How quitting smoking helps your lungs regenerate; a discovery could lead to new ways to repair damaged lungs; and encouraging news in a stroke recovery trial

Photo courtesy Lindsay Fox

Smoking is one of the leading causes of preventable death not just in the US, but worldwide. According to the US Centers for Disease Control and Prevention tobacco causes an estimated seven million deaths around the world, every single year. And for every person who dies, another 30 live with a serious smoking-related illness. Clearly quitting is a good idea. Now a new study adds even more incentive to do just that.

Scientists at the Welcome Trust Sanger Institute and University College London in the UK, found that quitting smoking did more than just stop further damage to the lungs. They found that cells in the lining of the lungs that were able to avoid being damaged, were able to regrow and repopulate the lung, helping repair damaged areas.

In an article in Science Daily Dr Peter Campbell, a joint senior author of the study, said: “People who have smoked heavily for 30, 40 or more years often say to me that it’s too late to stop smoking — the damage is already done. What is so exciting about our study is that it shows that it’s never too late to quit — some of the people in our study had smoked more than 15,000 packs of cigarettes over their life, but within a few years of quitting many of the cells lining their airways showed no evidence of damage from tobacco.”

The study is published in the journal Nature.

Researchers at UCLA have also made a discovery that could help people with lung disease.

They examined the lungs of people with cancer and compared them to the lungs of healthy people. They were able to identify a group of molecules, called the Wnt/beta-catenin signaling pathway, that appear to influence the activity of stem cells that are key to maintaining healthy lungs. Too much activity can tilt the balance away from healthy lungs to ones with mutations that are more prone to developing tumors.

In a news release Dr. Brigitte Gomperts, the lead author of the study, says although this work has only been done in mice so far it has tremendous potential: “We think this could help us develop a new therapy that promotes airway health. This could not only inform the treatment of lung cancer, but help prevent its progression in the first place.”

The study is published in the journal Cell Reports.

CIRM has funded some of Dr. Gomperts earlier work in this area.

And there’s encouraging news for people trying to recover from a stroke. Results from ReNeuron’s Phase 2 clinical trial show the therapy appears to help people who have experienced some level of disability following a stroke.

ReNeuron says its CTX therapy – made from neural stem cells – was given to 23 people who had moderate to severe disability resulting from an ischemic stroke. The patients were, on average, seven months post stroke.

In the study, published in the Journal of Neurology, Neurosurgery & Psychiatry, researchers used the Modified Rankin Scale (mRS), a measure of disability and dependence to assess the impact of the therapy. The biggest improvements were seen in a group of 14 patients who had limited movement of one arm.

  • 38.5% experienced at least a one-point improvement on mRS six months after being treated.
  • 50% experienced a one-point improvement 12 months after being treated.

If that doesn’t seem like a big improvement, then consider this. Moving from an mRS 3 to 2 means that a person with a stroke regains their ability to live independently.

The therapy is now being tested in a larger patient group in the PISCES III clinical trial.

Breakthrough image could lead to better therapies

Image of a blood stem cell in its natural environment: Photo courtesy UC Merced

When it comes to using stem cells for therapy you don’t just need to understand what kinds of cell to use, you also need to understand the environment that is best for them. Trying to get stem cells to grow in the wrong environment would be like trying to breed sheep in a pond. It won’t end well.

But for years scientists struggled to understand how to create the right environment, or niche, for these cells. The niche provides a very specific micro-environment for stem cells, protecting them and enabling them to self-renew over long periods of time, helping repair damaged tissues and organs in the body.

But different stem cells need different niches, and those involve both physical and chemical properties, and getting that mixture right has been challenging. That in turn has slowed down our ability to use those cells to develop new therapies.

UC Merced’s Joel Spencer in the lab: Photo courtesy UC Merced

Now UC Merced’s Professor Joel Spencer and his team have developed a way of capturing an image of hematopoietic or blood stem cells (HSCs), inside their niche in the bone marrow. In an article on UC Merced News, he says this could be a big step forward.

“Everyone knew black holes existed, but it took until last year to directly capture an image of one due to the complexity of their environment. It’s analogous with stem cells in the bone marrow. Until now, our understanding of HSCs has been limited by the inability to directly visualize them in their native environment.

“This work brings an advancement that will open doors to understanding how these cells work which may lead to better therapeutics for hematologic disorders including cancer.”

