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What do blood stem cells need to grow? Blood flow
May 14, 2009Blood stem cells literally go with the flow, according to a new report published as an immediate early publication in the journal Cell, a Cell Press journal, on May 13th. Researchers have found that a heart beat and blood circulation are critical signals for the production of blood-forming, or hematopoietic, stem cells in the developing embryo.
The evidence found in zebrafish and mice may lead to new methods to coax embryonic stem cell-like cells (known as induced pluripotent stem cells or iPS cells) into producing blood-forming stem cells for use in the clinic. Such a method could be a particular boon as an alternative source of life-giving cells for the two-thirds of people with leukemia who do not have a matched donor, typically a brother or sister, for bone marrow transplantation, said Leonard Zon of Harvard Medical School. Leukemia patients are often treated with high doses of chemotherapy, but the treatment also leaves them with a crippled immune system.
"It's easy to make an iPS cell into a red blood cell," Zon said. "The real question is whether anybody can make a [hematopoietic stem] cell that is more self-renewing" The most efficient way to do that is to go to the source and sort out all the signals the embryo uses, he added. The new findings are another step in that direction.
Definitive hematopoietic stem cells that are capable of self-renewal and production of all mature blood lineages arise during embryogenesis, the researchers explained. Both the timing of the blood-forming stem cells' induction and the gene programs regulating this process are well conserved across vertebrate species.
In the developing embryo, blood is produced in multiple waves, he noted. In humans, the first red blood cells are produced in the yolk sac. The second wave is produced in the embryonic aorta and those blood stem cells then colonize the liver, which becomes the major blood-producing organ in the fetus.
Zon's group has been on a mission in search of chemicals that could amplify the production of blood-forming stem cells in the aorta of developing zebrafish. The transparent embryos of zebrafish coupled with their sheer numbers - each female can lay 300 eggs every week - make them ideal for developmental studies.
"We were looking in real aortas in real vertebrate embryos to see the actual stem cells," Zon said. "This couldn't be done in tissue culture."
They earlier reported one important ingredient for boosting the stem cells' production, prostaglandin E2. Now, they show initiating blood flow is also key.
Embryos with a mutation known as silent heart, which lack a heartbeat and circulation showed severely reduced hematopoietic stem cells, they found. Flow-modifying compounds primarily affected the stem cells' induction after the onset of heartbeat. The only chemicals capable of boosting their numbers prior to circulation or in the silent heart mutants were nitric oxide donors, they show.
Nitric oxide (NO) is known to play a key role in blood vessels, where it controls vessel tone and the formation of new blood vessels. The findings suggest that NO signaling is also an important link between blood flow and hematopoietic stem cells' formation.
Further studies in mice showed that an NO synthesizing enzyme is active in the stem cell-forming embryonic region in mammals. Treatments that block that enzyme or mouse embryos lacking the gene also had a reduction of hematopoietic clusters and transplantable hematopoietic stem cells.
"Here, we established a conserved role for NO in the developing hematopoietic system," the researchers concluded. "NO can function in vessel formation and specification, blood flow regulation and hematopoietic cluster formation, demonstrating that it is required in the stem cell niche for hematopoietic stem cell production. Although the function of NO in the adult marrow is complex, our findings during embryogenesis indicate that modulation of blood flow or NO signaling might be therapeutically beneficial for patients undergoing stem cell transplantation."
In addition to their potential clinical application, the new findings also help to answer a biological question Zon said he has long wondered about: why embryos make their blood stem cells in the lining of the aorta.
"In the big picture, it answers why stem cells are in the aorta to begin with," he said. "It is an ideal place to sense changes in blood flow to time blood stem cells for the production of blood in the future."
Cell Press
Definitive hematopoietic stem cells that are capable of self-renewal and production of all mature blood lineages arise during embryogenesis, the researchers explained. Both the timing of the blood-forming stem cells' induction and the gene programs regulating this process are well conserved across vertebrate species.
In the developing embryo, blood is produced in multiple waves, he noted. In humans, the first red blood cells are produced in the yolk sac. The second wave is produced in the embryonic aorta and those blood stem cells then colonize the liver, which becomes the major blood-producing organ in the fetus.
Zon's group has been on a mission in search of chemicals that could amplify the production of blood-forming stem cells in the aorta of developing zebrafish. The transparent embryos of zebrafish coupled with their sheer numbers - each female can lay 300 eggs every week - make them ideal for developmental studies.
"We were looking in real aortas in real vertebrate embryos to see the actual stem cells," Zon said. "This couldn't be done in tissue culture."
