Olfactory Update Kefalonia
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1) Introduction

2) Dr. Carlos Lima's Insights

3) Insights from Animal Studies: Stem Cells vs. OECs


Laurance Johnston, Ph.D.

Under the traditional Hippocratic Oath, physicians swore to Asklepios, the Greek god of medicine who healed people and made them immortal. Asklepios’ healing was unacceptable to Hades, the god of the underworld, who considered these souls his property. Hades persuaded his brother Zeus, the king of gods, to hurl a lightning bolt through Asklepios’ head. Zeus declared that medicine thereafter could only be palliative, i.e., make patients more at ease while they either died or got well on their own. Cures were forbidden.

Given the immortality of stem cells and their ability to cure and restore function lost by disability, disease, or the entropy of aging, we may again incur Zeus’ wrath as we develop their full healing potential. Although risking being zapped to the Elysian Fields where Zeus’ victims were destined, numerous innovators throughout the world are developing stem-cell approaches to restore some function after spinal cord injury. 

One of the more promising approaches was first introduced in a May 2003 article. That article specifically described Portuguese neuropathologist Dr. Carlos Lima’s procedures for implanting regenerative-endowed, stem-cell-rich, olfactory tissue isolated from the patient’s nose into the spinal-cord injury site.

The 5+ years of experience using these procedures was recently reviewed at the 3rd International Symposium for Olfactory Mucosa Autografts and Rehabilitation held May 9-10th in Kefalonia, Greece – the birthplace of Asklepios, Hippocrates, and Western medicine in general. (photo: the authors in Kefalonia - L. Johnston, J. Peduzzi-Nelson, & C. Lima)

In addition to the transplantation technique itself, the meeting focused on how to best maximize restored function through post-surgical, aggressive rehabilitation. Although the transplantation procedures were developed in Portugal, many of Lima’s patients have undergone post-operative rehabilitation in US facilities. The insights gained at them are invaluable for not only assessing the potential of Lima’s program, but also providing direction to other function-restoring approaches that inevitably will be developed in the future.

In this article, innovator Lima shares his insights on important issues surrounding his program, and Dr. Jean Peduzzi-Nelson will summarize for the first time supporting studies using the procedures in rats. 


Because olfactory tissue is exposed to the air we breathe, it contains cells with considerable turnover potential, including renewable neurons, stem cells, and olfactory ensheathing cells (OECs).  Briefly, stem cells are progenitor cells that have the potential to transform into CNS tissue, and OECs produce insulating myelin sheaths around regenerating axons. Lima transplants whole olfactory tissue because he believes that more than one cell type is needed to maximize regeneration.

Lima’s Portuguese surgical team and international colleagues have treated nearly 130 patients from throughout the world. Many have reported functional recovery, ranging from the subtle to the fairly dramatic. Recently, the World Technology Network named Lima as a finalist for a prestigious innovation award in health and medicine.

A key procedure is the collection of about one fourth of the patient’s olfactory tissue through procedures that maximize the harvesting of that tissue but avoids the collection of closely associated nasal respiratory tissue. Because the transplanted tissue is from the patient, immunological rejection is minimized. The injury site is then surgically exposed, and regeneration-blocking scar tissue is removed. The isolated olfactory tissue is dissected into small pieces while immersed in the patient’s cerebrospinal fluid. The pieces are then implanted into the cavity.



Carlos Lima, MD, Egas Moniz Hospital, Lisbon, Portugal

I’m focusing my discussion on three key issues relevant to our OMA program: 1) the post-injury disconnection syndrome; 2) the regeneration-blocking scar; and 3) the use of whole olfactory tissue.

Disconnection Syndrome

Because SCI represents a disconnection syndrome, I believe functional recovery will require extensive reorganization of the neural circuits surrounding the injury site. This can be achieved through connection-building cell-transplantation strategies (e.g., OMA) followed by functional rewiring through post-operative, rehabilitation programs.

Studies suggest that there is little regeneration of the long, movement-controlling motor-neuron tracts that run down the spinal cord from the brain in the mature nervous system. As expected, the injury alters the sensory input that the brain receives from paralysis-affected body areas, which, in turn, causes brain neural circuits to reorganize. Although this reorganization promotes the death of injury-affected motor neurons emanating from the brain, it stimulates the sprouting of spinal-cord connective neurons (called propriospinal neurons) and the creation of new, function-restoring circuits between them in incomplete injuries.  This means that the modified and newly created neural pathways will be the ones responsible for mediating recovered function in patients with incomplete injuries rather than the pathways that dominated before injury. 

