Scientists create early sperm cells from stem cells in a lab-grown mini-testis

Researchers have taken an important step toward understanding male fertility by successfully generating immature sperm precursor cells from human stem cells inside a laboratory-grown "mini-testis." The findings, published in the journal Cell Stem Cell, could pave the way for new approaches to studying infertility and developing future fertility treatments.

Male infertility affects about 9% of men of reproductive age in the United States. One of its underlying causes is disruption of germline development—the biological process through which embryonic cells become sperm. Until now, scientists have lacked laboratory models that accurately reproduce this complex process.

To overcome this challenge, researchers used induced pluripotent stem cells (iPSCs) derived from human blood cells and rhesus macaque cells. These versatile cells can be reprogrammed into almost any cell type. By exposing them to carefully selected molecular signals, the team converted them into primordial germ cell-like cells (PGCLCs)—the earliest precursors of sperm cells.

Because these immature germ cells cannot develop without support, the researchers combined them with supportive cells from fetal mouse testes. The cells self-organized into a three-dimensional structure known as a xenogeneic reconstituted testis (xrTestis), which closely mimics the architecture of a natural testis.

Within this miniature organ, seminiferous tubules—the structures where sperm normally develop—began to form. The lab-grown germ cells closely resembled natural human germ cells in both appearance and gene activity during the earliest stages of sperm development.

To allow the tissue to mature further, the researchers transplanted the mini-testes into the kidneys of immunodeficient mice, where they continued developing for eight to nine months, far longer than would be possible in a conventional laboratory culture.

Using this approach, the team successfully produced human germ cells and, for the first time, generated macaque spermatogonia—immature sperm-forming cells—from stem cells. These laboratory-grown cells showed up to 97% similarity to naturally occurring germ cells in humans and monkeys.

The study also identified two proteins, NANOS3 and DND1, as essential for maintaining germ cell identity and preventing them from transforming into other cell types. In addition, the researchers found that retinoic acid, a derivative of vitamin A, serves as the signal that initiates sperm cell maturation.

Although the work does not produce fully mature, functional sperm and is not a treatment for infertility, it provides one of the most advanced laboratory models of early sperm development in primates to date. Scientists say the platform could help uncover the genetic causes of male infertility, improve disease modeling, and evaluate the safety and effectiveness of future fertility therapies before they are tested in humans.

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