Stem Cells of Worms and Humans Are Similar Than Expected

    Stem cells are cellular all-rounders and can differentiate into any tissue. They hold great potential for regenerative medicine, which is why they are subject to intense study. Planarians, small free-living flatworms, are especially interesting for researchers due to their remarkable ability to regenerate any lost body part through their many stem cells.

    When stem cells forsake pluripotency and embrace a particular developmental fate, they experience a shift from one pattern of gene expression to another, and much of this shift is accomplished at the level of RNA. Essentially, RNA undergoes one pattern of splicing before stem cell differentiation and another pattern after, causing the same stretches of DNA to give rise to different collections of proteins.

    This switch, this manifestation of a phenomenon called alternative splicing (AS), has been known to occur in mammals. But it is also, as has been recently discovered, something that occurs in planarians, invertebrate organisms that split off from the ancestors of mammals around 600 million years ago.

    The new find comes from an international team of scientists. In collaboration with Jordi Solana and Nikolaus Rajewsky and other colleagues from the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) in Germany and the University of Toronto, Manuel Irimia, a group leader at the Center for Genomic Regulation, examined the shifting patterns of gene activity in stem cells in planarians and reported their results in the journal eLife. Their paper, entitled, “Conserved Functional Antagonism of CELF and MBNL Proteins Controls Stem Cell-Specific Alternative Splicing in Planarians,” appeared August 9.

    The scientists noted how curious it is that a stem-cell-specific AS mechanism should be shared across such a wide evolutionary range. The scientists suggested that the mechanism must be very ancient, and that it may be equally important as transcription factors are for giving animal stem cells their unique properties.

    “We studied AS in a powerful in vivo model for stem cell biology, the planarian Schmidtea mediterranea,” wrote the article’s authors. “We discover a conserved AS program comprising hundreds of alternative exons, microexons and introns that is differentially regulated in planarian stem cells, and comprehensively identify its regulators.”

    The researchers identified splicing processes that operate only in the stem cells of the worms, and identified numerous alternative exons responsible for stem-cell-specific protein variants. Surprisingly, introns were often not removed from the RNA, which meant that no more functioning proteins could be generated. The researchers also found small exon snippets, “micro exons,” in fully developed cells.

    In subsequent experiments, the scientists switched off the proteins that control AS. One of these proteins is MBNL, which suppresses the production of stem-cell-specific protein variants. They also discovered that the CELF protein counteracts MBNL by stimulating the production of these variants. During development from a stem cell to a tissue cell, the two factors competed for predominance. This interaction between MBNL and CELF has been previously described only in mammalian cells.

    “In our study we identified new mechanisms that we weren’t aware of from the usual studies into mammalian stem cells. With this knowledge, it’s now possible for us to look in a targeted manner for the same processes in human cells,” said Solana.

    “I found it particularly fascinating that it’s impossible to understand how MBNL without knowing about the function of CELF,” observed group leader Prof. Nikolaus Rajewsky, who is an expert on the systems biology of RNA. “Maybe other splicing factors compete or cooperate in a similar way.”

    The scientists’ work also raises fundamental questions about the function of stem cells in animals. “To find the antagonism between MBNL and CELF in flatworms is interesting from an evolutionary biologist’s perspective,” noted Solana. “For the first time, we described mechanisms in stem cells in organisms from extremely distant branches of the evolutionary tree. What we found is probably a fundamental process throughout the animal kingdom.”