Olfactory Cells Prep SCI Recovery

Posted by Sam Maddox in Research News on June 17, 2016

Let’s look at a new research study from UCLA scientists supporting the promise of olfactory ensheathing cells (OEC, or sometimes OEG, the G is for glia). These cells originate in nose tissue and have been shown to regenerate when transplanted in the spinal cord.

OEC are unique – they wrap around and support the growth of axons of the olfactory receptor neurons that replace themselves endlessly. This regenerative property makes them an interesting candidate for nerve repair strategies. And indeed, we have detailed over the years many reports of spinal cord regeneration in animals after OEC treatment. (Here are two background OEG blogs, from June 2013, and July 2014.)

In the spinal cord injury field, olfactory cells became an international sensation in October 2014 (see coverage here and here) after it was reported that Polish fireman Darek Fidyka, two years after a knife-slice spinal cord injury, received an olfactory bulb cell implant at his injury site. Darek got a lot of recovery, but no one can say for sure it was the nose cells that did the trick. He also had scar removed from his cord, which was also untethered. He also got peripheral nerve grafts at the lesion, and took advantage of a vigorous post-surgery physical therapy program.

N of one, as they say – one subject and one result may heat up the media but lacks statistical power.

The new paper is fresh from the Journal of Neuroscience:Olfactory Ensheathing Cell Transplantation after a Complete Spinal Cord Transection Mediates Neuroprotective and Immunomodulatory Mechanisms to Facilitate Regeneration.” It comes from Patricia Phelps and her group at UCLA’s Department of Integrative Biology and Physiology, and Brain Research Institute. One of her co-authors is Reggie Edgerton, he of spinal cord stimulation fame (Until last year Edgerton ran one of the seven Reeve Foundation International Research Consortium on Spinal Cord labs, see archives from July 2015 and May 2011, leading you along the path to The Big Idea clinical trial for epidural stimulation).

Phelps has been working with OECs in animal models for many years. In 2008 she and colleagues, including Edgerton, showed that OEC were beneficial, especially if animals also got task-specific training. In 2011, this time with Edgerton as principal investigator and Phelps as a co-author, they reported that OEC transplants improved hindlimb function and “facilitated regeneration of axons across a complete mid-thoracic spinal cord transection.”

From the new Phelps paper. Rana R. Khankan, whose recent Ph.D. was advised by Phelps, is first author:

We used a complete spinal cord transection model and olfactory ensheathing cell (OEC) or fibroblast (FB; control) transplantation as a repair strategy. OECs, but not FBs, intermingled with astrocytes, facilitated astroglial scar border formation and sequestered invading peripheral cells. OECs attenuated immune cell infiltration, reduced secondary tissue damage, protected neurons and axons in the lesion core, and helped clear myelin debris.

.... Our results provide evidence that OECs are neuroprotective, mediate axon regeneration by providing a growth permissive substrate, and modify the inhospitable lesion site environment.

.... OEC transplantation appears to provide structural scaffolds that facilitate axon regeneration by promoting astrocyte bridges and OEC-lined conduits.

.... We now provide evidence that OECs can engulf myelin particles in vitro, reduce myelin debris in vivo after a complete spinal cord transection, and suggest that OECs likely contribute to clearing myelin debris.

I asked Professor Phelps to comment on her lab’s new work. She notes that while OEC have been showing regenerative promise for a while, “The lack of an OEC-specific marker has limited the investigation of mechanisms underlying their proregenerative effects.” Are you still looking for this clue?

Phelps: Actually I have given up thinking about finding a specific OEC marker as I consider [OECs] a hybrid cell type. It is neural crest derived and neural crest cells in general seem to change into many different phenotypes [cell types].

I wondered about Edgerton’s role in this work. Previously their collaborations included training. No training in this new paper.

Phelps: Our recent study is a short term one to see how long the OECs lived and how they modified the injury site. So we didn’t expect to see axon regeneration across the complete transection. In Rana Khankan’s Ph.D. study, Reg’s lab did the surgeries and my lab (i.e. Rana) cultured the OECs and did all of the lesion site analysis and immunohistochemistry.

The Raisman study studied human chronic SCI. The animal experiments in the new paper involve OEC injections right after animals are injured. Could OECs apply to older injuries?

Phelps: I think that the OECs could definitely be applied to a chronic injury. In fact in our most recent study we transplanted them two weeks later to hopefully decrease the immune response to the cells. It would probably be the next appropriate experiment to try.

The Raisman paper clearly reported recovery. Of course we’re not sure if the cells, the training, or even the scar resection, was effective. What's your take on his work?

Phelps: Raisman’s paper is the first study that used the patient’s OECs derived from the olfactory bulb and that is probably why they got some recovery. Earlier human studies tried to use nasal OECs and they do not integrate as well into the spinal cord. They did not get any positive changes. But so far Raisman’s paper is an N of 1!

These OECs are remarkable little cells, full of promise. You observe how they seem to clean up the injury site and prep it for recovery. Can you imagine them used clinically? Is it important to use the cells from the olfactory bulb, and do you anticipate an easier way to harvest the bulb cells other than major brain surgery (Note: Darek had to have his skull opened to get his bulb cells).

Phelps: Obviously I think that they are promising even for clinical use and I think that the OB-derived cells are critical. We will see how innovative the surgeons can be about getting the cells out of the OB!