Author: Nancy Fliesler

Why blood stem cells are in our bones: Evolutionary observation may inform better bone marrow transplants

blood stem cells melanocytes hematopoietic stem cells
In normal zebrafish, blood stem cells in the kidney are protected from sunlight by melanocytes. When this layer is stripped away, stem cell numbers go down. (Image and video below courtesy of the Zon Laboratory and the Howard Hughes Medical Institute.)

Since the late 1970s, biologists have known that blood develops in a specific body location. But they’ve wondered why different creatures house their blood stem cells in different places. In humans and other mammals, they’re in the bone. In fish, they’re in the kidney. Why?

Strange as it seems, the two stem cell “niches” share something in common, say researchers led by Leonard Zon, MD, of Boston Children’s Stem Cell Program, the Harvard Department of Stem Cell and Regenerative Biology (HSCRB) and the Harvard Stem Cell Institute. Both protect blood stem cells from sunlight’s harmful ultraviolet rays. The findings, published today in Nature, may contain lessons for improving blood stem cell transplants for cancer, blood disorders and other conditions.

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Mothers’ life experiences may affect their newborns’ telomeres — especially boys’

mother and newborn with telomeres

A new study adds to a growing body of evidence that mothers’ experiences affect their babies’ chromosomes. For the first time, it also shows a gender difference — with male babies more susceptible to maternal influence. And it even implicates experiences dating back to the mother’s own childhood.

The study, led by psychologist Michelle Bosquet Enlow, PhD, at Boston Children’s Hospital, may help explain why stress can have intergenerational effects within a family. It was published last month in the journal Psychoneuroendocrinology.

The researchers enrolled 151 socioeconomically diverse mothers and their infants, all born at Beth Israel Deaconess Medical Center in Boston. The mothers completed in-depth interviews during pregnancy. Cord blood was collected from the newborns so that their chromosomes could be examined — and in particular, the little caps at their tips known as telomeres.

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Precision medicine for end-stage kidney failure? 40 percent of kids needing transplants have identifiable mutations

People forming a kidney shape - indicating that not all ESRD is alike and that it can have multiple genetic causes

In adults, end-stage renal disease, or ESRD, is most commonly a complication of diabetes or hypertension. In children, teens and young adults, it’s a different picture entirely. New research finds that more than half of people needing a kidney transplant before age 25 have a congenital anomaly of the kidney or urinary tract, and that 40 percent have an identifiable genetic cause of ESRD. Knowing these genetic underpinnings can inform better care for patients with kidney disease, says study leader Friedhelm Hildebrandt, MD, chief of the Division of Nephrology at Boston Children’s Hospital.

Hildebrandt and his colleagues drew on 263 families whose child received a new kidney at Boston Children’s between 2007 and 2017, before the age of 25. In 68 families, the team was able to perform whole-exome sequencing, comparing their DNA with a normal reference sample.

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Poised pluripotency: A glimpse of the early embryo just as it’s implanting

poised pluripotency - a newly defined stem cell state
Fawn Gracey illustration (click to enlarge)

Stem cell researchers at Boston Children’s Hospital have, for the first time, profiled a highly elusive kind of stem cell in the early embryo – a cell so fleeting that it makes its entrance and exit within a 12-hour span. They describe this “poised pluripotent” cell in the journal Cell Stem Cell.

In mice, poised cells appear 4.75 to 5.25 days after egg and sperm join to form the embryo, right at the time when the embryo stops floating around and implants itself in the uterine wall.

“People have had a hard time capturing the peri-implantation period because it’s really hard to define,” says Richard Gregory, PhD, who led the research. “It’s a very dynamic stage. Everything happens within a few hours, which is quite remarkable considering the extent of the changes occurring in the properties of the cells.”

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Probing the brain’s earliest development, with a detour into rare childhood cancers

In early brain development there is an increase in ribosomes, contained in these nucleoli
Nucleoli, the structures in the cell nucleus that manufacture ribosomes, are enlarged in very early brain development, indicating an increase in ribosome production. Here, a 3D reconstruction of individual nucleoli. (Kevin Chau, Boston Children’s Hospital)

In our early days as embryos, before we had brains, we had a neural fold, bathed in amniotic fluid. Sometime in the early-to-mid first trimester, the fold closed to form a tube, capturing some of the fluid inside as cerebrospinal fluid. Only then did our brains begin to form.

In 2015, a team led by Maria Lehtinen, PhD, Kevin Chau, PhD and Hanno Steen, PhD, at Boston Children’s Hospital, showed that the profile of proteins in the fluid changes during this time. They further showed that these proteins “talk” to the neural stem cells that form the brain.

In new research just published in the online journal eLife, Lehtinen and Chau shed more light on this little-known early stage of brain development.

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Elusive epilepsy mutations begin to yield up their secrets

mosaic epilepsy mutations concept
Fawn Gracey illustration

Anti-seizure drugs don’t work in about a third of people with epilepsy. But for people with focal epilepsy, whose seizures originate in a discrete area of the brain, surgery is sometimes an option. The diseased brain tissue that’s removed also offers a rare opportunity to discover epilepsy-related genes.

Many mutations causing epilepsy have been discovered by testing DNA taken from the blood. But it’s becoming clear that not all epilepsy mutations show up on blood tests. So-called somatic mutations can arise directly in tissues like the brain during early prenatal development. Even within the brain, these mutations may affect only a fraction of the cells — those descended from the original mutated cell. This can create a “mosaic” pattern, with affected and unaffected cells sometimes intermingling.