In the past, studying HSCs involved transplanting them into a mouse or other animal that had undergone radiation to kill off its own bone marrow cells. It enabled researchers to track the HSCs but clearly the new environment was very different than the original, natural one. So, Spencer and his team developed new microscopes and imaging techniques to study cells and tissues in their natural environment.  

In the study, published in the journal Nature, Spencer says all this is only possible because of recent technological breakthroughs.

“My lab is seeking to answer biological questions that were impossible until the advancements in technology we have seen in the past couple decades. You need to be able to peer inside an organ, inside a live animal and see what’s happening as it happens.”

Being able to see how these cells behave in their natural environment may help researchers learn how to recreate that environment in the lab, and help them develop new and more effective ways of using those cells to repair damaged tissues and organs.

Two CIRM supported studies highlighted in Nature as promising approaches for blood disorders

Blood stem cells (blue) are cleared from the bone marrow (purple) before new stem cells can be transplanted.Credit: Dennis Kunkel Microscopy/SPL

Problems with blood stem cells, a type of stem cell in your bone marrow that gives rise to various kinds of blood cells, can sometimes result in blood cancer as well as genetic and autoimmune diseases.

It is because of this that researchers have looked towards blood stem cell transplants, which involves replacing a person’s defective blood stem cells with healthy ones take from either a donor or the patient themselves.

However, before this can be done, the existing population of defective stem cells must be eradicated in order to allow the transplanted blood stem cells to properly anchor themselves into the bone marrow. Current options for this include full-body radiation or chemotherapy, but these approaches are extremely toxic.

But what if there was a way to selectively target these blood stem cells in order to make the transplants much safer?

An article published in Nature highlights the advancements made in the field of blood stem cell transplantation, some of which is work that is funded by yours truly.

One of the approaches highlighted involves the work that we funded related to Forty Seven and an antibody created that inhibits a protein called CD47.

The article discusses how Forty Seven tested two antibodies in monkeys. One antibody blocks the activity of a molecule called c-Kit, which is found on blood stem cells. The other is the antibody that blocks CD47, which is found on some immune cells. Inhibiting CD47 allows those immune cells to sweep up the stem cells that were targeted by the c-Kit antibody, thereby boosting its effectiveness. In early tests, the two antibodies used together reduced the number of blood stem cells in bone marrow. The next step for this team is to demonstrate that the treatment clears out the old supply of stem cells well enough to allow transplanted cells to flourish.

You can read more about the CD47 antibody in a previous blog post.

Another notable segment of this article is the CIRM funded trial that is being conducted by Dr. Judith Shizuru at Stanford University. This clinical trial also uses an antibody that targets c-Kit found on blood stem cells.

The purpose of this trial is to wipe out the problematic blood stem cells in infants with X-linked Severe combined immunodeficiency (SCID), a rare fatal genetic disorder that leaves infants without a functional immune system, in order to introduce properly functioning blood stem cells. Dr. Shizuru and her team found that transplanted blood stem cells, in this case from donors who did not have the disease, successfully took hold in the bone marrow of four out of six of the babies.

You can read more about Dr. Shizuru’s work in a previous blog post as well.

Newly discovered “don’t eat me” signal shows potential for ovarian and triple-negative breast cancer treatment

Stanford researchers have found that cancer cells have a protein called CD24 on their surface that enables them to protect themselves against the body’s immune cells.
Courtesy of Shutterstock

Getting a breast cancer diagnosis is devastating news in and of itself. Currently, there are treatment options that target three different types of receptors, which are named hormone epidermal growth factor receptor 2 (HER-2), estrogen receptors (ER), and progesterone receptors (PR), commonly found in breast cancer cells, . Unfortunately, in triple-negative breast cancer, which occurs in 10-20% of breast cancer cases, all three receptors are absent, making this form of breast cancer very aggressive and difficult to treat.

In recent years, researchers have discovered that proteins on the cell surface can tell macrophages, an immune cell designed to detect and engulf foreign or abnormal cells, not to eat and destroy them. This can be useful to help normal cells keep the immune system from attacking them, but cancer cells can also use these “don’t eat me” signals to hide from the immune system. 

An illustration of a macrophage, a vital part of the immune system, engulfing and destroying a cancer cell. Antibody 5F9 blocks a “don’t eat me” signal emitted from cancer cells. Courtesy of Forty Seven, Inc.

In fact, because of this concept, a CIRM-funded clinical trial is being conducted that uses an antibody called 5F9 to block a “don’t eat me” signal known as CD47 that is found in cancer cells. The results of this trial, which have been announced in a previous blog post, are very promising.

