Reconstructing a niche for germ cells to mature

Researchers from the group of reNEW Principal Investigator Professor Susana Chuva de Sousa Lopes at Leiden University Medical Center (LUMC) have successfully advanced the maturation of stem cell–derived primordial germ cells in culture. By co-culturing these cells in two distinct human niche compartments, they observed two different developmental trajectories. The findings, published in Stem Cell Reports, underscore the importance of dynamic cellular niches in guiding germ cell development.

Human induced pluripotent stem cells (hiPSCs) have created valuable new opportunities to study human germ cell development. From hiPSCs, researchers can generate cells resembling early primordial germ cells, known as hPGCLCs. However, maturing these hPGCLCs to later developmental stages in vitro has remained a major challenge.

Although previous studies have shown progress by co-culturing hPGCLCs with mouse ovaries, it has been unclear whether exposure to a human environment would result in more efficient or more advanced maturation. The reNEW team therefore exposed hPGCLCs to human gonadal tissues and evaluated the impact on germ cell development.

Reconstituting the niche
“We used two approaches to recreate the natural niche of developing germ cells in the laboratory,” said Chuva de Sousa Lopes. “First, we dissociated human fetal ovaries and combined these cells with hPGCLCs. As observed in earlier studies using mouse ovaries, some hPGCLCs matured further into oogonia. However, the majority of the cells unexpectedly dedifferentiated rather than progressed in development.”

The researchers hypothesized that this outcome reflected a mismatch between the fetal ovary niche and the physiological environment of early germ cell progenitors in the human embryo. They therefore explored an alternative niche.

Different niche, different outcome
“We next co-cultured hPGCLCs with amniotic cells present at the corresponding stage of embryonic development. The results were striking,” Chuva de Sousa Lopes explained.

In contrast to the fetal ovary condition, hPGCLCs exposed to amniotic cells acquired migratory properties, reaching the subsequent maturation stage observed in vivo. This marked difference highlights how distinct cellular niches can steer hPGCLCs along divergent developmental paths. These migratory hPGCLCs may now respond more adequately to the ovary niche.

A foundation for future research
The migratory capacity gained by hPGCLCs after exposure to amniotic cells may represent a crucial intermediate step toward generating functional gametes in the laboratory. Beyond its implications for reproductive biology, the study also provides new insights into human germ cell development and may help advance research into the effects of environmental toxins and chemical compounds on this process.