Human embryonic stem cells (hESCs) have previously been converted into many different cell types including a number of nerve cell types. But until now no lab has been successful in converting hESCs into motor neurons. Motor neurons are the nerve cells that run down the spinal cord to send messages to muscle cells to cause muscles to contract. Your body won't motor around without motor neurons to order your muscles to push you along. Suffer from an injury that cuts your motor neurons in your spine and you'll find yourself desiring some replacement motor neurons about as soon as you regain consciousness and are apprised of you tragic predicament. Well, University of Wisconsin-Madison scientists Su-Chun Zhang and Xue-Jun Li have found a sequence of growth factors and other chemicals that can be allied to hESCs to turn them into motor neurons. (also found here)
MADISON - After years of trial and error, scientists have coaxed human embryonic stem cells to become spinal motor neurons, critical nervous system pathways that relay messages from the brain to the rest of the body.
The new findings, reported online today (Jan. 30, 2005) in the journal Nature Biotechnology by scientists from the University of Wisconsin-Madison, are important because they provide critical guideposts for scientists trying to repair damaged or diseased nervous systems.
Motor neurons transmit messages from the brain and spinal cord, dictating almost every movement in the body from the wiggling of a toe to the rolling of an eyeball. The new development could one day help victims of spinal-cord injuries, or pave the way for novel treatments of degenerative diseases such as amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. With healthy cells grown in the lab, scientists could, in theory, replace dying motor neurons to restore function and alleviate the symptoms of disease or injury.
Much sooner in the future, the advance will allow researchers to create motor neuron modeling systems to screen new drugs, says study leader Su-Chun Zhang, an assistant professor of anatomy and neurology in the Stem Cell Research Program at the Waisman Center at UW-Madison.
Scientists have long believed in the therapeutic promise of embryonic stem cells with their ability to replicate indefinitely and develop into any of the 220 different types of cells and tissues in the body.
But researchers have struggled to convert blank-slate embryonic stem cells into motor neurons, says Zhang. The goal proved elusive even in simpler vertebrates such as mice, whose embryonic stem cells have been available to scientists for decades.
There is a fairly small window in time during which developing embryo cells possess the capacity to turn into motor neurons.
One reason scientists have had difficulty making motor neurons, Zhang believes, may be that they are one of the earliest neural structures to emerge in a developing embryo. With the ticking clock of development in mind, Zhang and his team deduced that there is only a thin sliver of time - roughly the third and fourth week of human development - in which stem cells could be successfully prodded to transform themselves into spinal motor neurons.
I think it is inevitable that methods will be found to dedifferentiate (i.e. make less specialized or less committed to a single purpose) both adult stem cell types and fully specialized cell types (e.g. liver cells or skin fibroblast cells) to turn these cells back into less differentiated stem cells and even all the way back into embryonic stem cells. So for the production of motor neurons we will not always be limited to starting with embryonic stem cells to pass them through that 2 week window in early embryonic development during which embryonic stem cells can be converted into motor neurons. In fact, compounds that cause cellular dedifferentiation have already been found. I expect many more techniques for dediffentiating cells will be found.
Think of cells as enormously complex state machines. Currently it is much easier (though not easy in an absolute sense) to coax cells to switch from the embryonic state into other states. The reason for this is pretty obvious: Cells in the embryonic state must be capable of transitioning through a series of steps into all the other states (e.g. to the state that heart muscle cells are in or the state that liver cells are in or the state that insulin-secreting Pancreatic Isles of Langerham cells are in) because embryos develop to produce cells in all those states. They must have that capacity or else a full organism couldn't develop starting from an embryo. However, just because there are some cell state transitions that do not happen under normal conditions of development that doesn't mean that those transitions can't be made to happen with the right (and waiting to be discovered) sequences of hormones, growth factors, gene therapies, and other stimuli.
Just because some day we will have methods to turn non-embryonic cell types into all other cell types that does not mean that avoidance of the use of hESCs in developing therapies has no future cost in terms of the health of some fraction of the human population. There is a very real possibility that hESCs can be developed for some therapeutic uses faster than other cell types can be developed for all uses. My guess is that at least for some purposes hESCs will be ready to provide treatments faster than adult stem cell types can be coaxed to do the same. We will see more research results such as this paper offering the possibilty of a cell therapy treatment for which the development of alternative non-hESC based cell therapy treatments are a more distant prospect.
Zhang's group had to use precise timings of changes in the biochemical cocktails fed to the cells to produce the desired outcome.
In addition to the narrow time frame, it was also critical to expose the growing stem cells to an array of complex chemical cocktails. The cocktails constitute naturally secreted chemicals - a mix of growth factors and hormones - that provide the exact growing conditions needed to steer the cells down the correct developmental pathway. "You need to teach the [embryonic stem cells] to change step by step, where each step has different conditions and a strict window of time," says Zhang. "Otherwise, it just won't work."
To differentiate into a functional spinal motor neuron, the stem cells advanced through a series of mini-stages, each requiring a unique growing medium and precise timing. To start, the Wisconsin team generated neural stem cells from the embryonic stem cells. They then transformed the neural cells into progenitor cells of motor neurons, which in turn developed in a lab dish into spinal motor neuron cells.
Note that this group had to try many different compounds and timings to find a recipe that worked. Greater automation of lab equipment is accelerating and will continue to accelerate this kind of work by increasing the rate at which different chemical cocktails can be tried in searches for techniques to turn various cell types into other cell types. So I expect the rate of advance of stem cell research of all kinds to accelerate regardless of the likely outcomes of political debates about human embryonic stem cell research.
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