Further building on this concept, a CIRM-funded study has now discovered a potential new target for triple-negative breast cancer as well as ovarian cancer. Dr. Irv Weissman and a team of researchers at Stanford University have discovered an additional “don’t eat me” signal called CD24 that cancers seem to use to evade detection and destruction by the immune system.

In a press release, Dr. Weissman talks about his work with CD47 and states that,

“Finding that not all patients responded to anti-CD47 antibodies helped fuel our research at Stanford to test whether non-responder cells and patients might have alternative ‘don’t eat me’ signals.” 

The scientists began by looking for signals that were produced more highly in cancers than in the tissues from which the cancers arose. It is here that they discovered CD24 and then proceeded to implant human breast cancer cells in mice for testing. When the CD24 signaling was blocked, the mice’s immune system attacked the cancer cells.

An important discovery was that ovarian and triple-negative breast cancer were highly affected by blocking of CD24 signaling. The other interesting discovery was that the effectiveness of CD24 blockage seems to be complementary to CD47 blockage. In other words, some cancers, like blood cancers, seem to be highly susceptible to blocking CD47, but not to CD24 blockage. For other cancers, like ovarian cancer, the opposite is true. This could suggest that most cancers will be susceptible to the immune system by blocking the CD24 or CD47 signal, and that cancers may be even more vulnerable when more than one “don’t eat me” signal is blocked.

Dr. Weissman and his team are now hopeful that potential therapies to block CD24 signaling will follow in the footsteps of the clinical trials related to CD47.

The full results to the study were published in Nature.

How stem cells know the right way to make a heart . And what goes wrong when they don’t

Gladstone scientists Deepak Srivastava (left), Yvanka De Soysa (center), and Casey Gifford (right) publish a complete catalog of the cells involved in heart development.

The invention of GPS navigation systems has made finding your way around so much easier, providing simple instructions on how to get from point A to point B. Now, a new study shows that our bodies have their own internal navigation system that helps stem cells know where to go, and when, in order to build a human heart. And the study also shows what can go wrong when even a few cells fail to follow directions.

In this CIRM-supported study, a team of researchers at the Gladstone Institutes in San Francisco, used a new technique called single cell RNA sequencing to study what happens in a developing heart. Single cell RNA sequencing basically takes a snapshot photo of all the gene activity in a single cell at one precise moment. Using this the researchers were able to follow the activity of tens of thousands of cells as a human heart was being formed.

In a story in Science and Research Technology News, Casey Gifford, a senior author on the study, said this approach helps pinpoint genetic variants that might be causing problems.

“This sequencing technique allowed us to see all the different types of cells present at various stages of heart development and helped us identify which genes are activated and suppressed along the way. We were not only able to uncover the existence of unknown cell types, but we also gained a better understanding of the function and behavior of individual cells—information we could never access before.”

Then they partnered with a team at Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg which ran a computational analysis to identify which genes were involved in creating different cell types. This highlighted one specific gene, called Hand2, that controls the activity of thousands of other genes. They found that a lack of Hand2 in mice led to an inability to form one of the heart’s chambers, which in turn led to impaired blood flow to the lungs. The embryo was creating the cells needed to form the chamber, but not a critical pathway that would allow those cells to get where they were needed when they were needed.

Gifford says this has given us a deeper insight into how cells are formed, knowledge we didn’t have before.

“Single-cell technologies can inform us about how organs form in ways we couldn’t understand before and can provide the underlying cause of disease associated with genetic variations. We revealed subtle differences in very, very small subsets of cells that actually have catastrophic consequences and could easily have been overlooked in the past. This is the first step toward devising new therapies.”

These therapies are needed to help treat congenital heart defects, which are the most common and deadly birth defects. There are more than 2.5 million Americans with these defects. Deepak Srivastava, President of Gladstone and the leader of the study, said the knowledge gained in this study could help developed strategies to help address that.

“We’re beginning to see the long-term consequences in adults, and right now, we don’t really have any way to treat them. My hope is that if we can understand the genetic causes and the cell types affected, we could potentially intervene soon after birth to prevent the worsening of their state over time.

The study is published in the journal Nature.