To maximize restored function after OMA-transplantation, we believe intense rehabilitation is required - our ultimate goal being the patient relearning to walk.  Over-ground gait training with true weight bearing by the hips, knees and feet is especially important and should stimulate or strengthen the newly created neural pathways. Freedom of movement unrestricted by braces will facilitate the development of new motor patterns and functional connections, while hip and knee immobilization may limit such development. Likewise, we should not restrict rehabilitation to “normal” training patterns because “abnormal” conditioning will probably be needed to re-establish motor skills that now depend upon different nervous-system rewiring.


After injury, neural support cells (e.g., astrocytes) and cells from neighboring connective tissue (i.e., fibroblasts) generate a dense glial/connective scar at the injury site, which is a barrier to regenerating neurons.  Overall, from the experience we have accrued using OMA procedures for chronic injury, we have concluded that the scar is a “no-man’s land” with respect to regeneration. Therefore, we believe it is important to remove it before implanting enough regenerative-rich olfactory tissue to bridge both the normal rostral and distal (i.e., top & bottom) stumps of the spinal-cord. As our neurosurgical skills improve with experience, combined with the capability to monitor through electrophysiological and imaging methodology, the overall safety of scar removal will greatly increase.

Cell Source

In many severe injuries, the neuroplasticity or adaptability of residual connections will be inherently limited without some kind of bridging and rebuilding of nerve circuits. As such, it makes sense to transplant the patient’s own olfactory tissue - endowed with regenerative stem/precursor cells - into the patient’s injury site. We expect the implanted olfactory tissue to mimic its natural properties of replacing and repairing and will depend on Nature’s wisdom to do so when grafted into the spinal cord. Using these implantation procedures combined with rehabilitation, we believe we can bridge and re-establish function-restoring neural connections after SCI.

Cumulatively, it is a long and challenging process, perhaps taking years of effort to walk unassisted. But, nevertheless, it is an attainable goal with hard work and a steadfast conviction of what is, indeed, possible after injury. As Lao-Tsu stated: “A journey of a thousand miles begins with a single step.”


Jean Peduzzi-Nelson, Ph.D., Wayne State University, Detroit, Michigan

My laboratory evaluated Dr. Carlos Lima’s OMA approach using a rat model of contusive spinal cord injury. 

My early studies generated mysterious results.  Although transplants of either olfactory mucosa or bone-marrow-derived stem cells improved locomotion in rats with chronic, severe SCI, the combination of these two treatments resulted in much less improvement than either treatment alone.  This didn’t make sense because we thought that such a combination would produce much better recovery.  However, more recent studies (supported by France’s ALARME foundation) solved the mystery and provided further insight into the OMA mechanism. 

OMA transplants produce significant functional improvement  as measured by “blinded” assessors who did not know what treatment the rat received.

Interestingly, the olfactory-derived stem/progenitor cells produced slightly more functional improvement.  For several years, experts have assumed Lima’s clinical results were due to the OECs within the olfactory tissue. Indeed, this OEC emphasis has been embraced by Australian and UK researchers. However, our results strongly suggest that it is the stem-cells and not the OECs that are primarily responsible for functional improvement. Long suspected by Lima, it justifies his use of whole olfactory tissue rather than merely the OECs isolated from such tissue.

Another fascinating result was that although the stem cells produced greater functional improvement, it did not reach statistical significance.  The reason behind this and probably the reason that the previous combination treatment failed was that stem cells that are not from the same animal or an animal that is closely tissue matched (similar to blood matching) are not as effective. 

In the latest study, the various treatments were done in both inbred (closely matched – similar to a transplant from a sister or brother that have the same blood and tissue type) and outbred strains (similar to a transplant from a cousin that may not be of the same blood and tissue type).  Each inbred strain received cells or tissue from the same inbred strain, and each outbred strain received cells or tissue from the same outbred strain.

Results indicated that functional improvement was obtained when either olfactory or bone-marrow-derived stem cells are used in the inbred strain but not when used in an outbred strain.  It means that stem cells from the same individual or a closely related matched individual might cause functional improvement, while cells or tissue from a distantly related individual would not.  The reason could be that the stem cells that are foreign do not grow and mature as well, and therefore do not cause functional improvement.  There may also be some rejection of the foreign cells.  Although stem cells are generally not rejected, when the stem cells from a distantly related animal mature, they may acquire characteristics that the recipient considers foreign.

Now the mystery is solved concerning the combination treatment. Most likely, by combining two treatments in an outbred strain, it produced a greater rejection of the cells as foreign.  In conclusion, our findings support 1) the idea that olfactory-derived stem cells are responsible for the improvement after using function-restoring OMA procedures, and 2) the importance of using one’s own stem cells for functional recovery. 

Adapted from article appearing in August 2008 Paraplegia News (For subscriptions, call 602-224-0500) or go to www.pn-magazine.com