The tiny aquatic hydra looks fragile at first glance, with tentacles that are slender and translucent. But if you cut it in half, each fragment regenerates into a complete new animal. Scientists studying this amazing feat have discovered a surprising detail: to trigger healing, specialized cells first have to invade the wound in a manner similar to what cancer cells do as they spread through the body.

To facilitate that invasion, “the hydra actually breaks down a collagen layer that normally supports its body,” said Ben Cox, who performed this research while a postdoctoral fellow in the Department of Molecular and Cellular Biology. Tearing holes in this protective barrier allows stem cells to pass through it, so they can replace nerves and other cells on the other side, according to the new study, published in the journal Development.

Understanding how this happens could help scientists improve wound healing in humans – encouraging the regrowth of normal tissue, while avoiding scar tissue that impedes healing. The discovery could also shed light on other aspects of human biology. 

“Cell invasion is a really important part of development,” while the brain and other organs are taking shape in a growing fetus, said Cox. “It’s also a really important part of cancer.”

Stem Cells on the Move

The hydra lurks in streams, ponds, and fish tanks, attached by its stalk to rocks or plants. Like its saltwater cousins jellyfish and sea anemones, it uses tentacles to capture tiny prey, digesting them inside its hollow body.

“It is such a simple animal, and partly because of that, it provides a great opportunity to understand regeneration,” said Celina Juliano, an associate professor in the Department of Molecular and Cellular Biology, who has studied hydra for over a decade. 

The hydra’s stalk is a hollow tube comprising just two layers of cells, one on the outside and the other facing inside the tube, where food is digested. Those inner and outer cell layers are separated by a dense layer of collagen that supports the animal’s body.

But if a hydra has to regenerate after being torn in half, that strong, supportive layer suddenly becomes an obstacle that stands in the way of healing.

As the severed animal grows a new head with mouth and tentacles, its inner layer has to produce several types of cells, including nerve cells and food-digesting gland cells. But the stem cells that give rise to them only exist in the animal’s outer layer — on the other side of the collagen barrier.

“We were interested in how stem cells get where they need to go, to regenerate those specialized cells,” said Cox. In fact, this is a fundamental problem in human health, growth, and disease.

Cellular Invasion in Healing and Disease

Cox’s experiments showed that after a hydra is severed, the collagen barrier separating its inner and outer cell layers begins to thin near the wound, until it’s perforated, like a piece of Swiss-cheese. “This facilitates quick invasion by the stem cells from the outer layer into the inner one,” said Cox.

This local, temporary thinning is driven by cells in the inner layer, which release enzymes called ‘matrix metalloproteinases’ (MMP’s) that chew through the collagen. Stem cells then enter through the openings.

Human cancer cells spreading through the body also release MMP’s as they chew through barriers to invade other tissues. Scientists have even proposed drugs that target these enzymes as possible cancer treatments.

A similar kind of invasion happens during human development: as a fetus develops, the cells that will become its nerves are at first confined to a narrow ridge, or crest of cells running down the back. “A lot of cells have to move long distances during development, especially in the neural crest,” said Cox.

He and Juliano hope that their findings might eventually improve wound healing in humans — maybe even allow us to regenerate small body parts, like fingertips. 

“Despite the evolutionary distance between humans and hydra, we have a lot of really conserved genes doing similar jobs,” he said. This is especially true for the collagens and other proteins that form the ‘extracellular matrix’ which supports normal tissue. The similarity in genes means that lessons learned in hydra could potentially be applied to humans.

“The extracellular matrix plays a really important role in regeneration,” said Cox. “It can either inhibit regeneration” — forming scars — “or it can promote it.” Following in the huge footsteps of the tiny hydra, he and Juliano hope to accomplish the latter.

This research was funded by the National Institutes of Health, the Hartwell Foundation, the Society for Developmental Biology, the John Cuppoletti and Danuta H. Malinowska Fellowship, and the UC Davis Emerging Research Organisms Grant. This research utilized advanced scientific facilities at UC Davis, including the Light Microscopy Core.

Additional Authors on the paper include: Jasmine Mah and Angel Perez, UC Davis Department of Molecular and Cellular Biology.