CIRM funded study identifies potential drug target for deadly heart condition

Joseph Wu is co-senior author of a study that demonstrates how patient-derived heart cells can help scientists better study the heart and screen potential therapies. Photo courtesy of Steve Fisch

Heart disease continues to be the number one cause of death in the United States. An estimated 375,000 people have a genetic form of heart disease known as familial dilated cardiomyopathy. This occurs when the heart muscle becomes weakened in one chamber in the heart, causing the open area of the chamber to become enlarged or dilated. As a result of this, the heart can no longer beat regularly, causing shortness of breath, chest pain and, in severe cases, sudden and deadly cardiac arrest.

A diagram of a normal heart compared to one with the dilated cardiomyopathy

A CIRM funded study by a team of researchers at Stanford University looked further into this form of genetic heart disease by taking a patient’s skin cells and converting them into stem cells known as induced pluripotent stem cells (iPSCs), which can become any type of cell in the body. These iPSCs were then converted into heart muscle cells that pulse just as they do in the body. These newly made heart muscle cells beat irregularly, similar to what is observed in the genetic heart condition.

Upon further analysis, the researchers linked a receptor called PGDF to cause various genes to be more highly activated in the mutated heart cells compared to normal ones. Two drugs, crenolanib and sunitinib, interfere with the PGDF receptor. After treating the abnormal heart cells, they began beating more regularly, and their gene-activation patterns more closely matched those of cells from healthy donors.

These two drugs are already FDA-approved for treating various cancers, but previous work shows that the drugs may damage the heart at high doses. The next step would be determining the right dose of the drug. The current study is part of a broader effort by the researchers to use these patient-derived cells-in-a-dish to screen for and discover new drugs.

Dr. Joseph Wu, co-senior author of this study, and his team have generated heart muscle cells from over 1,000 patients, including those of Dr. Wu, his son, and his daughter. In addition to using skin cells, the same technique to create heart cells from patients can also be done with 10 milliliters of blood — roughly two teaspoons.

In a news release, Dr. Wu is quoted as saying,

“With 10 milliliters of blood, we can make clinically usable amounts of your beating heart cells in a dish…Our postdocs have taken my blood and differentiated my pluripotent stem cells into my brain cells, heart cells and liver cells. I’m asking them to test some of the medications that I might need to take in the future.”

The full results of this study were published in Nature.

Stories that caught our eye: FDA grants orphan drug status to CIRM-funded therapy; stunning discovery upends ideas of cell formation; and how tadpoles grow new tails

Gut busting discovery

Intestinal stem cells: Photo courtesy Klaus Kaestner, Penn Institute for Regenerative Medicine

It’s not often you read the word “sensational” in a news release about stem cells. But this week researchers at the University of Copenhagen released findings that are overturning long-held ideas about the development of cells in our stomachs. So perhaps calling it “sensational” is not too big a stretch.

In the past it was believed that the development of immature cells in our stomachs, before a baby is born, was predetermined, that the cells had some kind of innate sense of what they were going to become and when. Turns out that’s not the case. The researchers say it’s the cells’ environment that determines what they will become and that all cells in the fetus’ gut have the potential to turn into stem cells.

In the “sensational” news release lead author, Kim Jensen, says this finding could help in the development of new therapies.

“We used to believe that a cell’s potential for becoming a stem cell was predetermined, but our new results show that all immature cells have the same probability for becoming stem cells in the fully developed organ. In principle, it is simply a matter of being in the right place at the right time. Here signals from the cells’ surroundings determine their fate. If we are able to identify the signals that are necessary for the immature cell to develop into a stem cell, it will be easier for us to manipulate cells in the wanted direction’.

The study is published in the journal Nature.                             

A tale of a tail

African clawed frog tadpole: Photo courtesy Gary Nafis

It’s long been known that some lizards and other mammals can regrow severed limbs, but it hasn’t been clear how. Now scientists at the University of Cambridge in the UK have figured out what’s going on.

Using single-cell genomics the scientists were able to track which genes are turned on and off at particular times, allowing them to watch what happens inside the tail of the African clawed frog tadpole as it regenerates the damaged limb.

They found that the response was orchestrated by a group of skin cells they called Regeneration-Organizing Cells, or ROCs. Can Aztekin, one of the lead authors of the study in the journal Science, says seeing how ROCs work could lead to new ideas on how to stimulate similar regeneration in other mammals.

“It’s an astonishing process to watch unfold. After tail amputation, ROCs migrate from the body to the wound and secrete a cocktail of growth factors that coordinate the response of tissue precursor cells. These cells then work together to regenerate a tail of the right size, pattern and cell composition.”

