ScienceDaily (Sep. 10, 2008) ? Unlike some parents, adult stem cells don't seem to mind when their daughters get a tattoo. In fact, they're willing to pass them along.
The U of U researchers, led by Alejandro S?nchez Alvarado, Ph.D., professor of neurobiology and anatomy, identified 259 genes that help defined the earliest steps in the differentiation of adult stem cells in planarians?tiny flatworms that have the uncanny ability to regenerate cells and may have much to teach about human stem cell biology.
The findings, reported in the Sept. 11 issue of Cell Stem Cell establish planarians as an excellent model for studying adult stem cells in a live animal, rather than a laboratory culture dish.
"This allows us to study an entire stem cell population in its own environment," said S?nchez Alvarado, also an investigator with the Howard Hughes Medical Institute and the study's senior author. "It's likely that what we learned here can be applied to our own stem cell biology."
Planarians share similar biology with humans in many ways. They also, for reasons unknown, regenerate cells unlike any other animal?an entirely new worm can form from just a fragment of another worm. Planarians constantly regenerate new cells to replace those that die naturally or from injury.
The process begins when adult stem cells divide into two new cells (daughter cells): one becomes like its mother (a stem cell), while the other will move on to give rise to the cells that will serve specific functions in planarian life. For example, some cells may form part of the worm's musculature, while others will form part of the brain.
Because daughters and mother cells are indistinguishable from each other in appearance, the researchers devised methods to detect specific differences in gene expression in the BrdU-labeled cells. The researchers identified 259 genes associated with the stem cells and their daughters. When the U team disabled some of these genes, they found that in some cases no defects were observed, while in others deficiencies were detected in the way the cells were patterned in regenerating planarians.
S?nchez Alvarado and two colleagues then marked adult stem cells in the worms by injecting BrdU, a synthetic nucleotide that binds with DNA and leaves an unmistakable mark on it, much like a tattoo. (Nucleotides are the structural units of DNA and RNA.) When the adult stem cells divided into daughter cells as part of the worms' normal cell regeneration, the BrdU was passed to the daughter cells in their DNA, allowing the researchers to track these cells. By detecting which genes were expressed in which BrdU-labeled cells, the collection of identified genes allowed the researchers to work out for the first time the lineage of stem cells in planarians.
They found that the daughter cells that move on to differentiate into different cell types do so by going through at least two steps. Although the daughter cells, which the researchers labeled categories 2 and 3, are indistinguishable by appearance, they play different roles in cell differentiation
"It seems as if category 2 cells make category 3 cells," S?nchez Alvarado said. "We don't know which differentiated cells they make, but category 3 cells likely differentiate into many different cell types."
These findings open a window to understanding how multipotent stem cells take differentiation decisions. "This allows us to begin to understand how adult stem cells decide what their daughter cells will become when they grow up," S?nchez Alvarado said. "These molecular markers will help us identify specific differentiated cells and help us determine how a stem cell population decides how many of each of the differentiated cell types it needs to make."
The next big step for S?nchez Alvarado and his colleagues is to identify the molecules that act to restrict cell types into serving specific functions.
George T. Eisenhoffer is first author on the study and Hara Kang is co-author. Both authors are graduate students in the Department of Neurobiology and Anatomy at the University of Utah School of Medicine.
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U research leads to better understanding of stem cells
Updated: Thursday, September 11, 2008
Lucas Isley
George Eisenhoffer Jr., a Doctoral Candidate at the U, hopes that researching flatworms will hold keys on how to generate cells for treating degenerative disorders.
Flatworms may not have the brain power of humans, but their regenerative capabilities have helped U researchers further understand fundamental functions of stem cells.
The work on the stem cells of flatworms could help scientists learn how to generate specific cell types to help with treatments of diseases ranging from degenerative disorders to cancer.
Alejandro S?nchez Alvarado, a neurobiology and anatomy professor, started working with flatworms 10 years ago. The aim of his research is to study the basic biology of animal stem cells, particularly those capable of producing the differentiated cells of all tissue types, such as with nerves and muscles.
“You have one stem cell, a cell that when it divides, for example, produces a duplicate of itself and another cell that goes on to differentiate,” said S?nchez Alvarado, a Howard Hughes Medical Institute investigator. “Immediately after division, the resulting cells are indistinguishable from each other.”
Researchers have not been able to tell the difference between the cells produced after cell division in flatworms. But through a marking system that could experimentally distinguish between the two, S?nchez Alvarado and two of his graduate students found more than 200 genes that can label the stem cells and those that will go on to produce differentiated cell types.
“We found sets of genes that specifically marked one or the other undifferentiated cells produce by cell division,” S?nchez Alvarado said. “One set of genes marks the stem cells proper, which will go on to divide, while the other set of genes marks the remaining undifferentiated cells that will eventually produce specific differentiated cell types.”
George Eisenhoffer, a neurobiology and anatomy graduate student, said now they know how to distinguish between the stem and non-stem cells, and they can begin to look at how animals produce a certain number and type of cells.
“We basically propose that because (flatworms) share similar aspects to human biology, what we learn here may be applicable to how stem cells operate in our bodies,” he said.
Eisenhoffer and Hara Kang, another neurobiology and anatomy graduate student working in S?nchez Alvarado’s lab, generated a series of techniques to look at the molecules operating in specific types of cells.
“Hara Kang developed tools to examine the cell cycle status of the (flatworm) stem cells,” Eisenhoffer said. “I used this methodology to characterize the different cell types identified in our analyses.”
He said the marking technique allows them to tag, or tattoo, the cells to distinguish between them.
S?nchez Alvarado said most of the research was done in the live flatworm instead of looking through a petri dish.
“Eisenhoffer carried out the majority of the experiment,” he said. “I came up with the idea for the work, and we went back and forth with ideas.”
Flatworms were specifically useful in this type of experiment because of the larger number of stem cells they have.
Flatworms have 15 to20 percent of stem cells in their body. Of all the cells humans have in their bodies, less than a fraction of a percent of them are stem cells.
Eisenhoffer and Kang are completing their doctoral thesis work partly based on this research, but the work is far from over.
“Now that we can identify one type of cell from another, we can perturb the decision-making process and identify genes specifically involved in deciding which cell type these undifferentiated cells will turn into in the living organism,” S?nchez Alvarado said.
With the tools to identify each cell before they change, researchers may be able to determine when genes begin to cause cancer, for example.
S?nchez Alvarado said a possible practical application down the road is to force a stem cell to go into one cell type versus another in vivo to produce a specific cell that the body may need.
The study was published in the September issue of Cell Stem Cell.
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