A protein known as REST blocks the expression of a microRNA that prevents embryonic stem cells from reproducing themselves and causes them to differentiate into specific cell types, scientists at The University of Texas M. D. Anderson Cancer Center report in the journal Nature.
Researchers show RE1-silencing transcription factor (REST) plays a dual role in embryonic stem cells, said senior author Sadhan Majumder, Ph.D., professor in M. D. Anderson’s Department of Cancer Genetics. "It maintains self-renewal, or the cell’s ability to make more and more cells of its own type, and it maintains pluripotency, meaning that the cells have the potential to become any type of cell in the body."
The paper posted online March 23 in advance of publication grew from M. D. Anderson research on the protein’s role in medulloblastoma – an exceptionally aggressive pediatric brain cancer.
Embryonic stem cells are essentially blank slates. They have the unique ability to develop from identical, unspecialized cells and then differentiate into distinct types of cells with special functions. In the laboratory, scientists have been able to induce embryonic stem cells to develop into heart muscle cells or insulin-producing cells of the pancreas. The hope is that embryonic stem cells might one day be used to restore or replace failing cells in the human body and perhaps treat a wide range of diseases.
"Embryonic stem cells have a very high potential in medicine," Majumder said. "The critical thing is to learn the mechanisms that could be used to generate a lot of self-renewing embryonic stem cells and be able to differentiate them into various cell types." REST could play a key role in maintaining a steady supply of these cells and in preserving their differentiation capability.
Suppressing MicroRNA-21
In studies using mouse embryonic stem cells, the researchers found that REST disarms a specific microRNA called microRNA-21 or miR-21. MicroRNAs are tiny pieces of RNA that control gene expression by binding to the gene’s messenger RNA.
The team found that MiR-21 suppresses embryonic stem cell self-renewal and is associated with a corresponding loss of expression of critical self-renewal regulators, such as Oct4, Nanog, Sox2 and c-Myc. REST counters this by suppressing miR-21 to preserve the cells’ self-renewal and pluripotency.
The researchers discovered the roles of REST and miR-21 in a series of experiments using cultured mouse embryonic stem cells in either a self-renewal state or a differentiating state. They found that REST expression was significantly higher in the self-renewal state. Withdrawing REST reduced the stem cells’ ability to reproduce themselves and started differentiation — even when the cells were grown under conditions conducive to self-renewal. Adding REST to differentiating cells maintained their self-renewal.
These experiments also revealed that REST is bound to the gene chromatin of a set of microRNAs with the potential to target self-renewal genes. REST controls transcription of 11 microRNAs.
REST Implicated in Pediatric Brain Cancer
Previous laboratory research suggests that the qualities that make REST beneficial in stem cell production and pluripotency may contribute to the development of medulloblastoma, an aggressive type of children’s brain tumor. Medulloblastomas are believed to develop from undifferentiated neural stem cells in the external granule layer of the cerebellum.
In earlier research, Majumder’s group at M. D. Anderson discovered that about half of these tumors overexpress REST, which is not found in most neural cells. "We found that REST is a critical factor in this group of children’s brain tumors," Majumder said, "and that its major function is to keep a group of specific brain stem cells, or progenitor cells, in a state of stemness."
The researchers hypothesize that by maintaining the neural stem cells’ ‘stemness,’ REST prevents their differentiation into normal and distinct types of cells, leading instead to tumor formation. The M. D. Anderson scientists are now exploring whether microRNAs might also play a role in medulloblastomas.
Understanding REST function has applications in both medulloblastoma and embryonic stem cell biology. "Just as blocking REST function has therapeutic potential in medulloblastoma, blocking REST function to allow for differentiation of embryonic stem cells is a potentially critical step in regenerative medicine," Majumder said.
Source: University of Texas M. D. Anderson Cancer Center
Related stories:
Probing Question: Fishhooks of addiction
When the American writer Theodore Roethke taught at Penn State from 1936 to 1943, he was known for three things: being a good poet, coaching the men’s tennis team, and falling down drunk, perhaps the latter more than the former. Roethke, a brilliant and tortured man, knew well the seduction of drink and the agony of addiction. In his poem “Journey Into the Interior,” Roethke writes, “In the long journey out of the self, / There are many detours, washed-out interrupted raw places / Where the shale slides dangerously / And the back wheels hang almost over the edge / At the sudden veering, the moment of turning.”
Nerve cells derived from stem cells and transplanted into mice may lead to improved brain treatments
Scientists at the Burnham Institute for Medical Research have, for the first time, genetically programmed embryonic stem (ES) cells to become nerve cells when transplanted into the brain, according to a study published today in
The Journal of Neuroscience. The research, an important step toward developing new treatments for stroke, Alzheimer's, Parkinson's and other neurological conditions showed that mice afflicted by stroke showed tangible therapeutic improvement following transplantation of these cells. None of the mice formed tumors, which had been a major setback in prior attempts at stem cell transplantation.
'HiCy' drug regimen reverses ms symptoms in selected patients
A short-term, very-high dose regimen of the immune-suppressing drug cyclophosphamide seems to slow progression of multiple sclerosis (MS) in most of a small group of patients studied and may even restore neurological function lost to the disease, Johns Hopkins researchers report. The findings in nine people, most of whom had failed all other treatments, suggest new ways to treat a disease that tends to progress relentlessly.
Brain stem cells can be awakened, say scientists
Scientists at Schepens Eye Research Institute have identified specific molecules in the brain that are responsible for awakening and putting to sleep brain stem cells, which, when activated, can transform into neurons (nerve cells) and repair damaged brain tissue. Their findings are published online this week in the
Proceedings of the National Academy of Science (PNAS).
Researchers demonstrate safety of gene therapy using adult stem cells
A new study by UC Davis researchers provides evidence that methods using human bone marrow-derived stem cells to deliver gene therapy to cure diseases of the blood, bone marrow and certain types of cancer do not cause the development of tumors or leukemia. The study was published online in the May 6, 2008 issue of
Molecular Therapy.
Test of maturity for stem cells
Stem cells are extremely versatile: They can develop in 220 different ways, transforming themselves into a correspondingly diverse range of specialized body cells. Biologists and medical scientists plan to make use of this differentiation ability to selectively harvest cardiac, skin or nerve cells for the treatment of different diseases.
Computation to unravel how genes are regulated and shed light on how cells become different
A closer alliance between computational and experimental researchers is needed to make progress towards one of biology’s most challenging goals, understanding how epigenetic marks contribute to regulation of gene expression. This emerged from a recent workshop organised by the European Science Foundation (ESF), “Computational Approaches to the Role of Epigenetic Marks in Transcription Regulation”.
Neuronal regulators offer potential targets for cancer
Being too brainy can be a bad thing in a junior high cafeteria, where the social hierarchy favors other traits. "Braininess" also causes problems for cells. When a breast cell begins making the proteins normally produced in neurons, for example, it can acquire cancerous properties.