Researchers have found that manipulating stem cells prior to transplantation may hold the key to overcoming a critical obstacle to using stem cell technology to repair spinal cord injuries.
This particular research focused on a major support cell in the central nervous system called an astrocyte. When nerve fibers are injured in the spinal cord, the severed ends of the nerve fibers fail to regenerate and reconnect with the nervous system circuitry beyond the site of the injury. During early development, astrocytes are highly supportive of nerve fiber growth, and scientists believe that if properly directed, these cells could play a key role in regenerating damaged nerves in the spinal cord.
A team of scientists from the University of Rochester Medical Center and the University of Colorado Denver School of Medicine adopted an approach of pre-differentiating stem cells into better defined populations of brain cells. These were then selected for their ability to promote recovery. Here glial restricted precursor (GRP) cells – a population of stem cells that can give rise to several different types of brain cell – were induced to make two different astrocyte sub-types using different growth factors that promote cell formation during normal development. Although these astrocytes are made from the same stem cell population, they apparently have very distinct characteristics and functions.
The research team in Colorado, which consisted of Stephen Davies, Ph.D. and Jeannette Davies, Ph.D., transplanted the two types of astrocytes into the injured spinal cords of rats and found dramatically different outcomes.
One type of astrocyte was remarkably effective at promoting nerve regeneration and functional recovery, with transplanted animals showing very high levels of new cell growth and survival, as well as recovery of limb function. However, the other type of astrocyte not only failed to promote nerve fiber regeneration or functional recovery but also caused neuropathic pain, a severe side effect that was not seen in rats treated with the beneficial astrocytes. Moreover, transplantation of the precursor cells themselves, without first turning them into astrocytes, also caused pain syndromes without promoting regeneration.
"To our knowledge, this is the first time that two distinct sub-types of astrocytic support cells generated from a common stem cell-like precursor have been shown to have robustly different effects when transplanted into the injured adult nervous system," said Margot Mayer-Proschel, Ph.D, of the Rochester University half of the team.
"It has long been a concern that therapies that promote growth of nerve fibers in the injured spinal cord would also cause sprouting in pain circuits," said Stephen Davies, Ph.D, of the University of Colorado, Denver School of Medicine half of the team. "However by using the right astrocytes to repair spinal cord injuries we can have all the gains without the pain, while these other cell types appear to provide the opposite – pain but no gain."
The research teams in Denver and Rochester consider the dramatically dissimilar outcomes between the different astrocyte transplants a development that can change the way stem cell technologies are used to repair spinal cord injuries. To that end, the researchers are in the process of developing a safe, efficient and cost-effective way to use this approach to better define the optimal human astrocytes with an eye toward use for clinical trials.
Adapted from the University of Rochester Medical Center announcement through EurekAlert.
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