One of the first such mutations to be described, by Ann Poduri, MD, MPH, and colleagues at Boston Children’s Hospital in 2012, was in Dante, a young boy who was having relentless daily seizures. The entire right side of Dante’s brain was malformed and enlarged, and he underwent a drastic operation, hemispherectomy, to remove it. Only later, studying brain samples from Dante and similar children, did Poduri find the genetic cause: a mutation in the gene AKT3. It affected only about a third of Dante’s brain cells. 

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How well do gluten-free diets eliminate gluten, and is home gluten testing a good thing?

gluten testing could help predict intestinal health in patients with celiac disease

For patients with celiac disease, following a gluten-free diet is complicated and often challenging.

“Our patients are navigating a gluten-free diet without any feedback to guide them,” says Jocelyn Silvester, MD, PhD, director of research at the Celiac Disease Program at Boston Children’s Hospital. “Symptoms are not a reliable indicator of gluten exposure. Many patients may not have any symptoms at all.”

For clinicians, assessing how well patients are doing on a gluten-free diet can be equally difficult. “There are no good measures of how well the gluten-free-diet is working or how well patients are following the diet,” Silvester says.

Moreover, tolerance to gluten can vary in celiac disease. Some children have symptoms despite being (apparently) on a gluten-free diet. Others have no symptoms after a gluten exposure, yet show severe atrophy of the nutrient-absorbing villi on intestinal biopsy. Villous atrophy poses a risk for complications, such as poor growth, anemia and osteoporosis.

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Science Seen: An intestinal toxin’s trick, a potential cancer fighter

Crystal structure of the C. difficile toxin bound to its receptor, causing intestinal damage
Adapted from Science May 11, 2018. DOI: 10.1126/science.aar1999

Clostridium difficile, also called “C. diff,” causes severe gastrointestinal tract infections and tops the CDC’s list of urgent drug-resistant threats. In work published in Nature in 2016, Min Dong, PhD, and colleagues found the elusive portal that enables a key C. diff toxin, toxin B, to enter the intestines’ outer cells and break down the intestinal barrier (above right).

Interestingly, the same portal, known as the Frizzled receptor, also receives signals that maintain the intestine’s stem cells. When toxin B docks, it blocks these signals, carried by a molecule known as Wnt. But exactly how it all works remained a puzzle — until new research published today in Science.

Liang Tao, PhD in Dong’s lab, working with the labs of Rongsheng Jin, PhD, at UC-Irvine, and Xi He, PhD, at Boston Children’s, captured the crystal structure of a fragment of toxin B (in orange above) as it joined to the Frizzled receptor (in green). The structure revealed lipid molecules within the Frizzled receptor (in yellow and red) that play a central role. Normally, when Wnt binds to Frizzled, it nudges these lipids aside. But the team showed that when the toxin fragment binds to Frizzled, it locks these lipids in place, preventing Wnt from engaging with the cell.

Just as stem cells rely on Wnt signaling for growth and regeneration, so do many cancers. Now that its mechanism is known, Dong thinks this toxin B fragment, which by itself isn’t toxic, could be a useful anti-cancer therapeutic. They’re currently developing a new generation of Wnt signaling modulators and testing them in animal models of cancer. (For further information, contact Rajinder.Khunkun@childrens.harvard.edu of Boston Children’s Technology & Innovation Development Office.)

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Very-low-carb diet can safely curb blood sugar in type 1 diabetes, study suggests

very-low-carb diet shows promise in type 1 diabetes

David Ludwig, MD, PhD, an endocrinologist at Boston Children’s Hospital, has written popular books espousing a low-glycemic, low-carbohydrate diet for weight control. He has argued that high-glycemic diets are contributing to the epidemic of type 2 diabetes.  But he hadn’t given much thought to carbohydrate restriction for type 1 diabetes until 2016.

At a conference, Ludwig met a surgeon with type 1 diabetes who maintains normal hemoglobin A1c levels (indicating high blood sugar control) on a very-low-carbohydrate diet. This surprised and impressed him: he had never seen any patient with type 1 diabetes able to completely normalize their hemoglobin A1cs. Moreover, most diabetes experts discourage very-low-carb diets, believing they pose a risk for hypoglycemia, or a dangerous drop in blood sugar.

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Stick-on respiratory monitor allows early detection of breathing problems

Toddler wearing ExSpiron respiratory monitor
A mock-up of the ExSpiron monitoring a toddler’s breathing

Children can be at risk for compromised breathing after surgery or from conditions like asthma, congestive heart failure or sleep apnea. Opioid therapy and sedation for medical procedures can also depress breathing. Unless a child is sick enough to have a breathing tube, respiratory problems can be difficult to detect early. Yet early detection can mean the difference between life and death.

“There is currently no real-time objective measure,” says Viviane Nasr, MD, an anesthesiologist with Boston Children’s Hospital’s Division of Cardiac Anesthesia. “Instead, respiratory assessment relies on oximetry data, a late indicator of respiratory decline, and on subjective clinical assessment.”

A new device, recently cleared by the FDA for children 1 year and older in medical settings, provides an easy, noninvasive way to tell how much air the lungs are receiving in real time. It can signal problems as much as 15-30 minutes before standard pulse oximetry picks up low blood oxygenation, according to one study.

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