When Dr. Young moved to Rutgers he changed his research focus from acute to chronic injury studies. We developed new techniques to do long term treatments, care, and functional recovery in animals after contusion injuries. We have studied a number of therapies for spinal cord contusion, some examples include:
- L1 Cell Adhesion Molecule. This cell adhesion molecule stimulates axons to grow. Called L1, the molecule is expressed by growing axons so that the axons grow in bundles and ‘egg’ each other on. We published the first paper showing that L1 stimulates regeneration and recovery in rats after contusion. Presently Dr. Melitta Schachner, a member of the Center Faculty, is continuing the L1 work by genetically manipulating stem cells to express L1. The group has published many papers showing the beneficial effects of L1-expressing stem cells.
- Olfactory ensheathing glia. Dr. Hungyun Huang trained in this laboratory where he learned to grow olfactory ensheathing glia (OEG) cells. Kai Liu, a graduate student of Dr. Wise Young, developed many methods which showed that OEG cells myelinate axons in the contused rat spinal cord and Dr. Martin Grumet's lab showed that adult OEG also myelinate axons but at a slower rate than neonatal OEG. Dr. Huang has transplanted over 700 patients with OEG cells in China. Now many laboratories are trying to develop sources of OEG cells that would be immunecompatible.
- Neonatal blood mononuclear cells. In 2006, when ChinaSCINet decided to study umbilical cord blood mononuclear cells as cells to transplant into people with chronic spinal cord injury , we carried out development studies to discover the best preparation and transplantation methods. We tried hundreds of preparations and discovered the best way to isolate, purify, and ship the cells. We successfully transferred the technology to the commercial sector for clinical trial.
- Lithium. In 2004, Yick, et al. at Hong Kong University reported that lithium stimulates regeneration in the spinal cord. This surprising finding led us to study the effects of lithium on umbilical cord blood cells. We found that lithium strongly stimulates mononuclear cells to proliferate (produce more cells), increasing the number of cells in culture and when transplanted into the spinal cord by 3-4 fold. In addition, we discovered that lithium stimulates cord blood cells to produce large amounts of neurotrophins, specifically NGF, NT-3, and GDNF, the growth factors reported by many scientists to stimulate regeneration in the spinal cord. We have since gone ahead to study the pharmacokinetics and pharmacodynamics of lithium in animals (so that we design the clinical trials for lithium). These include very surprising findings that lithium may be selectively transported and bound in the brain. In addition, we have studied the mechanisms by which lithium stimulates stem cells to proliferate and to produce neurotrophins, showing that the former results from the nuclear factor NFAT and the latter results form WNT/beta-catenin.
- Prevention of Teratoma Formation. One of the major risks and fears of embryonic stem cell and induced pluripotent stem cell transplantation is the likelihood of teratoma formation by the pluripotent cells. The standard way to prevent this is to differentiate the cells as much as possible so that they are no longer pluripotent and therefore have a smaller risk of teratoma formation. However, if even one out of a million cells were to be pluripotent, the risk of tumor formation remains. One of the faculty at the Center, Dr. Yi Ren, has developed a unique and innovative way to stopping teratoma formation by targeting a factor called Migration Inhibition Factor (MIF). She showed the absence of this factor prevents teratoma formation in MIF-knockout mice. She and her co-workers went on to show the mechanism by which this occurs and now has a treatment that can positively prevent teratoma formation by pluripotent stem cells.
- Chondroitinase Studies. One of the faculty in the Center, Dr. Martin Grumet, has been studying the effects of chondroitinase on injured spinal cords. Chondroitnase is a bacterial enzyme that breaks down chondroitin-6-sulfate-proteoglycans (CSPG), an important inhibitor of axonal growth in injured spinal cords. A postdoctoral fellow, Dr. Iseda, did studies showing a single injection of chondroitinase in the contused spinal cord will clear all CSPG from within a cm of the injection site for several weeks.
- Neural stem cells in the repair of lumbosacral spinal cord injury. To restore function to lumbosacral injuries, neurons, particularly motorneurons need to be replaced. Motorneurons innervate muscle and interneurons that form the reflex circuits and programmed functions of the spinal cord. To develope and assess neuronal replacement therapies, we have developed a contusion model of the lumbosacral spinal cord (LSCI) that produces graded neuronal loss and functional loss in rats. Neural stem cells (NSC) harvested from the subventricular zone (SVZ) of a neonatal Fischer rat expressing green fluorescent protein (GFP) are being transplanted into the LSCI model. Earlier studies show that lithium stimulates NSC to produce more neurons [2]. By pre-treating NSC with lithium, we hope to stimulate the NSC to produce more neurons that are primed to grow axons soon after transplantation.
- Spinal cord injury is exacerbated by abnormal inflammatory responses, which can last for long times after injury. Mesenchymal stem cells (MSC) respond to pro-inflammatory factors by releasing anti-inflammatory factors, and thereby can suppress inflammation after spinal cord injury. In addition, MSC release growth factors, which can help promote regeneration. Given that MSC are highly migratory, they can be injected at sites distant from an injury and migrate to injury sites where they can release beneficial factors locally. MSC can be injected in the lumbar spine by a much less invasive procedure than surgery at the injury site. Studies are ongoing using biomolecular encapsulation of MSC that allows the cells to survive for long times in the lumbar spine while they secrete factors into the cerebrospinal fluid, which can promote recovery from spinal cord injury.
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