I love the spectacular symbiosis of my vegetable garden as harvest time approaches. Beanstalks spiral up cornstalks, their tendrils teasing nearby tomato…
Humans aren’t very good at regeneration — we can do it for skin, bone, and liver, but that’s about it.
Flatworms, zebrafish, cockroaches, and salamanders can regenerate entire limbs. Yet even these abilities are unimpressive compared to those of Hydractinia symbiolongicarpus, aka a “squishy sea creature.”
Only Simpler Animals Regenerate
Hydractinia, along with jellyfish, sea anemones, hydra, and corals, are among 11,000 or so species in phylum Cnidaria, from the Greek cnidos for “stinging nettle.” The tiny animals have soft bodies, circular symmetry, and sting. The hydractinia are among the most ancient of the Cnidaria. We last shared an ancestor with these animals more than 600 million years ago. They live in saltwater and are small and tube-shaped, clinging to hermit crabs.
Simpler animals like Hydractinia can actually regrow most of their bodies, even entire bodies, rapidly and accurately, a skill uncommon among more complex members of our kingdom. Regeneration is thought to be a trade-off of sorts. It enables animals with simpler body forms to renew and regrow parts, yet the same controlling signals in more complex animals trigger the runaway cell division of cancer and the ravages of excess inflammation that accompany aging.
Cnidarians don’t appear to age. Instead, their cells enter a state of senescence – not dividing, gradually deteriorating, but under certain conditions quietly able to recapitulate a body if injury triggers the biochemical signals to do so.
Cell senescence differs between us and simpler animals.
“Typically, in humans, senescent cells stay senescent, and cause chronic inflammation and induce aging in adjacent cells. Most studies on senescence are related to chronic inflammation, cancer, and age-related diseases. From animals like Hydractinia, we can learn about how senescence can be beneficial and expand our understanding of aging and healing,” said Andy Baxevanis, senior scientist at the National Human Genome Research Institute and co-author of a study recently published in Cell Reports.
Stem Cells Lie Behind Development and Regeneration
In humans stem cells mainly function during early development. When they divide, stem cells self-renew, replacing themselves, as well as give rise to the specialized daughter cells that form tissues and organs.
Simpler organisms like Hydractinia that regenerate missing body parts readily access their stem cell supplies throughout their life cycle. These cells reside in the “main body axis,” the elongated part that supports the head. Extensions emerge from the head region, waving upward. An “oral tip” at the center of the head is an opening within a ring of tentacles. That’s the hypostome – the animal’s mouth.
Chopping off the head of the cnidarian sends signals to stem cells about two-thirds of the way down the stalk, nudging them to migrate to the wound and begin rapidly dividing. Within 3 days, a new head appears.
A Surprise Finding
In a series of astounding experiments, researchers from the NHGRI and the University of Galway found that just a head amputated from a Hydractinia body can regenerate a new body! Imagine growing a person from a severed head.
The ability of Hydractinia to regrow a body from a disembodied head is especially puzzling because a head doesn’t have stem cells. Instead, the experiments showed that some senescent cells in the head send signals to nearby, specialized cells, prompting them to dedifferentiate and then function as stem cells. The newbie stem cells divide, as stem cells do, yielding both another stem cell and a specialized cell.
Experiments using different stains revealed the choreography of development from the isolated mouthparts.
Days 1 to 3 are a period of senescence, when cells lose their “sense” of their position in space – front or back, top or bottom.
On days 3 and 4, the cell cycle resumes, cells lose their specializations, and front and back ends emerge.
On day 6, stem cells form and are set aside.
During days 6 to 16, cells differentiate and a new small body forms as the axis appears and tentacles extend.
The short, initial period of cell senescence is essential for the reprogramming that drives regeneration. It’s a Goldilocks situation, because sufficient cell division is necessary to build a new body part, but not too much that cancer results.
Although the researchers followed all of these events with color-labeled DNA, the details of how the cells at the injury site are reprogrammed into a state of stemness are still a mystery. But the investigators were surprised to discover that the mouths eject some of the senescent cells, almost as if the animal knows that if these cells hang around too long they might cause cancer or bring on the changes of aging, like they do in more complex animals.
Analyzing RNA Revealed the Regeneration
The researchers analyzed RNA to reconstruct the steps to regeneration. Considering DNA reveals what an organism has inherited, but analyzing RNA transcripts, which impart a gene’s instructions to make specific proteins, indicates how a cell uses the genetic information. It’s a little like comparing instructions for building a zeppelin (DNA) to actually building one from specific parts (RNA).
The researchers discovered RNA transcripts known to be involved in senescence in the disembodied heads. Do humans have similar genes? They identified three, and one corresponds to a gene expressed at the wound site in Hydractinia.
Geneticists like to remove a gene’s function and see what happens to figure out what a gene does. Deleting the regeneration gene in Hydractinia corresponding to the human one blocked cell senescence, and the disembodied heads could no longer regenerate bodies. The signals to produce new stem cells and regenerate was cut off.
The conclusion? In us, cell senescence leads to decrepitude, while in the forever-young Hydractinia, the process fuels regeneration. The senescence genes in the “squishy sea creature” hold clues to the evolution of the aging process in us, according to the investigators. Because Hydractinia has been around a lot longer than humans, perhaps the fact that we age, rather than grow new parts, reflects an ancient detour in development.
So was regeneration the original function of senescence in the first animals?
“We suggest that senescence is an ancient mechanism, instructing cells adjacent to an injury site to prepare for a regenerative event. We also speculate that other consequences of senescence that have been observed in mammals, such as long-term retention and accumulation of senescent cells, aging, chronic inflammation, and cancer, are side effects that evolved later, perhaps as a consequence of the increase in cell fate stability and morphological complexity. Understanding the senescent environment and its role in cellular plasticity could pave the way for new treatments to enhance regeneration in poorly regenerating mammals,” wrote the researchers.
Added Baxevanis, “We still don’t understand how senescent cells trigger regeneration or how widespread this process is in the animal kingdom. Fortunately, by studying some of our most distant animal relatives, we can start to unravel some of the secrets of regeneration and aging — secrets that may ultimately advance the field of regenerative medicine and the study of age-related diseases as well.”