They earlier reported one important ingredient for boosting the stem cells' production, prostaglandin E2. Now, they show initiating blood flow is also key.
Embryos with a mutation known as silent heart, which lack a heartbeat and circulation showed severely reduced hematopoietic stem cells, they found. Flow-modifying compounds primarily affected the stem cells' induction after the onset of heartbeat. The only chemicals capable of boosting their numbers prior to circulation or in the silent heart mutants were nitric oxide donors, they show.
Nitric oxide (NO) is known to play a key role in blood vessels, where it controls vessel tone and the formation of new blood vessels. The findings suggest that NO signaling is also an important link between blood flow and hematopoietic stem cells' formation.
Further studies in mice showed that an NO synthesizing enzyme is active in the stem cell-forming embryonic region in mammals. Treatments that block that enzyme or mouse embryos lacking the gene also had a reduction of hematopoietic clusters and transplantable hematopoietic stem cells.
"Here, we established a conserved role for NO in the developing hematopoietic system," the researchers concluded. "NO can function in vessel formation and specification, blood flow regulation and hematopoietic cluster formation, demonstrating that it is required in the stem cell niche for hematopoietic stem cell production. Although the function of NO in the adult marrow is complex, our findings during embryogenesis indicate that modulation of blood flow or NO signaling might be therapeutically beneficial for patients undergoing stem cell transplantation."
In addition to their potential clinical application, the new findings also help to answer a biological question Zon said he has long wondered about: why embryos make their blood stem cells in the lining of the aorta.
"In the big picture, it answers why stem cells are in the aorta to begin with," he said. "It is an ideal place to sense changes in blood flow to time blood stem cells for the production of blood in the future."
Cell Press
Stem Cells Current Events and Stem Cells News RSSFirst reconstitution of an epidermis from human embryonic stem cells
Stem cell research is making great strides. This is yet again illustrated by a study carried out by the I-STEM* Institute (I-STEM/ Inserm UEVE U861/AFM), published in the Lancet on 21 November 2009. The I-STEM team, directed by Marc Peschanski has just succeeded in recreating a whole epidermis from human embryonic stem cells.
Bone Implant Offers Hope for Skull Deformities
A synthetic bone matrix offers hope for babies born with craniosynostosis, a condition that causes the plates in the skull to fuse too soon.
Your Own Stem Cells Can Treat Heart Disease
The largest national stem cell study for heart disease showed the first evidence that transplanting a potent form of adult stem cells into the heart muscle of subjects with severe angina results in less pain and an improved ability to walk. The transplant subjects also experienced fewer deaths than those who didn't receive stem cells.
Is hepatic differentiation of embryonic stem cells induced by valproic acid and cytokines?
Embryonic stem (ES) cells, known for their capacity to proliferate indefinitely and differentiate into almost all types of cells including hepatocytes, have raised the hope of cellular replacement therapy for liver failure.
Paradoxical protein might prevent cancer
One difficulty with fighting cancer cells is that they are similar in many respects to the body's stem cells. By focusing on the differences, researchers at Karolinska Institutet have found a new way of tackling colon cancer. The study is presented in the prestigious journal Cell.
U of M researchers find 2 units of umbilical cord blood reduce risk of leukemia recurrence
A new study from the Masonic Cancer Center, University of Minnesota shows that patients who have acute leukemia and are transplanted with two units of umbilical cord blood (UCB) have significantly reduced risk of the disease returning.
The use of stem cells in regenerative medicine may also be detrimental for health
The use of stem cells in regenerative medicine is not always beneficial for human health, it may even be harmful according to a work done by the University of Granada and University of León. Scientists have demonstrated that transplantation of human mononuclear cells isolated from umbilical cord blood exerted a deleterious effect in rats with liver cirrhosis.
Penn Study Provides First Clear Idea of How Rare Bone Disease Progresses
An international team of scientists, led by researchers at the University of Pennsylvania School of Medicine, is taking the first step in developing a treatment for a rare genetic disorder called fibrodysplasia ossificans progressiva (FOP), in which the body's skeletal muscles and soft connective tissue turns to bone, immobilizing patients over a lifetime with a second skeleton.
Iowa State University researcher discovers key to vital DNA, protein interaction
A researcher at Iowa State University has discovered how a group of proteins from plant pathogenic bacteria interact with DNA in the plant cell, opening up the possibility for what the scientist calls a "cascade of advances."
Scientists successfully reprogram blood cells
Researchers have transplanted genetically modified hematopoietic stem cells into mice so that their developing red blood cells produce a critical lysosomal enzyme -preventing or reducing organ and central nervous system damage from the often-fatal genetic disorder Hurler's syndrome.
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