Do these star-shaped cells promote spinal repair or do they just cause pain?
By Earline Gilley
When you think of the spinal cord, you may automatically think of neurons. It’s only logical to think that the repair and replacement of damaged neurons would be key to curing spinal cord injury (SCI)-related paralysis. Until very recently, however, it had long been thought that neurons, unlike skin and blood cells, for example, could not regenerate. But conventional wisdom has been proven wrong.
In the past two decades, researchers have found that there are indeed adult neural stem cells that can be used to grow new neurons. They are not easy to find and they do not regenerate the way that skin and blood cells do. As medical research delves deeper into the complexity of the central nervous system in an effort to harness these stem cells and revolutionize the treatment of paralysis, researchers are sometimes confronted with difficulties that show how far we still have to go.
The Pain Problem
Imagine that you are involved in a clinical trial to help cure your paralysis. This trial involves using stem cells to repair the damage in your spinal cord. A few weeks after the stem cell transplantation, however, you discover that, instead of repairing your spinal cord, these foreign cells cause you to experience an intense neurological pain such as you have never felt before.
Neuropathic pain is a complex problem that arises from damaged nerve cells. Researchers are finding that it is not just neurons that are part of the pain process.
We are all familiar with neurons, those cells that conduct electricity throughout our bodies, passing messages regarding body movement, sensation, and pain at lightning speed. But neurons are not the most abundant cell type in the central nervous system. Only 10% of the spinal cord and brain are made up of neurons; the other 90% consists of a supportive type of cell collectively called glia.
Glia is Greek for “glue,” and, appropriately enough, the glia make a sticky substance that holds neurons in place. These glue cells come in several types and sizes, of which astrocytes are the biggest and most abundant. An astrocyte’s job is to clean up neurochemical transmitters that neurons leave behind, to build up scar tissue when neural damage occurs, and to facilitate communication between neurons. It’s their role in scarring and repair of damaged neural tissue that makes astrocytes relevant to stem-cell research. But scientists are finding that these star-shaped cells could also have a major impact upon neuropathic pain progression
Researchers from the University of Colorado Denver School of Medicine, in conjunction with the University of Rochester Medical Center, have discovered that one key to avoiding the initiation of neuropathic pain, is to have signal molecules, also known as growth factors, create a specific type of astrocyte before transplantation into the spinal cord. Astrocytes created using a particular growth factor triggered spinal repair. When the researchers used a different growth factor, however, the new astrocytes not only failed to trigger spinal repair but they actually caused a delayed onset of neuropathic pain.
Manufacturing Astrocytes
Along with other types of glial cells, astrocytes have been generally misunderstood and under researched. For that reason, researchers are now digging deeper into the functions that these cells perform and how glial stem cells could potentially repair spinal injuries.
To understand how an astrocyte, or any other human cell, is first made, we need to talk about sex When a human sperm fertilizes an egg, a zygote is formed. This single-celled zygote quickly moves on to become a blastocyst. The blastocyst is made up of the inner cell mast, which will become the embryo, and the trophoblast, which will become the placenta. Once the embryo has formed, cellular differentiation will occur.
The process of cellular differentiation makes us into the complex creatures that we are. We are made up of bone, muscles, skin, nerves, and more than 200 other types of cells. All of these cells come from the plain, nondescript cells of the embryo. In order for the basic embryonic cells to become cells that would normally occur in the spinal cord, they must be stimulated by a protein called a growth factor. Differentiation is the process by which a growth factor stimulates a stem cell into becoming a bone cell, a neuron, a skin cell, or any other type of cell that makes up the human body.
Embryonic stem cells are like most teenagers at a career-fair: they have no idea what they will become when they grow up until something stimulates them. Using the teenager analogy, embryonic stem cells are the students who have not met with their guidance counselor and are thrown into the workforce without a clue for the future. Cells that have gone through the differentiation process are the students who have met with the guidance counselor and decided upon a career path.
Guidance counselors are the growth factors in our stem cell stimulation story. But we all know there is more than one way to inspire a teenager, and there is more than one way to stimulate a stem cell as well. There are numerous growth factors that can prompt a cell into fulfilling its destiny, just as there are music teachers, coaches, parents, and siblings that can prompt a teenager into discovering his life’s passion. Some growth factors work exceptionally well, while other growth factors actually cause harm.
In order to create a particular type of cell, researchers perform directed differentiation on an embryonic stem cell. They provide a stimulating molecule that will turn the stem cells into whatever cell type is needed. In this case, the researchers needed to create an astrocyte. After the new cells were created researchers placed the astrocytes into the injured spinal cords of rats. They waited, watched and documented the changes that occurred in the nervous system.
What the researchers at the University of Rochester and University of Colorado have discovered is that not all growth factors are created equally, and that some can actually do more harm than good. When an astrocyte was created using a growth factor called bone morphogenetic protein 4 (BMP-4) and then placed in the body, researchers observed excellent spinal cell growth and repair. When an astrocyte was created using a growth factor called gp130 agonist ciliary neurotrophic factor (GDAscntf ) and then injected in the body, not only was there no spinal repair but there was also a delayed onset of neuropathic pain. They also discovered that it is advisable to predifferentiate the cells prior to injection into the body in order to avoid a transplant related pain syndrome.
Conclusion
Astrocytes created from stem cells can promote spinal repair or they can cause neuropathic pain. It all depends on the protein used to create the new cell.
This research, and the many stem cell related discoveries that preceded it, brings hope to the spinal cord injured community. Not only are clinical trials something that may happen in our lifetime, but we are also getting a better picture of neuropathic pain. Researchers are winnowing down into the details of how stem cells become differentiated and how the differentiation process makes therapeutic cells versus damaging cells. They are gaining a deeper understanding of the complex machinery that makes up 90% of the central nervous system, the glial cells that act as part support group and part janitorial service for our neurons.
Earline Gilley is a freelance writer based in Jacksonville, Florida.
References
Davies J, Proschel C, Zhang N, Noble M, Mayer-Proschel M, Davies S. Transplanted astrocytes derived from BMP- or CNTF-treated glialrestricted precursors have opposite effects on recovery and allodynia after spinal cord injury. Journal of Biology [serial online]. 2008 Journal of Biology; 7:24. Available at: jbiol.com/content/7/7/24 Accessed September 29, 2008.
Walker RS. Pain Types-Somatic, Visceral, Neuropathic, Sympathetic. The Pain Clinic. 2008. Available at: www.painclinic.org/aboutpain-paintypes.htm . Accessed October 3, 2008.
National Institute of Health. Rebuilding the nervous system with stem cells. In Stem Cells: Scientific Progress and Future Research Directions. Available at: stemcells.nih.gov/info/scireport/chapter8.asp. Accessed October 11, 2008.
Steusse SL, Crisp T, McBurney DL, Schecter JB, Lovell JA, Cruce WLR. Neuropathic pain in aged rats: behavioral responses and astrocytic activation. Experimental Brain Research. March 2001;137: 219-227.
