How Hydras regenerates decapitated buds

FFrom the tail of salamanders to deer antlers, the innate ability of some animals to regenerate lost body parts has captivated scientists for centuries and has led research into the molecular mechanisms of such healing in the hope that humans may one day do the same.

Even among regenerating organisms, hydras, not mythical beasts, but aquatic animals of the genus Hydra– are distinguished by their ability to push back any part of their body after cutting it, including the head. However, a study published last week (December 8) in Biology and evolution of the genome sheds new light on the genetic and epigenetic mechanisms that allow these animals to achieve this regenerative feat.

Vulgar hydra are freshwater, tube-shaped organisms 1 to 3 centimeters long that adhere to objects such as sticks and rocks and, like their relatives the sea anemone and jellyfish, hunt using of stinging tentacles. They are considered immortal. Unless something kills them, they will continually replenish lost tissues and body parts. They can also clone themselves through an asexual reproduction process called budding in which a new hydra grows from the original and breaks off, “much like the way the petals would come out” of a flower, University of California , Irvine, cell biologist Ali Mortazavi tells The scientist.

Mortazavi led a team of researchers that attempted to answer a long-standing question in the field: whether the genetic and epigenetic processes guiding reproductive growth and regenerative regrowth are similar. “That’s a very interesting question because it’s one of the mysteries of cnidarians in general: they all have these fantastic modes of reproduction, and the big question is, do they recap a process? Is regeneration like budding? But we don’t really know much, ”explains Chiara Sinigaglia, a developmental and evolutionary biologist at the Lyon Institute of Functional Genomics who did not work on the study.

This mystery is “a question that people have been trying to approach from different angles” for years, adds Sinigaglia. “It’s very tricky because you see the same genes being used over and over again” in both processes.

Vulgar hydra

Typically, researchers studying Vulgar hydra regeneration focused on the activity of one specific gene or one biological process at a time. For example, research published in eLife in March highlighted the role of the Wnt signaling pathway in reconstructing a Vulgar hydramouth after decapitation. In contrast, Mortazavi and his colleagues took a more holistic approach, mapping which genes were turned on and upregulated at different times and in various tissues throughout the processes of budding and regeneration.

Scientists conducted several experiments in which they beheaded the Vulgar hydra to determine which genes have been expressed as part of the head regeneration process. They also used ChIP sequencing, a technique that reveals epigenetic changes in the form of histone modifications, to determine which promoter and enhancer regions actively up-regulate the expression of different genes at different times for regenerating hydras. and budding. The team followed this up with ATAC sequencing, a technique that identifies open chromatin regions of a genome, to find out which genes were accessible to these candidate transcription factors.

For reproduction and regeneration of the head, Vulgar hydra rely on their head organizer, a group of 50 to 100 cells at the apical end of the head that signals neighboring cells to differentiate into part of the head or tentacles. When the head is cut off, the researchers found that a cascade of genetic and epigenetic activities quickly triggers the growth of a new head organizer from any remaining cells, allowing the Hydra to regenerate the rest of his head as well. The study identified hundreds of genes that are expressed differently in this process than in reproduction, as well as thousands of open chromatin regions (candidate gene promoters and activator-like regions) that appear to be reshaped in response to injury. in order to drive the regeneration process, creating a genetic landscape different from that existing during budding.

These epigenetic changes and the dynamic modeling of enhancers and promoters appear to trigger genes at different times depending on the form of head generation that the Hydra is ongoing, according to the study. Sinigaglia says a takeaway is “that the two processes converge towards the same result – a little hydra with tentacles – but the trajectory, the course of time, they are not really aligned”.

The study produced an unprecedented scale of data on the expression of genes from Hydra regeneration and development. Harvard University evolutionary biologist Mansi Srivastava, who studies regeneration in worms and has not contributed to the new study, says The scientist that the real importance of the article lies in these datasets.

See “When cut, this solitary tunicate grows back as three new animals

“This paper, it doesn’t give us the exact answer, but it generates the raw material,” says Srivastava. “This is a powerful data set that is part of this longer-term effort” to unravel regeneration.

“It really is an incredible resource for the hydra field,” agrees Blair Benham-Pyle, a cell biologist who studies flatworm regeneration at the Stowers Institute for Medical Research who did not work on the study. “I think it’s great for generating hypotheses.”

Emergency reconstruction

Like the month of March eLife indicated paper, a beheaded Hydra will quickly reassemble his mouth as a survival mechanism. Mortazavi speculates that the same urgency is what motivates the expression of some genes over others during regeneration. On the other hand, a budding Hydra The normally developing clone doesn’t need to prioritize wound healing or survival, he says, and can progress at its own pace.

“Even though the processes are different, they still use the same developmental factors or genes, but in different ways,” says lead author of the study and University of California, Irvine, evolutionary biologist Macias-Muñoz Aid . The scientist. “I think it’s because it’s easier to co-opt things that are already doing something. They are already used in development to develop a head, so why not use similar things to develop a head again? But this is a different process because you have to do it really quickly and stop it at some point.

You want to look at it one head at a time first, and then you want to look at it with thousands of cells per head.

—Ali Mortazavi, University of California, Irvine

However, the study can only go so far as to identify candidate genes and transcription factors and generate hypotheses about which ones lead to regeneration, budding, or both, Srivastava Remarks. In order to test and confirm the roles of genes, as well as those of candidate promoters and enhancer regions, researchers will need to conduct knock-down or knock-out functional studies, Macias-Muñoz explains.

Some of this work is already underway. Macias-Muñoz says she is nearing completion of the follow-up research that complements this comprehensive analysis with single-cell studies in the hopes of learning how cells play different roles in response to decapitation compared to normal development. The single-cell analysis, she explains, will allow her to “better trace these connections that we have identified.”

“You want to look at it one head at a time first, then you want to look at it with thousands of cells per head,” says Mortazavi.

Benham-Pyle is particularly interested in seeing single-cell studies that identify how individual cells of different types communicate with each other to contribute to the signaling cascades that trigger budding versus regeneration – in particular, what types of cells existing head organizers signal and recruit into head development.

Untangling evolution

The heat maps and datasets generated by the new study provide an “important part of the story” of how regeneration first emerged in evolutionary history, Srivastava explains.

Hydra has been part of this story for a long time: Researchers began studying its regenerative abilities in 1744, when Abraham Tremblay first discovered the bizarre property. But other organizations have drawn more attention and detailed studies, and many questions about Hydra regeneration remain unanswered.

Experts still do not know if regeneration is a shared ancestral characteristic that emerged in an ancient organism, or if creatures such as Hydra, the worms studied by Srivastava and Benham-Pyle, mammals, salamanders and others that can regenerate some or all of their lost parts have developed this ability independently.

The article notes that some of the tools needed for regeneration must have emerged before the branch lines to which Hydra belongs, Cnidaria, separated from the rest of the animal kingdom. One likely possibility, Sinigaglia adds, is that regenerating and non-regenerating organisms have inherited a largely similar toolkit –Wnt3 is expressed during embryonic development even in non-regenerating species, for example, that regenerating organisms have subsequently adapted independently to their own regrowth marks.

“It’s pretty good to see similarities between all of these different organisms,” says Benham-Pyle, “because it makes it more likely that we can take advantage of that biology to help humans. “

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