Stories about: blood stem cells

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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A breakthrough in our understanding of how red blood cells develop

Artist's rendering of red blood cells
Red blood cells.

By taking a deep dive into the molecular underpinnings of Diamond-Blackfan anemia, scientists have made a new discovery about what drives the development of mature red blood cells from the earliest form of blood cells, called hematopoietic (blood-forming) stem cells.

For the first time, cellular machines called ribosomes — which create proteins in every cell of the body — have been linked to blood stem cell differentiation. The findings, published today in Cell, have revealed a potential new therapeutic pathway to treat Diamond-Blackfan anemia. They also cap off a research effort at Boston Children’s Hospital spanning nearly 80 years and several generations of scientists.

Diamond-Blackfan anemia — a severe, rare, congenital blood disorder — was first described in 1938 by Louis Diamond, MD, and Kenneth Blackfan, MD, of Boston Children’s. The disorder impairs red blood cell production, impacting delivery of oxygen throughout the body and causing anemia. Forty years ago, David Nathan, MD, of Boston Children’s determined that the disorder specifically affects the way blood stem cells become mature red blood cells.

Then, nearly 30 years ago, Stuart Orkin, MD, also of Boston Children’s, identified a protein called GATA1 as being a key factor in the production of hemoglobin, the essential protein in red blood cells that is responsible for transporting oxygen. Interestingly, in more recent years, genetic analysis has revealed that some patients with Diamond-Blackfan have mutations that block normal GATA1 production.

Now, the final pieces of the puzzle — what causes Diamond-Blackfan anemia on a molecular level and how exactly ribosomes and GATA1 are involved — have finally been solved by another member of the Boston Children’s scientific community, Vijay Sankaran, MD, PhD, senior author of the new Cell paper.

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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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Routing gene therapy directly into the brain

Image of mouse brain that received a transplantation of hematopoietic stem cells. The image shows the transplanted cells (green) rapidly engrafted and gave rise to new cells (also green) that have widely distributed throughout the entire brain. 
Image of a mouse brain that received a direct transplantation of hematopoietic stem cells. The image reveals the transplanted cells (green) rapidly engrafted and gave rise to new cells (also green) that have widely distributed throughout the entire brain.

A therapeutic technique to transplant blood-forming (hematopoietic) stem cells directly into the brain could herald a revolution in our approach to treating central nervous system diseases and neurodegenerative disorders.

The technique, which could be used to transplant donor-matched hematopoietic stem cells (HSCs) or a patient’s own genetically-engineered HSCs into the brain, was reported in Science Advances today by researchers from the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and the San Raffaele Telethon Institute for Gene Therapy.

In their study, the team tested the technique in a mouse model to treat lysosomal storage disorders, a group of severe metabolic disorders that affect the central nervous system.

The team’s findings are groundbreaking because, until now, it was thought that HSCs — from a healthy, matched donor or a patient’s own genetically-corrected cells — needed to be transplanted indirectly

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Pre-treated blood stem cells reverse type 1 diabetes in mice

autoimmune attack in type 1 diabetes
In type 1 diabetes, autoreactive T-cells (like the one in yellow) attack insulin-producing beta cells in the pancreas. What if blood stem cells could be taught to neutralize them? (Image: Andrea Panigada)

Type 1 diabetes is caused by an immune attack on the pancreatic beta cells that produce insulin. To curb the attack, some researchers have tried rebooting patients’ immune systems with an autologous bone-marrow transplant, infusing them with their own blood stem cells. But this method has had only partial success.

New research in today’s Science Translational Medicine suggests a reason why.

“We found that in diabetes, blood stem cells are defective, promoting inflammation and possibly leading to the onset of disease,” says Paolo Fiorina, MD, PhD, of Boston Children’s Hospital, senior investigator on the study.

But they also found that the defect can be fixed — by pre-treating the blood stem cells with small molecules or with gene therapy, to get them to make more of a protein called PD-L1.

