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A cluster of neural cells were derived from human embryonic stem cells in the lab of Su-Chun Zhang. The motor neurons are shown in red, neural fibers appear green, and the blue specks indicate DNA in cell nuclei. Photo courtesy of UW-Madison.
A research team at the University of Wisconsin-Madison has succeeded in enticing human embryonic stem cells to become spinal motor neurons, the cells that transmit messages from the brain to the rest of the body.
The work on this phase of the project was completed some time ago but the findings were just published Monday in the advance online version of the journal Nature Biotechnology
Influencing the cells to become motor neurons and gathering all the necessary background information in a nascent corner of medical research required years of trial-and-error work, according to study leader Dr. Su-Chun Zhang, assistant professor of anatomy and neurology in the Stem Cell Research Program at the UW's Waisman Center.
"It was a little bit hard, because no one had done any work on human motor neurons," Zhang told WTN. "Actually, when we started, nothing was done even on mouse cells. There were no reports whatsoever. That's why it took a little big longer."
In their research, Zhang and his team discovered that timing is truly everything in coaxing tabula rasa stem cells into specific fates. The team found that there is a narrow window of time, roughly between the third and fourth week of human development, in which those stem cells could be influenced to become spinal motor neurons. At the same time, the cells' environment-the arrays of growth factors and hormones that the cells were exposed to at any given time-had to provide the exact conditions needed to guide them to the desired result.
"The timing, the environment-you have to be perfect. Otherwise you will get [results] all over the place," Zhang said. "That's really why the scientific community is more interested in this piece of work. It could potentially impact the field in general.
"You have to follow the timing," he added. "[If] you train a baby before they can sit to go to the toilet or walk around, it's just not possible. So that's the message we are trying to deliver."
The real fruit of the project was that the team was able to document those procedures for the stem cell research community at large.
"I think the important part is that we found the basic principle of guiding stem cells to specialize themselves," Zhang said. "You have to follow the need of the stem cells in order to guide them toward a specific, specialized cell."
In addition to potentially aiding victims of spinal cord injuries, the Zhang team's findings could lead to novel treatments for degenerative neurological diseases such as amyotrophic lateral sclerosis (ALS), or Lou Gehrig's Disease, researchers say. In the short term, the findings give neurological disorder researchers a step up in testing various compounds that affect motor neurons.
ALS is a progressive, always-fatal neurological disease that attacks the neurons responsible for controlling voluntary muscles.
"It is the first report of making human embryonic stem cells into motor neurons, so it's clearly the right tissue and the right cell type we're looking for in ALS [research]," said Lucie Bruijn, Ph.D., science direction and vice president at the ALS Association
, a major funder of Zhang's research. "The most immediate and exciting application is that it certainly is an excellent research tool to try to screen drugs in these motor neurons."
Even though there are progenitor cells in the human brain, it is very difficult for the brain to replace large cells such as motor neurons. With their long axons and the sheer distance they have to travel, it is unrealistic to expect that scientists will be able to get human motor neurons to reproduce and reattach in the body properly in the short term, according to Bruijn. But there is hope.
"It does provide us with a first important step, that we can actually make these cells in culture systems and we can use them in a variety of studies to understand why these cells die and to manipulate them in a dish and certainly, in model systems, to try to work on transplanting them and encouraging them to reconnect appropriately," Bruijn said. "It's a fantastic study, and it's certainly a group of scientists that have worked very hard at making this achievement, and I think it's a huge step forward. I think everyone would wish that it would be an immediate therapy, but clearly that's down the line in terms of the challenges of transplants."
The ALSA announced this week that it also has awarded funding to Zhang for a new project phase in which Zhang and his team will graft the human motor neurons into the spinal cords of chicken embryos and mice as a next step in their research.
"The basic work is the continuation of the current project," Zhang said. "That is, to confirm or to test whether the new (human) motor neurons produced in a Petri dish survive or do something in live animals – such as chickens and mice – in embryos or even [animals] in a diseased condition."