WIKIMEDIA, NISSIM BENVENITSKYPluripotent stem cells are capable of generating all embryonic cell lineages but, until now, scientists could seldom manipulate induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) to generate extra-embryonic cell types, such as placental cells. A study published this week (January 12) in Science has now shown that removing one particular microRNA—miR-34a—from a stem cell can kick off a molecular pathway that induces endogenous retroviruses and, at the same time, enables iPSCs and ESCs to consistently form extra-embryonic cells in a dish.
The results suggest that a particular class of noncoding RNA works in concert with the latent viral elements of the genome work to limit stem cell potential, and that removing a key miRNA can lift this limitation—at least in vitro.
“At first we were a bit dubious about our findings,” said coauthor Lin He, an associate professor of developmental biology at the University of California, Berkeley. “In this experiment, we definitively show that the progeny [of embryonic stem cells] can go to both embryonic and extra-embryonic lineages. That was a pretty incredible moment for us, because we actually convinced ourselves that this finding was real.”
Although stem cells can give rise to virtually any cell type inside the embryo, they have limited potential to give rise to extra-embryonic cell types. He and colleagues sought to explore how the body restricts iPSC and ESC potential.
He and colleagues suspected that miRNAs—small, noncoding RNAs that regulate gene expression—might provide one piece of the puzzle, in part because “microRNAs have been shown to play important roles in almost all cellular and molecular processes related to development and disease,” she said.
Indeed, when the researchers knocked out miR-34a in murine stem cells in vitro, they found that this set off an odd molecular pathway that simultaneously increased expression of the MERVL endogenous retrovirus and allowed stem cells that have only rarely been shown to produce extra-embryonic cell types to produce them consistently, in great numbers with greater efficiency than existing techniques, such as somatic cell nuclear transfer (SCNT).
The researchers suspect that the Gata2 gene, an important miR-34a target, plays an essential role in both increasing endogenous retrovirus expression and in the stem cells’ newfound bidirectional potential. Indeed, when the team knocked down Gata2 in the lab, this had no effect on wild-type murine ESCs, but did prevent MERVL endogenous retrovirus expression in ESCs that were missing miR-34a.
“This opens up a lot of possibilities,” He said. “We identified a new pathway that regulates pluripotency, and that’s only the beginning. Using this as an entry point, we may be able to identify additional components in this molecular pathway.”
“Overall, this is really nice work,” said Robert Blelloch, an expert in ESCs and miRNA at the University of California, San Francisco, who was not involved in the research.
Blelloch noted that prior work has shown that a small number of cells independently develop the potential to produce extra-embryonic cell types, even without genetic manipulation, and that the process was previously linked to endogenous retroviruses. The present study “shows you can increase the number of these cells by removing miRNA [and] that miRNAs stabilize the pluripotent state,” he said. “Maybe, with somewhat small manipulations, we could expand [our] repertoire of cells.”
Y. J. Choi et al., “Deficiency of microRNA miR-34a expands cell fate potential in pluripotent stem cells,” Science, doi:10.1126/science.aag1927, 2017.