Stories about: stem cell research

In zebrafish, a way to find new cancer therapies, targeting tumor promoters

A new study suggests the power of zebrafish as tools for cancer drug discovery (PHOTO: KATHERINE C. COHEN)

The lab of Leonard Zon, MD, has long been interested in making blood stem cells in quantity for therapeutic purposes. To test for their presence in zebrafish, their go-to research model, they turned to the MYB gene, a marker of blood stem cells. To spot the cells, Joseph Mandelbaum, a PhD candidate in the lab, attached a fluorescent green tag to MYB that made it easily visible in transparent zebrafish embryos.

“It was a real workhorse line for us,” says Zon, who directs the Stem Cell Research Program at Boston Children’s Hospital.

In addition to being a marker of blood stem cells, MYB is an oncogene. About five years ago, Zon was having lunch at a cancer meeting and, serendipitously, sat next to Jeff Kaufman, who was also interested in MYB. Kaufman was excited to hear about Zon’s fluorescing MYB zebrafish, which can be studied at scale and are surprisingly similar to humans genetically.

“Have you ever heard of adenoid cystic carcinoma?” he asked Zon.

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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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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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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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Science and medicine in 2018: What’s the forecast?

2018 predictions for biomedicine

Vector consulted its many informants to find out which way the wind will blow in 2018. Here are their predictions for what to expect in genetics, stem cell research, immunology and more.

GENETICS

Gene-based therapies mature

We will continue to see successes in 2018 reflecting the maturation of gene therapy as a viable, generalizable platform for curing many rare diseases. Also, we will see exciting new applications of other maturing platforms, like CRISPR/Cas9 gene editing and oligonucleotide therapies for neurologic diseases, building on the success of nusinersen for spinal muscular atrophy.

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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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2017 pediatric biomedical advances at Boston Children’s Hospital: Our top 10 picks

New tools and technologies fueled biomedicine to great heights in 2017. Here are just a few of our top picks. All are great examples of research informing better care for children (and adults).

1. Gene therapy arrives

(Katherine C. Cohen)

In 2017, gene therapy solidly shed the stigma of Jesse Gelsinger’s 1999 death with the development of safer protocols and delivery vectors. Though each disease must navigate its own technical and regulatory path to gene therapy, the number of clinical trials is mounting worldwide, with seven gene therapy trials now recruiting at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. In August, the first gene therapy won FDA approval: CAR T-cell therapy for pediatric acute lymphoblastic leukemia.

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3D organoids and RNA sequencing reveal the crosstalk driving lung cell formation

lung disease
A healthy lung must maintain two key cell populations: airway cells (left), and alveolar epithelial cells (right). (Joo-Hyeon Lee)

To stay healthy, our lungs have to maintain two key populations of cells: the alveolar epithelial cells, which make up the little sacs where gas exchange takes place, and bronchiolar epithelial cells (also known as airway cells) that are lined with smooth muscle.

“We asked, how does a stem cell know whether it wants to make an airway or an alveolar cell?” says Carla Kim, PhD, of the Stem Cell Research Program at Boston Children’s Hospital.

Figuring this out could help in developing new treatments for such lung disorders as asthma and emphysema, manipulating the natural system for treatment purposes.

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Stem cell workaround cracks open new leads in Diamond Blackfan anemia

Diamond Blackfan anemia iPS cells hematopoietic progenitor cells
Though not bona-fide stem cells, hematopoietic progenitor cells produce red blood cells when exposed to certain chemicals. Could some of these compounds lead to new drugs for Diamond Blackfan anemia?

Diamond Blackfan anemia (DBA) has long been a disease waiting for a cure. First described in 1938 by Louis K. Diamond, MD, of Boston Children’s Hospital and his mentor, Kenneth Blackfan, MD, the rare, severe blood disorder prevents the bone marrow from making enough red blood cells. It’s been linked to mutations affecting a variety of proteins in ribosomes, the cellular organelles that themselves build proteins. The first mutation was reported in 1999.

But scientists have been unable to connect the dots and turn that knowledge into new treatments for DBA. Steroids are still the mainstay of care, and they help only about half of patients. Some people eventually stop responding, and many are forced onto lifelong blood transfusions.

Researchers have tried for years to isolate and study patients’ blood stem cells, hoping to recapture the disease process and gather new therapeutic leads. Some blood stem cells have been isolated, but they’re very rare and can’t be replicated in enough numbers to be useful for research.

Induced pluripotent stem (iPS) cells, first created in 2006 from donor skin cells, seemed to raise new hope. They can theoretically generate virtually any specialized cell, allowing scientists model a patient’s disease in a dish and test potential drugs.

There’s been just one hitch. “People quickly ran into problems with blood,” says hematology researcher Sergei Doulatov, PhD. “iPS cells have been hard to instruct when it comes to making blood cells.”

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Rainbow-hued blood stem cells shed new light on cancer, blood disorders

color-coded blood stem cells
These red blood cells bear color tags made from random combinations of red, green and blue fluorescent proteins. Same-color cells originate from the same blood stem cell (Nature Cell Biology 2016, Henninger et al).

A new color-coding tool is enabling scientists to better track live blood stem cells over time, a key part of understanding how blood disorders and cancers like leukemia arise, report researchers in Boston Children’s Hospital’s Stem Cell Research Program.

In Nature Cell Biology today, they describe the use of their tool in zebrafish to track blood stem cells the fish are born with, the clones (copies) these cells make of themselves and the types of specialized blood cells they give rise to (red cells, white cells and platelets). Leonard Zon, MD, director of the Stem Cell Research Program and a senior author on the paper, believes the tool has many implications for hematology and cancer medicine since zebrafish are surprisingly similar to humans genetically.

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