Human stem cells improve movement in paralyzed rats

June 27, 2003

In the current issue of the Journal of Neuroscience, Johns Hopkins researchers report that injection of human stem cells into the fluid around the spinal cord of each of 15 paralyzed rats clearly improved the animals' ability to control their hind limbs -- but not at all in the way the scientists had expected.

"Our first hypothesis was that functional recovery came from human cells reconstituting the nerve circuits destroyed by the paralysis-inducing virus we gave the rats," says first author Douglas Kerr, M.D., Ph.D., assistant professor of neurology at the Johns Hopkins School of Medicine. "Some of the tens of thousands of implanted primitive human stem cells did become nerve cells or the like, but not enough to account for the physical improvements.

"Instead, these human embryonic germ cells create an environment that protects and helps existing rat neurons -- teetering on the brink of death -- to survive," he says.

It turns out that the implanted human cells spew out two important molecules that help protect rats' existing nerve circuits. One of the molecules helps promote nerve cells' survival, and the other encourages nerve cells to stay connected to their neighbors, says Kerr.

"The rats that got human stem cells were still far from normal, but even the improvements we saw could be important clinically," says Kerr, who emphasizes that any clinical application is still many years away.

In their experiments, spearheaded and majorly funded by the private organization Project ALS, the scientists first infected rats with a virus (Sindbis) they developed that selectively destroys nerve cells that control muscles in the hind limbs. Lou Gehrig's disease, also known as ALS or amyotrophic lateral sclerosis, is similarly marked by a gradual loss of the nerves that control muscles, although its cause is unknown.

One-third of the animals then received transplants of human embryonic germ cells, which are capable of becoming any cell type, into their spinal fluid. The other rats served as controls and received either hamster kidney cells or human cells that don't have stem cell properties.

Twelve weeks later, the 15 paralyzed rats that got human stem cells partially recovered control of their hind limbs. Moreover, their hind limbs were 40 percent stronger than control animals'. By 24 weeks, 11 of the 15 turned over at least three seconds faster when placed on their backs than before getting the human cells. Control rats did not improve, on average, over the 24 weeks of the study.

In paralyzed rats, Kerr and his team found that most of the implanted human cells migrated into the spinal cord, and many became cells of the nervous system -- astrocytes, neurons and even motor neurons -- while in uninjured animals the transplanted cells just sat on the spinal cord's outer surface. However, even in injured animals, only about four human cells per rat became motor neurons that actually extended out of the spinal cord and into muscle, potentially creating a circuit that could control movement.

"We saw some physical recovery, and we saw human stem cells that had become motor neurons, but it turns out that the two observations weren't related," says Kerr. "We saw functional recovery that wasn't due to new neurons, and we had no idea how that could be possible."

Kerr then discovered that the rats' own neurons were healthier in animals that received human stem cells. In subsequent laboratory experiments, Kerr found that the human stem cells produced copious amounts of two key growth signals. These were transforming growth factor-alpha (TGF-alpha), which promotes neurons' survival, and brain derived neurotrophic factor (BDNF), which strengthens their connections to other neurons. When the scientists blocked these two signals in the laboratory, the stem cells' beneficial effects disappeared.

"Even before motor neurons die, connecting neurons peel back as if they sense a sinking ship," says Kerr. "Simply keeping a neuron alive can't improve physical abilities if it's not connected to other neurons. It must be part of a circuit.

"In some ways our results reduce stem cells to the non-glamorous role of protein factories, but the cells still do some amazing, glamorous things we can't explain," he adds. "For example, the white matter that surrounds the spinal cord was thought to be an impenetrable barrier to axon growth, but some of the transplanted cells not only migrated into the spinal cord, but also sent axons back out. It is just incredible."

"These are important first steps as we begin to analyze the potential of various types of stem cells in disorders of motor neurons," adds Jeffrey Rothstein, M.D., Ph.D., director of the Robert Packard Center for ALS Research at Johns Hopkins and a participant in the research team. "The unexpected role of non-neuronal cells in the recovery of motor function may have important therapeutic implications someday."

