OLFACTORY TISSUE TRANSPLANTATION FOR SPINAL CORD INJURY
Laurance Johnston, Ph.D.
In an earlier aromatherapy article, I explained how nasal tissue captures odor molecules; this, in turn, triggers signals to be sent to the brain that affect the entire body. Due to the tissue’s unique characteristics, it possesses extraordinary regenerative potential, which many scientists believe can be exploited to restore function after spinal cord injury (SCI).
Building upon a foundation of animal experimentation, scientists in Portugal, Australia, and China, have begun to transplant olfactory tissue or cells into the injury site of humans with chronic injuries. Part 1 of this two-part article will review olfactory tissue’s unique properties, laying the foundation for Part 2’s summary of Portugal’s Dr. Carlos Lima’s pioneering work in humans.
Olfactory tissue covers about 2.5 centimeters (1 cm = .39 inches) of the upper 1-cm surface of each nasal cavity. Integrated into this tissue are bipolar olfactory neurons, which, starting at the tissue’s surface, are composed of 1) dendrites, hair-like projections that receive informational molecules; 2) the olfactory knob from which the dendrites are attached; 3) the cell body, containing the neuron’s nucleus and metabolic center; and 4) the signal-conducting axon. Receptors on the dendrite surface capture inhaled odor molecules, which, like a key turning a lock, trigger nerve impulses to the brain through the axon.The axons come together to form bundles (fascicles) that are enveloped by olfactory ensheathing cells (OEC’s), a special type of glial or neuronal support cell that guides the axon and supports its elongation. The bundles travel to the base of the tissue and cross over to the cranial cavity through a perforated area of bone named the cribriform plate. They then enter the brain’s olfactory bulb, a relay station where they make connections with second-order neurons that lead to other brain areas via the olfactory tract.
As a simple analogy, visualize an olfactory neuron as a potbellied dachshund with a long tail sticking through a fence hole. The dog’s side of the fence represents the nose’s olfactory tissue, the tail side the brain’s olfactory bulb, and the fence the cranial barrier. Except for the tail, the dog resides on the fence’s olfactory-tissue side. The dog’s whiskers represent dendrites that are attached to the dog’s head (i.e., olfactory knob), its potbelly represents the nucleus-containing cell body, and its long tail represents the axon.
When a small fly (i.e., the odor molecule) stimulates the dog’s whiskers, his nose twitches, initiating a shake (i.e., nerve impulse) that quickly descends down his body until his tail wags on the other side of the fence. This wagging excites dogs that live on the other side (i.e., second-order neurons), who, in turn, signal the whole neighborhood (i.e., brain, then body).
Scientists are excited about olfactory tissue because, unlike spinal cord tissue, it contains so many cells with regenerative potential, including a source of renewable neurons, progenitor stem cells, and remyelinating OEC’s.
These are unique in many ways. For example, most nerves are either a part of the central nervous system (CNS) - i.e., brain and spinal cord - or the peripheral nervous system (PNS), which connects organs and extremities to the CNS. Each system’s cellular environment is hostile to the other’s nerves. For example, injured peripheral nerves will stop regrowing when they hit the spinal cord. However, this classification is ambiguous for olfactory neurons, which are comfortable in both the PNS and CNS.
In another example, olfactory neurons are the body’s only surface neurons with direct access to the external environment, i.e., the air we breathe. Like all surface cells, they readily replicate and regenerate, turning over every 60 days throughout life. In olfactory tissue, there are always neurons in different stages of neurogenesis. As neurons mature, they migrate from the base to the surface of the tissue and replace mature neurons, which die through apoptosis, a form of programmed cell death.
Olfactory Stem Cells:
The source of these new neurons is a pool of progenitor stem cells that reside at the tissue’s base. Due to their potential to differentiate into cells that can treat neurological disorders, stems cells have been the focus of much research and also controversy because they have often been isolated from fetal tissue, a stigma olfactory-derived stem cells avoid.
Olfactory Ensheathing Cells:
Axonal regenerative potential is enhanced by OEC’s, which 1) although they do not do so with olfactory neurons themselves, produce insulating myelin sheaths around both growing and damaged axons in the spinal cord, 2) secrete various growth-enhancing neurotrophic agents, and 3) produce structural and matrix macromolecules that lay the tracks for axonal elongation. Because of these features, OEC’s promote axonal regrowth, including when implanted in areas that normally do not readily regenerate, such as the spinal cord. For example, OEC-remyelinated spinal cord axons have been shown to penetrate the inhibitory glial scar at the injury site, and then to migrate to their correct targets, restoring function.