Orphan Drug Designation for CIRM-funded therapy

Poseida Therapeutics got some good news recently about their CIRM-funded therapy for multiple myeloma. The US Food and Drug Administration (FDA) granted them orphan drug designation.

Orphan drug designation is given to therapies targeting rare diseases or disorders that affect fewer than 200,000 people in the U.S. It means the company may be eligible for grant funding toward clinical trial costs, tax advantages, FDA user-fee benefits and seven years of market exclusivity in the United States following marketing approval by the FDA.

CIRM’s President and CEO, Dr. Maria Millan, says the company is using a gene-modified cell therapy approach to help people who are not responding to traditional approaches.

“Poseida’s technology is seeking to destroy these cancerous myeloma cells with an immunotherapy approach that uses the patient’s own engineered immune system T cells to seek and destroy the myeloma cells.”

Poseida’s CEO, Eric Ostertag, said the designation is an important milestone for the company therapy which “has demonstrated outstanding potency, with strikingly low rates of toxicity in our phase 1 clinical trial. In fact, the FDA has approved fully outpatient dosing in our Phase 2 trial starting in the second quarter of 2019.”

3D brain model shows potential for treatment of hypoxic brain injuries in infants

Image of 3D brain cultures in the Sergiu Pasca lab.
Photo courtesy of Timothy Archibald.

A baby’s time in the womb is one of the most crucial periods in terms of its development. The average length of gestation, which is defined as the amount of time in the womb from conception to birth, is approximately 40 weeks. Unfortunately, for reasons not yet fully understood, there are times that babies are born prematurely, which can lead to problems.

These infants can have underdeveloped portions of the brain, such as the cerebral cortex, which is responsible for advanced brain functions, including cognition, speech, and the processing of sensory and motor information. The brains of premature infants can be so underdeveloped that they are unable to control breathing. This, in combination with underdeveloped lungs, can lower oxygen levels in the blood, which can lead to hypoxic, or low oxygen related, brain injuries.

In a previous study, doctors Anca and Sergiu Pasca and their colleagues at Stanford developed a technique to create a 3D brain that mimics structural and functional aspects of the developing human brain.

Using this same technique, in a new study with the aid of CIRM funding, the team grew a 3D brain that contained cells and genes similar to the human brain midway through the gestational period. They then exposed this 3D brain to low oxygen levels for 48 hours, restored the oxygen level after this time period, and observed any changes.

It was found that progenitor cells in a region known as the subventricular zone, a region that is critical in the growth of the human cortex, are affected. Progenitor cells are “stem cell like” cells that give rise to mature brain cells such as neurons. They also found that the progenitor cells transitioned from “growth” mode to “survival” mode, causing them to turn into neurons sooner than normal, which leads to fewer neurons in the brain and underdevelopment.

In a press release, Dr. Anca Pasca is quoted as saying,

“In the past 20 years, we’ve made a lot of progress in keeping extremely premature babies alive, but 70% to 80% of them have poor neurodevelopmental outcomes.”

The team then tested a small molecule to see if it could potentially reverse this response to low oxygen levels by keeping the progenitor cells in “growth” mode. The results of this are promising and Dr. Sergiu Pasca is quoted as saying,

“It’s exciting because our findings tell us that pharmacologically manipulating this pathway could interfere with hypoxic injury to the brain, and potentially help with preventing damage.”

The complete findings of this study were published in Nature.

Stories that Caught Our Eye: New ways to heal old bones; and keeping track of cells once they are inside you

broken bones

How Youth Factor Can Help Repair Old Bones

As we get older things that used to heal quickly tend to take a little longer to get better. In some cases, a lot longer. Take bones for example. A fracture in someone who is in their 70’s often doesn’t heal as quickly, or completely, as in someone much younger. For years researchers have been working on ways to change that. Now we may be one step closer to doing just that.

We know that using blood stem cells can help speed up healing for bone fractures (CIRM is funding work on that) and now researchers at Duke Health believe they have figured out how that works.

The research, published in the journal Nature Communications, identifies what the Duke team call the “youth factor” inside bone marrow stem cells. It’s a type of white blood cell called a macrophage. They say the proteins these macrophages produce help stimulate bone repair.

In a news story in Medicine News Line  Benjamin Alman, senior author on the study, says:

“While macrophages are known to play a role in repair and regeneration, prior studies do not identify secreted factors responsible for the effect. Here we show that young macrophage cells play a role in the rejuvenation process, and injection of one of the factors produced by the young cells into a fracture in old mice rejuvenates the pace of repair. This suggests a new therapeutic approach to fracture rejuvenation.”