Human embryonic germ cells, derived from fetal tissue, were first isolated in the laboratory of co-author John Gearhart at Johns Hopkins. They are one of two types of human cells collectively referred to as pluripotent stem cells. The experiments were funded by Project ALS, Families of SMA and Andrew's Buddies/FightSMA. Authors on the paper are Kerr, Jeronia Llado, Michael Shamblott, Nicholas Maragakis, David Irani, Thomas Crawford, Chitra Krishnan, Sonny Dike, John Gearhart and Rothstein, all of The Johns Hopkins University School of Medicine.
-end-
Under a licensing agreement between Geron Corporation and The Johns Hopkins University, Gearhart and Shamblott are entitled to a share of royalty received by the University on sales of products described in this article. Gearhart, Shamblott, and the University own Geron Corporation stock, which is subject to certain restrictions under University policy. The terms of this arrangement are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.

Note to Producers: A video of a paralyzed rat and of a paralyzed rat that received a transplant of human stem cells can be found at: http://www.hopkinsmedicine.org/press/2003/June/video.htm

On the Web:
http://www.jneurosci.org/
http://projectals.org

Johns Hopkins Medical Institutions' news releases are available on an Embargoed basis on EurekAlert at http://www.eurekalert.org and from the Office of Communications and Public Affairs' direct e-mail news release service. To enroll, call 410-955-4288 or send e-mail to bsimpkins@jhmi.edu.

On a Post-embargoed basis find them at http://www.hopkinsmedicine.org.

Johns Hopkins Medicine

Related Stem Cells Articles from Brightsurf:

SUTD researchers create heart cells from stem cells using 3D printing
SUTD researchers 3D printed a micro-scaled physical device to demonstrate a new level of control in the directed differentiation of stem cells, enhancing the production of cardiomyocytes.

More selective elimination of leukemia stem cells and blood stem cells
Hematopoietic stem cells from a healthy donor can help patients suffering from acute leukemia.

Computer simulations visualize how DNA is recognized to convert cells into stem cells
Researchers of the Hubrecht Institute (KNAW - The Netherlands) and the Max Planck Institute in Münster (Germany) have revealed how an essential protein helps to activate genomic DNA during the conversion of regular adult human cells into stem cells.

First events in stem cells becoming specialized cells needed for organ development
Cell biologists at the University of Toronto shed light on the very first step stem cells go through to turn into the specialized cells that make up organs.

Surprising research result: All immature cells can develop into stem cells
New sensational study conducted at the University of Copenhagen disproves traditional knowledge of stem cell development.

The development of brain stem cells into new nerve cells and why this can lead to cancer
Stem cells are true Jacks-of-all-trades of our bodies, as they can turn into the many different cell types of all organs.

Healthy blood stem cells have as many DNA mutations as leukemic cells
Researchers from the Princess Máxima Center for Pediatric Oncology have shown that the number of mutations in healthy and leukemic blood stem cells does not differ.

New method grows brain cells from stem cells quickly and efficiently
Researchers at Lund University in Sweden have developed a faster method to generate functional brain cells, called astrocytes, from embryonic stem cells.

NUS researchers confine mature cells to turn them into stem cells
Recent research led by Professor G.V. Shivashankar of the Mechanobiology Institute at the National University of Singapore and the FIRC Institute of Molecular Oncology in Italy, has revealed that mature cells can be reprogrammed into re-deployable stem cells without direct genetic modification -- by confining them to a defined geometric space for an extended period of time.

Researchers develop a new method for turning skin cells into pluripotent stem cells
Researchers at the University of Helsinki, Finland, and Karolinska Institutet, Sweden, have for the first time succeeded in converting human skin cells into pluripotent stem cells by activating the cell's own genes.

Read More: Stem Cells News and Stem Cells Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.