For a severed axon attempting to grow through this glial scar, it is the physiological equivalent of running the gauntlet, in which the clubs preventing the axon’s passage are the glial scar’s inhibitory molecules. Because of this gauntlet, the truncated axon retreats into safety. So to speak, the implanted OEC’s provide an insulating armor that enables the struggling axon to fend off the inhibitory molecular clubs, pass through the gauntlet, and travel back home in a more receptive environment.
In addition, although many structurally intact neurons routinely circumvent the injury glial-scar, the majority of them do not conduct because they have been demyelinated. By providing new, conduction-restoring, myelin insulation, OEC’s once again come to the rescue.
Because only a small amount of functional neurons (10-15%) are needed to regain significant function, olfactory-tissue’s regeneration-fostering properties cumulatively portend much promise for SCI.
Many animal studies have documented olfactory tissue’s potential to restore function after SCI.
In a key 1994 study, Drs. Ramon-Cueto and Nieto-Sampedro (Madrid) severed rat dorsal nerve roots, the location where sensory nerves connect to the spinal cord. After reconnecting these nerves, they implanted OEC’s, which promoted axonal growth back into the cord, a process that normally does not happen,
In 1998, Dr. Imaizumi and colleagues (PVA/EPVA Center for Neuroscience and Regeneration Research, Yale U.), and Dr. Li et al., (London) independently demonstrated that OEC’s could remyelinate the experimentally injured rat spinal cord.
In 2000, Dr. Ramon-Cueto et al. showed that OEC’s injected into the transected rat spinal cord could promote axonal regrowth across the scar and functional improvement, including locomotion, weight bearing, and sensory perception.
Last year, Dr. Lu et al. (Australia) demonstrated that OEC’s promote regeneration and locomotion in the rat spinal cord when implanted four weeks (i.e., a animal model for chronic injury) after cord transection.
Currently, under Dr. Lima’s guidance in Dr. Peduzzi’s lab (U. Alabama, Birmingham), rats with severe, chronic injuries received transplants of their own olfactory tissue that includes not only OEC’s but also regenerating neurons and stem cells. These studies are essential for U.S. FDA clinical trial approval to replicate the ongoing Portuguese clinical trial by Dr. Lima’s team.
If the patient is the source of transplantation material (i.e., called autologous grafting), immunosuppressive drugs will not be needed to minimize tissue rejection. Patient tissue can be obtained by a simple biopsy through the nostril, which will not affect long-term olfactory capability. This procedure is clearly preferable to penetrating the cranium to access the olfactory bulb, the OEC source in much animal research.
Scientists have transplanted both OEC’s and olfactory tissue into patients with SCI. For example, Portugal’s Dr. Lima implanted autologous olfactory tissue back into the spinal cords of seven patients. Lima believes that more than one cell type is needed to maximize regeneration in the injured cord, including, in addition to OEC’s, neurons in different developmental stages, and precursor stem cells. (photo: Lima removes about 25% of the patient's olfactory tissue, which is then minced and implanted into the spinal cord)
In contrast, in Australia Dr. Alan MacKay-Sim’s team has implanted OEC’s previously isolated and cultured from the patient back into the cord. Scientists, who by nature are concerned about cause-and-effect mechanisms, like such an approach because it reduces the number of confounding factors that could exert an effect.
China’s Dr. Hongyuan Huang offers a third approach. He transplanted OEC’s isolated from fetal tissue into more than 150 patients. Because of fetal tissue’s undifferentiated nature, immunosuppression drugs have not been required so far.
Although these preliminary efforts are promising, much still needs to be learned before a definitive judgment can be made on the therapy’s true potential. For example, in some cases, the surgery may result in the decompression of the spinal cord, which by itself could result in functional recovery.
Growing evidence indicates that olfactory tissue and ensheathing cells have considerable potential to repair the traumatically injured spinal cord. Based on this potential, scientists have begun to treat humans with chronic injuries, including Portugal’s Dr. Carlos Lima, whose work will be summarized in Part 2.