Next step, testing this in people.

A new way to track stem cells in the body

It’s one thing to transplant stem cells into a person’s body. It’s another to know that they are going to go where you want them to and do what you want them to. University of Washington researchers have invented a device that doesn’t just track where the cells end up, but also what happens to them along the way.

The device is called “CellTagging”, and in an article in Health Medicine Network, Samantha Morris, one of the lead researchers says this could help in better understanding how to use stem cells to grow replacement tissues and organs.

“There is a lot of interest in the potential of regenerative medicine — growing tissues and organs in labs — to test new drugs, for example, or for transplants one day. But we need to understand how the reprogramming process works. We want to know if the process for converting skin cells to heart cells is the same as for liver cells or brain cells. What are the special conditions necessary to turn one cell type into any other cell type? We designed this tool to help answer these questions.”

In the study, published in the journal Nature, the researchers explain how they use a virus to insert tiny DNA “barcodes” into cells and that as the cells travel through the body they are able to track them.

Morris says this could help scientists better understand the conditions needed to more effectively program cells to do what we want them to.

“Right now, cell reprogramming is really inefficient. When you take one cell population, such as skin cells, and turn it into a different cell population — say intestinal cells — only about 1 percent of cells successfully reprogram. And because it’s such a rare event, scientists have thought it is likely to be a random process — there is some correct set of steps that a few cells randomly hit upon. We found the exact opposite. Our technology lets us see that if a cell starts down the right path to reprogramming very early in the process, all of its related sibling cells and their descendants are on the same page, doing the same thing.”

CIRM Supported Scientist Makes Surprising Discovery with Parasitic Gut Worms

 

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Image of gut lining and parasites.  Photo courtesy of UCSF/ Michael Fortes

 

It’s no secret that researchers have long believed adult stem cells could contribute to wound healing in the gut and skin, but in a new paper in Nature — a group of scientists at UC San Francisco made a surprising discovery.

Through several experiments using parasitic worms in the mouse gut, they found that as parasites dug into the intestinal walls of mice, the gut responded in an unexpected way – by reactivating a type of cell growth previously seen in fetal tissues.

So why is this important?

Simply put, it gives scientists new targets to go after. According to UCSF CIRM supported scientist Ophir Klein, MD, Ph.D., this discovery could be paradigm-shifting in terms of our understanding of how the mammalian body can repair damage and could help scientists develop more ways to enhance the body’s natural healing abilities.

Adult stem cells in the intestines are vital for maintaining the digestive status quo. The gut lining is made up of epithelial cells which absorb nutrients and produce protective mucus. These cells are replaced every few days by the stem cells at the base of crypts — indentations in the gut lining. Researchers expected that the same stem cells could also help repair tears in the gut.

How did they do it?

Larvae from parasites like H. polygyrus invade the gut lining in a mouse’s intestine, burying themselves to develop in the tissue. Based on prevailing ideas in the field, the scientists predicted that, in response, nearby stem cells would increase their productivity and patch up the worm-created wounds, but that is not what happened.

Instead, signs of the stem cells in worm-infected areas disappeared entirely; fluorescent markers that should have been expressed by one of the genes in the regular stem cell program completely vanished. And yet, even with no identifiable stem cells in the area, the wounded tissue regenerated more quickly than ever.

Researchers spent years trying to resolve this mystery and after a number of false starts and dead ends, the team eventually noticed the recurrence of a different gene, known as Sca-1.

Using antibody staining for the Sca-1 protein, the researchers realized that where the stem cell genes had disappeared, a different gene program was expressed instead: one that resembled the way that mouse guts develop in utero.

Upon their discovery, the researchers wondered whether the reactivation of this fetal program was a specific response to parasite infections, or if it could be a general strategy for many kinds of gut injury. Additional experiments showed that shutting down gut stem cells with irradiation or genetically targeting them for destruction triggered aspects of the same response: despite an absence of detectable stem cell activity, undifferentiated tissue grew rapidly nonetheless.

Later, once the acute injury is repaired, the gut may return to the normal stem cell program of producing differentiated cells that perform specific functions.

Many other injured tissues could benefit from the ability to quickly and efficiently make generalized repairs before returning to specialized adult cell production, opening up therapeutic opportunities. For example, developing treatments that bestow an ability to control the change between adult and fetal genetic programs might offer new strategies to manage conditions such as inflammatory bowel disease (IBD).