Here is a short but sweet report regarding neural progenitors that I’ve been meaning to write about for a while. Previous work from this lab showed that neural progenitors could be implanted into the brains of mice and help recover function after stroke. They showed that the implanted progenitors had migrated into the stroke region. This study is an extension of the previous work and attempted to determine if migration was due to a signal provoked by a stroke.

More details after the jump.

NPC Transplant

Neural progenitor cells (NPCs) are neural stems that show stem-cell like qualities. They can divide indefinitely or differentiate into some type of neuron or glial cell. As in the previous study, NPCs were transplanted into mice brains. These NPCs were first labeled with superparamagnetic iron oxides (SPIO) so that their movement could be tracked using magnetic resonance imaging (MRI).

Twelve mice received the transplanted cells into the right cortex of the brain. Seven days after transplanted, the mice were imaged. At this point, it was clear that there was no migration away from the transplantation site. Six of the 12 mice were selected for distal middle cerebral artery occlusion (dMCAO) surgery. dMCAO is a useful technique to model strokes in animals. It involves injecting small particles, similar to blood clots involved in strokes, into the arteries of target brains. These animals then experience ischemic strokes very similar to those seen in humans. The other six animals were used as a control and received what is called a “sham” surgery. A sham surgery is just that: a fake surgery. The mouse is opened up then closed again with no alteration of the brain.

NPC Migration

Three days after surgery all the animals were re-imaged. Those that received the dMCAO surgery showed significant NPC migration towards the site of surgery. The sham mice, however, had migration levels comparable to pre-operation levels. There was no significant movement. Three weeks after the surgery, the stroke-mice showed even more drastic migration. There was a straight bee-line from the NPC transplant area to the stroke surgery region. Upon reaching the stroke area, the NPCs formed a ring around the area. The sham mice showed only minimal expansion of the NPC transplant area. It should be noted that the NPC migration in stroke mice was only towards the surgery site. There was no radial migration in all directions, it was highly directional.

The MRI results were confirmed with histology studies. BrdU-positive (a marker for proliferation) cells were seen migrating away from the site of NPC transplant. It was also shown that cells originally located in the NPC transplant region were now in the stroke-region, 31 days later. The sham mice showed neither of these features and only exhibited minor enlargement of the NPC transplant region.

One grain of salt that should be considered is related to the MRI technique. Cells are tagged with SPIO, but it is not specific to any one type of cell. If a NPC dies and is then phagocytosed (ie. “eaten?) by surrounding cells, such as microglia. Microglia act as immune cells in the brain and would be responsible for cleaning up dead cells. As such, any microglia that eats a dead NPC would then become tagged. Microglia are highly mobile, so these results might skew the results.

To determine the amount of skewing, the lab labeled the cells with an antibody specific to microglia. It was found that 10-15% of the SPIO cells were microglial cells, presumably migrating with the mass of NPCS. This still leaves roughly 85% migration due to NPCs, which is a fairly significant number.

Conclusions and future work

This report builds upon the lab’s previous work and shows some interesting data. It is now apparent that NPCs can migrate towards sites of injury, and importantly, require some type of signal to perform this migration. The signal is obviously directional and only produced during an injury. This is interesting because it seems the brain is capable of repairing itself via NPC migration, but seems to be lacking a large source of free NPCs.

The next step, I would assume, is to try and elucidate the mechanism for such long distance signaling. I would also be curious about the fates of the NPCs that arrive at the damaged zone. Do the differentiate or remain as NPCs? Are the dead neurons removed from the area?

In the future, perhaps an artificial signal can be produced to target areas of damage, forming one of the first regenerative techniques for repairing the brain. Exciting work, to be sure.

References

Guzman, R., Bliss, T., Angeles, A.D., Moseley, M., Palmer, T., Steinberg, G. (2007). Neural progenitor cells transplanted into the uninjured brain undergo targeted migration after stroke onset. Journal of Neuroscience Research. [E-Pub: Ahead of print] DOI: 10.1002/jnr.21542