HEALING WOUNDS WITH CELLS

To repair and restore themselves after damage, body tissues need new cells. To get them, researchers are discovering, tissues sometimes recruit ordinary mature cells and revert them to a highly proliferative state usually associated with fetuses.
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To Heal Wounds, Cells Time-Travel Back to a Fetal State

An embryo starts out as just a single cell. It’s not long before it divides into two cells, then four, then eight, and so on — a process marked by rapid growth, in which these early, unspecialized cells proliferate wildly to start building all the tissues of the body. As development proceeds, these embryonic (and later fetal) stem cells become more specialized, differentiating into the precursors of various cell lineages, which in turn give rise to more mature cells: blood cells, nerve cells, muscle cells, intestinal cells. Major functional changes in these tissues continue to take place after birth, as the organism adapts to life outside the uterus, for the first time using its lungs to breathe air and its digestive system to process food.

A few cell populations retain some of that early plasticity as adult stem cells, helping both to maintain tissues on a day-to-day basis and to heal wounds. In recent years, moreover, it’s become clear that those aren’t the only cells that stay flexible: Sometimes, when the repair process calls for it, more specialized cells can take a few steps back, or “de-differentiate,” to re-enter a stemlike state, too.

But new results suggest that that plasticity may go even deeper than scientists have thought. Three research teams have observed that during tissue regeneration, the typical solutions offered by adult stem cells (and the de-differentiated cells resembling them) aren’t enough. Instead, the cells of the damaged tissue turn the clock back all the way to a more fetal state, tapping into the proliferative power that once characterized development — and a program thought to have long gone silent.

Atom Bombs and Self-Renewing Cells

In the early 1900s, scientists theorized that the specific blood cell types they’d learned to distinguish from one another under a microscope — red blood cells, white blood cells and platelets — came from a common, more primitive source: a stem cell. But it wouldn’t be until the 1950s and ’60s that researchers could offer definitive proof of their existence and begin to delineate their unique properties.

The discovery of the first stem cells came about indirectly from the atomic bombings of Hiroshima and Nagasaki in 1945. Medical workers observed that exposure to radiation caused a precipitous drop in the survivors’ white blood cell counts, and experiments in mice showed that bone marrow transplants could offset those losses. Work over the following decades gradually revealed why: A population of cells in the marrow could both self-renew and differentiate into various, more specialized blood cell lineages. These were the blood-making stem cells.

They departed from the behavior of more specialized cells in several key ways. When a differentiated cell divided, it produced two copies of itself — and depending on the cell type, the number of times it could do so was limited. That wasn’t the case with the stem cells isolated from the bone marrow. When they divided, they did so over extremely long periods of time, in a process known as proliferation. Moreover, those divisions were asymmetric: Each stem cell produced not only a copy of itself but also a daughter cell fated to become a specific type of blood cell. For those daughter cells that gained a differentiated identity, there was generally no going back.

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As stem cell populations were later found in other organs as well, that “paradigm … serve[d] as a template to interpret experimental observations on any other mammalian tissue,” Hans Clevers, a molecular geneticist at the Hubrecht Institute in the Netherlands and one of the world’s top experts on stem cells, wrote in 2015. But that wasn’t necessarily a good thing. “Attempts to fit observations on solid tissues into the [blood stem cell] hierarchy mold,” Clevers continued, “have led to confusing theories, terminologies, experimental approaches and heated debates, many of which remain unresolved.”

The Plasticity of Everything

Still, by the time Clevers penned those words, the conception of what it meant to be a stem cell was already undergoing a massive overhaul. In the late 1990s, stem cells from human embryos were isolated and cultured for the first time, revealing that unlike adult stem cells, which could give rise only to cell types found in their tissue of origin (a blood stem cell in the bone marrow might generate a neutrophil, for instance, but wouldn’t differentiate into a nerve cell in the brain), embryonic stem cells harbored the potential to become any cell type in the body.

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Meanwhile, adult stem cells found in tissues other than bone marrow didn’t always seem to act similarly to the blood stem cells. Ones discovered in the intestine and characterized throughout the 1990s and 2000s indicated that certain stem cell populations could replicate far more vigorously than those residing in the bone marrow, and could sometimes divide symmetrically. Several organs, including the pancreas and kidney, didn’t seem to have populations of cells that functioned exclusively as stem cells at all — implying that other cells in those tissues might have to assume stemlike duties in certain cases. In Clevers’ words: “The search for stem cells as a physical entity may need to be replaced by the search for stem cell function.”

Richard Locksley (left) and Ophir Klein (right) of the University of California, San Francisco, observed a new kind of wound healing in the intestines of mice. In response to damage by parasites, the intestine’s adult stem cell program switched off in favor of a more fetal one. Courtesy of Richard Locksley; Steve Babuljak

“But we quickly saw the whole thing go sideways,” Locksley said. He’d expected stem cells located close to where the worms had burrowed into the tissue to become more active, generating new lineages and making the necessary repairs. Instead, the genetic markers used to identify those stem cells disappeared entirely. Yet, even with that population depleted, the cells around the wounds began dividing more rapidly than usual. “It suggested that maybe the cells had shifted into a new, injury-responsive state,” said Ysbrand Nusse, the lead author of the Nature paper the team published in June about these findings.

It would take years for them to figure out what was controlling that shift. Locksley started collaborating with Klein, his UCSF colleague and a stem cell biologist: The unanticipated result had piqued his interest. They found that a particular immune response was activated, and that the gene Sca-1 was being expressed at high levels in the damaged tissue. When cultivated in a dish, those Sca-1 cells formed blobs of tissue that looked more fetal than adult — a connection made possible only a few years earlier, when scientists first started describing the development of the fetal intestine in molecular terms.

Klein and Locksley’s team found that a slew of other genes expressed during development had been transiently reactivated. The same cellular reprogramming occurred after irradiation and other kinds of injuries, too. In response to various types of damage related to inflammation, then, the cells seemed to be invoking some kind of fetal memory (though the researchers are careful to point out that this doesn’t represent a complete return to a fully fetal state). That implies that “adult cells can reactivate the same pathways that are normally used during the patterning of the tissue in the first place,” said Kelley Yan, a gastroenterologist at the Columbia University Irving Medical Center in New York, who was not involved in the study.

 

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