Human Primordial Germ Cells in a Dish

Abstract

Researchers have cultured cells that look and act like human primordial germ cells (PGCs)—and they have done it reproducibly, in abundance. Analysis of these cells, derived from both human embryonic stem cells and induced pluripotent cells, reveals some of the factors that drive PGC specification and development [1]. Researchers have previously produced mouse PGCs in a dish, but this transformation has proven more recalcitrant from human stem cell lines, which give rise to PGCs only at low frequency. Jacob Hanna and M. Azim Surani overcame this barrier, starting with a protocol they had previously developed to generate embryonic stem cells or induced pluripotent stem cells. Their protocol yields ‘‘naive’’ pluripotent cells that resemble the blastocyst inner cell mass, in contrast with previous methods, which yielded cells with a slightly more differentiated state, akin to cells of the epithelial postimplantation epiblast. The researchers could handily generate PGC-like cells by applying a molecular cocktail similar to that used to derive PGC-like cells from mouse stem cells. The resulting cells had similar RNA profiles as human germline tumor cells and primordial germ cells derived from aborted human fetuses. The cultured cells also showed signs of epigenetic changes—DNA demethylation—known to occur in PGCs. Further analysis, including gene knockout studies, identified some differences and similarities with mouse PGCs. For instance, the researchers found that the transcriptional regulator SOX17 is a key regulator of PGC-like fate in human cells—a role that it does not seem to serve in mice, where it is better known for specifying endoderm. The researchers identified some of the factors downstream of SOX17, including BLIMP1, which seems to repress somatic genes during specification of PGCs. BLIMP1 is also involved in mouse PGC fate. The findings open the door to the possibility of generating sperm and egg cells in cell culture. But for the more immediate future, this experimental system should be invaluable for answering basic questions about human development at its earliest stages.