Long distance ectopic masses after neural stem cell transplantation

by Alexey Bersenev on February 4, 2014 · 0 comments

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Few days ago I came across very interesting story, discussed in the last issue of Cell journal. Two years ago Paul Lu published a study, which demonstrated remarkable long-distance axonal growth from transplanted neural stem cells in spinal cord injury model. Interestingly, Oswald Steward decided to replicate Lu’s study:

As part of the NIH-supported replication project (Facilities of Research Excellence-Spinal Cord Injury), we repeated key parts of that study. Because this is a surgical intervention that may depend on skills that require extensive experience, we felt that the goals of the replication would be best served if the same surgeon performed the lesion surgeries and transplants.

They were able to reproduce Lu’s results, but with a twist:

There was exuberant axon outgrowth from the grafts into the host spinal cord as reported by Lu et al., 2012 (Figure 1B). We were surprised, however, to find ectopic colonies of graft-derived cells at long distances from the transplant site, including in the central canal of the spinal cord, adhered to the surface of the spinal cord, and in the fourth ventricle of the brainstem.

They carefully examined all rats and found ectopic cell masses all over CNS in about 50% of animals (n=20). Steward makes cautious conclusion:

The very surprising discovery of the presence of ectopic cell clusters at long distances from the transplant site raises concerns in terms of therapies involving stem cell transplants. It is especially concerning that NSCs continue to proliferate at ectopic locations, which could enlarge the cell masses.

Whether these ectopic colonies are harmful or not remains to be determined, but their presence highlights an important potential safety monitoring issue for therapies involving stem cell transplantation into the injured spinal cord.

Cell masses in the fourth ventricle are concerning because they could grow to compress brainstem structures.

In the reply, Paul Lu’s group, went through possible explanations of this phenomenon. They started from re-examination of their 2012 findings and confirmed that “ectopic cell deposits were found in three of six animals with complete transections”. Lu concludes in his commentary:

Caution is prudent in generalizing findings from a single cell type, a single lesion model, and a unique high-pressure injection system, to all approaches that utilize neural stem cells. We consider the most notable feature of neural stem cell biology, relayed in our report (Lu et al., 2012), to be the astonishing ability of multipotent neural progenitor cells to extend axons in high numbers and over very long distances through the injured adult spinal cord. This suggests many fruitful avenues for further investigation, including studies focused on both mechanism and translation. Adequate safety and biodistribution studies should always be performed prior to initiation of human clinical trials using neural stem cells for any indication.

Yet another twist of this story is in the cell line, which was used in 2012 Lu’s study. NSI-566RSC cell line was isolated from human 8-week fetal spinal cord and used in NeuralStem clinical trials. From NeuralStem PR:

The cells that Neuralstem contributed to the study, NSI-566, are the same cells used in the recently completed Phase 1 clinical trial for the treatment of amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease). Neuralstem has also submitted an application to the FDA for a trial to treat chronic spinal cord injury with these cells.

However, in “replication study”, cells were not obtained from NeuralStem, but prepared from rat embryos “in house”:

Also, because the cells could be considered to be a “product” that was obtained for use in much the same way as stem cells from a company, the cells were prepared at UCSD and were delivered to UCI on the day of the grafting procedure.

So, quite different cells (rat versus human), but the same protocol. I’m puzzled by the fact that cell prep was done by the authors of original study, but not by replicating group. The authors of original 2012 study and current reply to Steward did not disclose any conflicts of interest.

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