Stories about: Regenerative medicine

More surprises about blood development — and a possible lead for making lymphocytes

blood development chart
Blood development in the embryo begins with cells that make myeloid and erythroid cells – but not lymphoid cells. Why? A partial answer is in today’s Nature.

Hematopoietic stem cells (HSCs) have long been regarded as the granddaddy of all blood cells. After we’re born, these multipotent cells give rise to all our cell lineages: lymphoid, myeloid and erythroid cells. Hematologists have long focused on capturing HSCs’ emergence in the embryo, hoping to recreate the process in the lab to provide a source of therapeutic blood cells.

But in the embryo, oddly enough, blood development unfolds differently. The first blood cells to show up are already partly differentiated. These so-called “committed progenitors” give rise only to erythroid and myeloid cells — not lymphoid cells like the immune system’s B and T lymphocytes.

Researchers in the lab of George Q. Daley, MD, PhD, part of Boston Children’s Hospital’s Stem Cell Research program, wanted to know why. Does nature deliberately suppress blood cell multipotency in early embryonic development? And could this offer clues about how to reinstate multipotency and more readily generate different blood cell types?

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News Note: Cell ‘barcodes’ trace the natural development of blood

in situ blood development
(Credit: Stem Cell Program, Boston Children’s Hospital)

Genetic labels, or “barcodes,” are shedding new light on the natural process of blood development and immune-cell production, finds a study published in Nature this week. It was led by Fernando Camargo, PhD, and first author Alejo Rodriguez Fraticelli, PhD, at Boston Children’s Hospital’s Stem Cell Research Program, the Harvard Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute.

Most of what we know about blood production is through observing what happens when blood stem and progenitor cells are transplanted into an animal. To observe what happens “in the wild,” researchers went in and tagged the blood stem and progenitor cells of mice, using genetic elements called transposons. This allowed them to track how the cells differentiated into five kinds of blood cells (above: megakaryocytes, erythroid cells, granulocytes, monocytes and B-cell progenitors).

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Delivered through amniotic fluid, stem cells could treat a range of birth defects

Transamniotic stem cell therapy, or TRASCET, is like amniocentesis is reverse.
Amniotic fluid is routinely withdrawn for prenatal testing. It could also be a delivery route for fetal cell therapy to treat congenital anomalies, with broader applications than once thought.

The amniotic fluid surrounding babies in the womb contains fetal mesenchymal stem cells (MSCs) that can differentiate into many cell types and tissues. More than a decade ago, Dario Fauza, MD, PhD, a surgeon and researcher at Boston Children’s Hospital, proposed using these cells therapeutically. His lab has been exploring these cells’ healing properties ever since.

Replicated in great quantity in the lab and then reinfused into the amniotic fluid in animal models — a reverse amniocentesis if you will — MSCs derived from amniotic fluid have been shown to repair or mitigate congenital defects before birth. In spina bifida, they have induced skin to grow over the exposed spinal cord; in gastroschisis, they have reduced damage to the exposed bowel. Fauza calls this approach Trans-Amniotic Stem Cell Therapy, or TRASCET.

New research findings, reported this month in the Journal of Pediatric Surgery, could expand TRASCET’s therapeutic potential.

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Novel therapeutic cocktail could restore fine motor skills after spinal cord injury and stroke

CST axons sprout from intact to injured side
Therapeutic mixture induces sprouting of axons from healthy (L) into the injured (R) side of the spinal cord.

Neuron cells have long finger-like structures, called axons, that extend outward to conduct impulses and transmit information to other neurons and muscle fibers. After spinal cord injury or stroke, axons originating in the brain’s cortex and along the spinal cord become damaged, disrupting motor skills. Now, reported today in Neuron, a team of scientists at Boston Children’s Hospital has developed a method to promote axon regrowth after injury.

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Optic nerve regeneration: One approach doesn’t fit all

alpha retinal ganglion cells optic nerve regeneration
Alpha-type retinal ganglion cells (RGCs) in part of an intact mouse retina. The cell axons lead to the optic nerve head (top right) and then exit into the optic nerve. The alpha RGCs are killed by the transcription factor SOX11 despite its pro-regenerative effect on other types of RGCs. (Fengfeng Bei)

Getting a damaged optic nerve to regenerate is vital to restoring vision in people blinded through nerve trauma or disease. A variety of growth-promoting factors have been shown to help the optic nerve’s retinal ganglion cells regenerate their axons, but we are still far from restoring vision. A new study published yesterday in Neuron underscores the complexity of the problem.