In experiments, the treated stem cells homed to the pancreas and reversed hyperglycemia in diabetic mice, curing almost all of them of diabetes in the short term. One third maintained normal blood sugar levels for the duration of their lives.

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Medical milestone: Making blood stem cells in the lab

blood stem cells
The gradation of pink-to-blue cells illustrates the transition from hemogenic endothelial cells to blood progenitor cells during normal embryonic blood development. Daley, Sugimura and colleagues recreated this process in the lab, then added genetic factors to produce a mix of blood stem and progenitor cells. (O’Reilly Science Art)

Pluripotent stem cells can make virtually every cell type in the body.  But until now, one type has remained elusive: blood stem cells, the source of our entire complement of blood cells.

Since human embryonic stem cells (ES cells) were isolated in 1998, scientists have tried to get them to make blood stem cells. In 2007, the first induced pluripotent stem (iPS) cells were made from human skin cells, and have since been used to generate multiple cell types, such as neurons and heart cells.

But no one has been able to make blood stem cells. A few have have been isolated, but they’re rare and can’t be made in enough numbers to be useful.

Now, the lab of George Daley, MD, PhD, part of Boston Children’s Stem Cell Research program as finally hit upon a way to create blood stem cells in quantity, reported today in Nature.

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Supercharged marrow transplant: Zebrafish reveal drugs that aid engraftment

Zebrafish stem cell engraftment bone marrow
(Jonathan Henninger and Vera Binder)

Bone marrow transplantation, a.k.a. stem cell transplantation, can offer a cure for certain cancers, blood disorders, immune deficiencies and even metabolic disorders. But it’s a highly toxic procedure, especially when a closely matched marrow donor can’t be found. Using stem cells from umbilical cord blood banked after childbirth could open up many more matching possibilities, making transplantation safer.

Except for one problem. “Ninety percent of cord blood units can’t be used because they’re too small,” says Leonard Zon, MD, who directs the Stem Cell Research Program at Boston Children’s.

But what if the blood stem cells in those units could be supercharged to engraft more efficiently in the bone marrow and grow their numbers faster? That’s been the quest of the Zon lab for the past seven years, in partnership with a see-through zebrafish called Casper.

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Live imaging captures how blood stem cells take root in the body

For years, the lab of Leonard Zon, MD, director of the Stem Cell Research Program at Boston Children’s Hospital, has sought ways to enhance bone marrow transplants for patients with cancer, serious immune deficiencies and blood disorders. Using zebrafish as a drug-screening platform, the lab has found a number of promising compounds, including one called ProHema that is now in clinical trials.

But truthfully, until now, Zon and his colleagues have largely been flying blind.

“Stem cell and bone marrow transplants are still very much a black box: cells are introduced into a patient and later on we can measure recovery of their blood system, but what happens in between can’t be seen,” says Owen Tamplin, PhD, in the Zon Lab. “Now we have a system where we can actually watch that middle step.”

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Seeding medical innovation: The Technology Development Fund

Monique Yoakim Turk Technology Development FundMonique Yoakim-Turk, PhD, is a partner of the Technology Development Fund and associate director of the Technology and Innovation Development Office at Boston Children’s Hospital

Since 2009, Boston Children’s Hospital has committed $6.2 million to support 58 hospital innovations ranging from therapeutics, diagnostics, medical devices and vaccines to regenerative medicine and healthcare IT projects. What a difference six years makes.

The Technology Development Fund (TDF) was proposed to Boston Children’s senior leadership in 2008 after months of research. As a catalyst fund, the TDF is designed to transform seed-stage academic technologies at the hospital into independently validated, later-stage, high-impact opportunities sought by licensees and investors. In addition to funds, investigators get access to mentors, product development experts and technical support through a network of contract research organizations and development partners. TDF also provides assistance with strategic planning, intellectual property protection, regulatory requirements and business models.

Seeking some “metrics of success” beyond licensing numbers and royalties (which can come a decade or so after a license), I asked recipients of past TDF awards to report back any successes that owed at least in part to data generated with TDF funds. While we expected some of the results, we would have never anticipated such a large impact.

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