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Master regulatory gene found that guides fate of blood-producing stem cells
August 02, 2005Discovery may lead to new therapies for leukemia, other blood disorders
(Philadelphia, PA)-Researchers from the University of Pennsylvania School of Medicine found that a protein called NF-Ya activates several genes known to regulate the development of hematopoietic stem cells (HSC), or blood-producing stem cells, in bone marrow. Knowing the details of this pathway may one day lead to new treatments for such blood diseases as leukemia, as well as a better understanding of how HSCs work in the context of bone-marrow and peripheral-stem-cell transplantation. The authors published their findings in the early August issue of the Proceedings of the National Academy of Sciences.
"Understanding the biology behind how the body precisely controls stem-cell fate is one of the most important issues in stem-cell biology," says senior author Stephen G. Emerson, MD, PhD, Associate Director of Clinical Research for Penn's Abramson Cancer Center and Chief of the Division of Hematology-Oncology. When HSCs divide, they have one of three fates: develop into two more stem cells, which is called self-renewal; differentiate to become one of several mature blood-cell types; or strike a balance in which one daughter cell becomes an HSC and the other becomes a mature blood-cell type.
"We know that in diseases like leukemia, the first scenario-no differentiated cells, two HCSs developing-must occur because more and more stem cells are made," explains Emerson. In conditions like bone-marrow failure, the second scenario-two differentiated cells and no HCSs-happens because the body runs out of HSCs.
"We want to figure out how this process is normally regulated in the body, so that we can learn to control it for therapeutic purposes," says Emerson. "For some clinical purposes, we might want to shift the balance so that we can grow more stem cells, for those who need them. Conversely, for patients in whom this process has gone awry, such as acute leukemia, we might block the regulatory gene to shift the balance of self-renewal versus differentiation so that all the immature, leukemic cells differentiate and die.
Over the past 10 years, several gene families have been suggested to be important in regulating HSC fate-for example homebox, wnt, notch 1, and telomerase genes. Emerson and colleagues figured that one transcription factor, called NF-Y, was required for activating promoters of all of these genes. What's more, they found that fully assembled NF-Y was activated in stem cells and disappeared when the stem cells became mature cell types, through the induction and loss of one its subunits, NF-Ya.
"When we overexpressed NF-Ya in stem cells, the stem cells produced ten- to twenty-fold more stem cells after transplantation," says Emerson. "This makes NF-Ya the prime candidate for a master-regulatory gene for multiple, if not all, stem-cell division programs.\\\
University of Pennsylvania School of Medicine
"We know that in diseases like leukemia, the first scenario-no differentiated cells, two HCSs developing-must occur because more and more stem cells are made," explains Emerson. In conditions like bone-marrow failure, the second scenario-two differentiated cells and no HCSs-happens because the body runs out of HSCs.
"We want to figure out how this process is normally regulated in the body, so that we can learn to control it for therapeutic purposes," says Emerson. "For some clinical purposes, we might want to shift the balance so that we can grow more stem cells, for those who need them. Conversely, for patients in whom this process has gone awry, such as acute leukemia, we might block the regulatory gene to shift the balance of self-renewal versus differentiation so that all the immature, leukemic cells differentiate and die.
Over the past 10 years, several gene families have been suggested to be important in regulating HSC fate-for example homebox, wnt, notch 1, and telomerase genes. Emerson and colleagues figured that one transcription factor, called NF-Y, was required for activating promoters of all of these genes. What's more, they found that fully assembled NF-Y was activated in stem cells and disappeared when the stem cells became mature cell types, through the induction and loss of one its subunits, NF-Ya.
"When we overexpressed NF-Ya in stem cells, the stem cells produced ten- to twenty-fold more stem cells after transplantation," says Emerson. "This makes NF-Ya the prime candidate for a master-regulatory gene for multiple, if not all, stem-cell division programs.\\\
University of Pennsylvania School of Medicine
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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