A research team led by Fengfeng Bei, PhD, of Brigham and Women’s Hospital, Zhigang He, PhD, and Michael Norsworthy, PhD, of Boston Children’s Hospital, and Giovanni Coppola, MD, of UCLA conducted a screen for transcription factors that regulate the early differentiation of RGCs, when axon growth is initiated. While one factor, SOX11, appeared to be critical in helping certain kinds of RGCs regenerate their axons, it simultaneously killed another type — alpha-RGCS (above)— when tested in a mouse model.

At least 30 types of retinal ganglion cell message the brain via the optic nerve. “The goal will be to regenerate as many subtypes of neurons as possible,” says Bei. “Our results here suggest that different subtypes of neurons may respond differently to the same factors.”

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Potential cure for diabetes may be in the stomach

diabetes stomach beta cells
The yellow-green cells in this “mini-stomach” are capable of making insulin. The mini-organ was made from biopsied cells from mouse stomachs, with reprogramming factors added.

If only there were a cure. David Breault, MD, PhD, associate chief of the Division of Endocrinology at Boston Children’s Hospital, was seeing patient after patient with Type I diabetes. Children facing lifetimes of insulin injections, special diets and the threat of long-term complications including blindness, heart disease and kidney failure.

Breault knew that patients with type I diabetes mysteriously destroy their own insulin-producing beta cells. He had read reports of researchers transplanting beta cells to supplement insulin. These transplants, even when successful, required powerful immunosuppressant medications to prevent patients’ immune systems from attacking the donor cells.

But Breault was also aware that investigators had, for a decade, been looking to stem cells as the source of a constantly renewing supply of beta cells. Advancing that promise, he has now found a way to convert patients’ own cells — from the stomach and intestine — into beta cells that produce insulin.

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Stem cells and birth defects: Could gastroschisis be treated in utero?

gastroschisis birth defects
Although Gianna was treated surgically, Dario Fauza, MD, hopes to someday use stem cells from the amniotic fluid, multiplied and returned to the womb, to naturally heal gastroschisis and other birth defects. (Courtesy Danielle DeCarlo)

Except when spreading awareness about her condition, 6-year-old Gianna DeCarlo prefers not to wear two-piece bathing suits because of the long vertical scar on her stomach. “Even though nobody’s said anything, she feels like she’ll be made fun of,” says her mother, Danielle. “I do what I can to make her love her body.”

Gianna doesn’t remember her three surgeries or the nasogastric tube she needed as an infant, before she was able to eat normally. She was born with gastroschisis, a striking birth defect in which the abdominal wall doesn’t seal fully during fetal development. As a result, her intestines developed outside her body. She was fed through an IV for several weeks, and was finally stitched fully shut at age 2.

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An inner ear in a dish

lab-grown inner ear organs
Images courtesy Eri Hashino

Could regenerative techniques restore hearing or balance by replacing lost sensory cells in the inner ear? Lab-created inner-ear organs, described today in Nature Communications, could provide helpful three-dimensional models for testing potential therapies.

The lab-built sac-like structure above, about 1 millimeter in size, contains fully-formed balance organs resembling the utricle and saccule, which sense head orientation and movement and send impulses to the brain. The tiny organs were built from mouse embryonic stem cells in a 3-D tissue culture in work led by Jeffrey Holt, PhD, of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital and Eri Hashino, PhD, of the University of Indiana.

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Inside bridge-enhanced ACL repair

An anterior cruciate ligament (ACL) tear can be a devastating sports injury. Every year, 400,000 people, many of them teen and young adult athletes, sustain ACL injuries or tears. Martha Murray, MD, an orthopedic surgeon at Boston Children’s Hospital, worked with a team of colleagues to create a new procedure known as bridge-enhanced ACL repair (BEAR) that encourages natural healing. Watch this animation to see how it works:

Why do surgeons need a better way to repair ACL injuries?

The current standard of care, surgical ACL reconstruction, is a good solution. But it is linked with a 20 percent risk of re-tearing the ACL, and many young patients face an increased risk of arthritis. Instead of removing the torn ACL and replacing it with a tendon graft, the BEAR technique uses a special protein-enriched sponge to encourage the torn ends to reconnect and heal. The researchers have completed a 20-patient safety trial and are enrolling additional patients in a 200-patient clinical study.

Learn more about Murray’s research.

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News notes: Headlines in science & innovation

An occasional roundup of news items Vector finds interesting.

Blood-brain barrier on chip

vector news - blood brain barrier chip
(Wyss Institute at Harvard University)

The blood-brain barrier protects the brain against potentially damaging molecules, but its gate-keeping can also prevent helpful drugs from getting into the central nervous system. Reporting in PLoS One, a team at the Wyss Institute for Biologically Inspired Engineering describes a 3-D blood-brain barrier on a chip — a hollow blood vessel lined with living human endothelial cells and surrounded by a collagen matrix bearing human pericytes and astrocytes.

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