First Randomized, Placebo-Controled Trial Shows Spinal Cord Regeneration in Dogs

Spinal cord injuries are a very difficult challenge for regenerative medicine. The damaged spinal cord is a toxic waste dump encased in a barrier that prevents regenerating cells from entering or exiting. However, a group of stem cells that have been used in clinical trials have produced extremely encouraging results for spinal cord injury patients.

Collaboration between the Cambridge University’s Veterinary School and Medical Research Council’s Regenerative Medicine Centre, has given scientists a chance to test a particular type of stem cell found inside your nose to regenerate the damaged part of the spinal cord of dogs. The researchers are cautiously optimistic that their work could play an important role in the future treatment of human patients who suffer from similar injuries, but only if they are used in combination with other treatments.

For over a decade, scientists have known about olfactory ensheathing cells (OECs) and their potential usefulness for treating damaged spinal cords. OECs have unique properties, since they have the ability to support nerve fiber growth. This is the role OECs play in the nose; they maintain a pathway for the growth and extension of nerve fibers between the nose and the brain.

Olfactory Ensheathing Cells

Previous research in laboratory animals has shown that OECs can aid regeneration of those extensions of nerve cells that transmit signals (axons). The growth and re-extension of damaged neurons helps them form a kind of bridge between damaged and undamaged spinal cord tissue. A Phase 1 trial in human patients with spinal cord injuries (SCI) established that transplantation of OECs into the spinal cords of SCI patients is safe.

This present study was published in the latest issue of the neurology journal Brain, and it is the first double-blinded randomized controlled trial to test the effectiveness of OEC transplants to improve function in ‘real-life’ spinal cord injury. The trial was performed on animals that had spontaneous and accidental injury rather than in the controlled environment of a laboratory. Unlike other experiments, these test subjects had suffered their spinal cord injuries at least one year ago. Thus, this experiment more closely resembles the way in which this procedure might be used in human patients.

The 34 pet dogs had all suffered severe spinal cord injuries. Twelve months or more after the injury, they were unable to use their back legs to walk and unable to feel pain in their hindquarters. Not surprisingly, many of the dogs were dachshunds, which are particularly prone to this type of injury because of their long body and short legs. Additionally, dogs are more likely to suffer from SCIs because the spinal cord may be damaged as a result of what in humans is the relatively minor condition of a slipped disc. Thus while four-leggedness has its advantages, it also has its drawbacks.

In this study, which was funded by the MRC, one group of dogs had OECs from the lining of their own nose injected into the injury site. The other group of dogs was injected only with the liquid in which the cells were transplanted. Neither the researchers nor the owners (nor the dogs!) knew which injection they were receiving.

The dogs were observed for adverse reactions for 24 hours before being returned to their owners. After this time, the animals were tested at one month intervals for neurological function and to have their gait analyzed on a treadmill while being supported in a harness. In particular, researchers were interested in the ability of the dogs to coordinate the movement of their front and back limbs.

The group of dogs that had received the OEC injection showed considerable improvement that was not seen in the other group. Just view this video here to see the amazing improvement in the OEC transplanted animals. These animals moved previously paralyzed hind limbs and coordinated all their movement with their front legs (again, see this video). This means that in these dogs neuronal messages were being conducted across the previously damaged part of the spinal cord. However, the researchers established that the new nerve connections accounting for this recovery were occurring over short distances within the spinal cord and not over the longer distances required to connect the brain with the spinal cord.

Professor Robin Franklin, a co-author of the study from the Wellcome Trust-MRC Cambridge Stem Cell Institute, University of Cambridge, said: “Our findings are extremely exciting because they show for the first time that transplanting these types of cell into a severely damaged spinal cord can bring about significant improvement. We’re confident that the technique might be able to restore at least a small amount of movement in human patients with spinal cord injuries but that’s a long way from saying they might be able to regain all lost function. It’s more likely that this procedure might one day be used as part of a combination of treatments, alongside drug and physical therapies, for example.”

