with BPH.

The findings, published Sept. 10 in The Journal of Pathology, could provide new clues about the biological processes that cause BPH and ultimately point to more precise ways to prevent or treat the condition.

BPH is characterized by an overgrowth of prostate cells that becomes increasingly common with age. As the prostate enlarges, it can squeeze the urethra and interfere with the flow of urine, causing symptoms including frequent or nighttime urination, a weak urine stream and difficulty completely emptying the bladder.

"Although BPH affects millions of men worldwide, scientists still do not fully understand why it develops primarily in a region of the prostate known as the transition zone, while other regions of the gland remain relatively unaffected," says senior author of the study Vasan Yegnasubramanian, M.D., Ph.D., professor of oncology, pathology, and radiation oncology and molecular radiation sciences at the Johns Hopkins Kimmel Cancer Center, and director of inHealth Precision Medicine at Johns Hopkins Medicine.

The prostate is divided into several anatomical regions, including the peripheral, central and transition zones. These regions have different cellular characteristics and different susceptibilities to disease. BPH arises almost exclusively in the transition zone, while most prostate cancers develop in the peripheral zone.

To better understand these differences, the research team, led by Yegnasubramanian, Rulin Wang, M.D., research associate, and Angelo De Marzo, M.D., Ph.D., professor of pathology at the Johns Hopkins University School of Medicine and associate director of cancer research pathology at the Kimmel Cancer Center, studied noncancerous prostate tissue collected from 10 men undergoing surgery for localized prostate cancer.

They obtained tissue from the three major zones of the prostate and examined which genes are turned on or off in nearly 130,000 individual cells. The researchers first identified the major types of cells found throughout the prostate, and then took a closer look at basal epithelial cells, which help form the lining of the prostate.

They discovered four distinct types of basal cells. One type stood out because it expressed high levels of WIF1 and several other genes concentrated in the transition zone. Additional laboratory tests confirmed that the cells, called WIF1-positive basal cells, were abundant in the transition zone but nearly absent from the peripheral and central zones.

"The analysis revealed that these cells possess molecular features associated with tissue remodeling that could contribute to prostate enlargement as well as an ability to communicate with neighboring cells, suggesting they may help establish the unique biological environment of the transition zone," says Wang, first author of the study.

We also found that WIF1-positive basal cells are expanded in BPH tissues, raising the possibility that they contribute to the regional processes that make the transition zone particularly susceptible to BPH."

Rulin Wang, M.D., Research Associate, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

By uncovering this distinct cell population associated with the region where BPH begins, the research provides new insight into the cellular mechanisms underlying prostate growth and remodeling, the researchers say. These findings, they add, offer a foundation for future studies aimed at understanding how BPH develops, and may ultimately support the development of more precise ways to prevent, diagnose and treat this common condition.