For the first time, scientists discovered that specific human cells, generated from stem cells and transplanted into spinal cord injured rats, provide tremendous benefit, not only repairing damage to the nervous system but helping the animals regain function as well.
The study, published today in the journal PLoS ONE, focuses on human astrocytes – the major support cells in the central nervous system – and suggests that transplantation of these cells may represent a new avenue for the treatment of spinal cord and other central nervous system injuries.
“We’ve shown in previous research that astrocytes are beneficial, but this study brings it up to the human level, which is a huge step,” said Chris Proschel, Ph.D., lead study author and assistant professor of Genetics at the University of Rochester Medical Center. “What’s really striking is the robustness of the effect. Scientists have repaired spinal cord injuries in rats before, but the benefits have been variable and rarely as strong as what we’ve seen with our transplants.”
There is one caveat to the finding – not just any old astrocyte will do. Using cells known as human fetal glial precursor cells, researchers generated two types of astrocytes by switching on or off different signals in the cells. Once implanted in the animals, they discovered that one type of human astrocyte promoted significant recovery following spinal cord injury, while another did not provide any benefit.
“The study is unique in showing that different types of astrocytes, derived from the exact same population of precursor cells, have completely different effects when it comes to repairing the central nervous system,” noted Proschel. “Clearly, not all astrocytes are equal in regards to their therapeutic value.”
Proschel and study co-authors from Rochester and the University of Colorado School of Medicine also found that transplanting the original stem cells directly into spinal cord injured rats did not aid recovery. Researchers believe this approach – transplanting undifferentiated stems cells into the damaged area and hoping the injury will cause the stem cells to turn into the most useful cell types – is probably not the best strategy for injury repair.
According to Mark Noble, Ph.D., director of the University of Rochester Stem Cell and Regenerative Medicine Institute, “This study is a critical step toward the development of improved therapies for spinal cord injury, both in providing very effective human astrocytes and in demonstrating that it is essential to first create the most beneficial cell type in tissue culture before transplantation. It is clear that we cannot rely on the injured tissue to induce the most useful differentiation of these precursor cells.”
To create the astrocytes used in the experiment, researchers exposed human glial precursor cells to two different signaling molecules used to instruct cell fate – BMP (bone morphogenetic protein) or CNTF (ciliary neurotrophic factor). Transplantation of the BMP astrocytes provided extensive benefit, including great protection of existing spinal cord neurons, support for nerve fiber growth and recovery of movement and overall function, as measured by a rat’s ability to run quickly and easily with no mistakes over a ladder-like track.
In contrast, transplantation of the CNTF astrocytes, and of the undifferentiated stem cells, failed to provide any benefit. Researchers don’t know why BMP astrocytes performed so much better than CNTF astrocytes, but say multiple complex cellular mechanisms are probably involved.
An added bonus of the BMP astrocytes is that they didn’t have to stick around in the injury environment for very long to aid recovery. The cells came in, did their job and were gone, likely absorbed by the rats – a positive finding since transplanted cells that persist can lead to negative immune responses and raise the risk of tumor development.
With these results, Proschel’s team is moving forward on the necessary next steps before they can implement the approach in humans, including testing the transplanted astrocytes in different injury models that more closely resemble severe, complex spinal cord injuries in people.
According to Proschel, “In the end, astrocyte therapy is not going to be the golden bullet. Injured patients may need other transplants or drug therapy, and they will certainly benefit from intensive physiotherapy. But because of the multi-modal effects that we see with this astrocyte-based therapeutic approach, we’ve made a big leap ahead for spinal cord injury repair.”
“Studies like this one bring increasing hope for our patients with spinal cord injuries,” said Jason Huang, M.D., associate professor of Neurosurgery at the Medical Center and Chief of Neurosurgery at Highland Hospital. “Treating spinal cord injuries will require a multi-disciplinary approach, but this study is a promising one showing the importance of modifying human astrocytes prior to transplantation and has significant clinical implications.”
In addition to Proschel and Noble, Margot Mayer-Proschel, Ph.D., and Chung-Hsuan Shih, from the University of Rochester Medical Center, and Stephen Davies, Ph.D., and Jeannette Davies, Ph.D., from the University of Colorado School of Medicine contributed to the research. Portions of this research were funded by the New York State Spinal Cord Injury Research Program, the Carlson Stem Cell Fund and private donations by the international spinal cord injury community.
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