The head of Regenerative Medicine at the Medical Research Council, Dr. Rob Buckle, commented: “This proof of concept study on pet dogs with the type of injury sustained by human spinal patients is tremendously important and an excellent basis for further research in an area where options for treatment are extremely limited. It’s a great example of collaboration between veterinary and regenerative medicine researchers that has had an excellent outcome for the pet participants and potentially for human patients.”

The researchers stress that human patients with a spinal injury rate a return in sexual function and continence far higher than improved mobility. Some of the dogs in the study did regain bowel and bladder control but the number of these was not statistically significant.

Mrs. May Hay, the owner of a dog named Jasper, who took part in the trial (and can be seen in the video), said: “Before the trial, Jasper was unable to walk at all. When we took him out we used a sling for his back legs so that he could exercise the front ones. It was heartbreaking. But now we can’t stop him whizzing round the house and he can even keep up with the two other dogs we own. It’s utterly magic.”

Human patients have already been treated with their own OECs.  Jacki Rabon traveled to Brazil to receive an OEC transplantation with her own OECs.  Today, even though she has been severely spinal cord injured, she can walk with braces.  Read her story here.  Another patient, Laura Dominguez, was also treated by the same Brazilian physician.  See her video here.  It certainly seems as though we have hit upon a sound strategy upon which to build.  Let’s pursue this rather than killing human embryos.

Human Blood Vessel-Derived Stem Cells Repair the Heart After a Heart Attack

Recently, I blogged on blood vessel-making stem cells located in the walls of blood vessels. New work on these cells from the University of Pittsburgh has shown that these CD146+ cells can also abate heart damage after a heart attack.

The ability of endothelial progenitor cells or EPCs to repair skeletal muscle is well established, but the ability of these cells to repair a damaged heart is unknown. Johnny Huard from the McGowan Institute for Regenerative Medicine at the University of Pittsburgh and his group investigated the therapeutic capabilities of human blood vessel-derived EPCs that had been isolated from skeletal muscle to treat heart disease in mice.

When mice that had been given infusions of EPCs after a heart attack were compared with mice that had received a placebo, the EPC transplanted mice definitely fared much better. Echocardiographic studies of the hearts showed that EPC transplantation reduced enlargement of the left ventricle (the main pumping chamber of the heart), and also significantly improved the ability of the heart to contract.

In addition to comparing the ability of EPCs to improve the function of the heart after a heart attack with placebos, they were also compared to stem cells known to make skeletal muscle. These stem cells are called “CD56+ myogenic progenitor cells,” which is a mouthful. CD56+ myogenic progenitor cells or CD56+ MPCs can form skeletal muscle; and infusions of them can improve the structure of the heart after a heart attack and prevent it from deteriorating. However, transplanted EPCs were superior to CD56+ MPCs in their ability to heal the heart after a heart attack.

The transplanted EPCs were able to substantially reduced scarring in the heart, and significantly reduced inflammation in the heart. In fact, then the culture medium in which EPCs were grown was injected into mouse hearts after a heart attack, this medium also suppressed inflammation in the heart.

When Huard and his co-workers examined the genes made in the EPCs, they found that these stem cells cranked out proteins known to decrease inflammation (IL-6, LIF, COX-2 and HMOX-1 for those who are interested), especially when the cells were grown under low oxygen conditions. This is significant because in the heart after a heart attack, blood vessels have died off and the supply of blood to the heart is compromised. The fact that these cells are able to do this under these harsh conditions shows that they make exactly the most desirable molecules under these conditions.

The biggest boon for these cells came from examinations of blood vessel formation in the heart. Blood vessel production in the EPC-transplanted hearts was significantly increased. The EPCs formed a host of new blood vessels and extending “microvascular structures” or smaller supporting blood vessels and larger capillary networks too.

Once again, when grown under oxygen poor conditions, the EPCs jacked up their expression of pro-blood vessel-making molecules (VEGF-A, PDGF-β, TGF-β1 and their receptors). When EPCs were labeled with a green-glowing protein, fluorescence tracking showed that they actually fused with heart cells, although it must be emphasized that this was a minor event.

These pre-clinical studies show remarkable improvements in the heart after a heart attack, and they apparently induce these improvements through several different mechanisms. They make new structures and they secrete useful molecules. These significantly successful results should provide the basis for clinical trials with these cells.