Mouse model demonstrates cell-to-cell connections between implanted stem cells and diseased cells

Investigators at Sanford-Burnham Medical Research Institute (Sanford-Burnham, formerly Burnham Institute for Medical Research), the Karolinska Institutet, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School and Universit- Libre de Bruxelles have demonstrated in mouse models that transplanted stems cells, when in direct contact with diseased neurons, send signals through specialized channels that rescue the neurons from death. These direct cell-to-cell connections may also play a role in normal development by laying down the blueprint for more mature electrical connections between neurons and other cells. The research was published in the journal Proceedings of the National Academy of Sciences on February 1.

While it was already known that stem cells will seek out diseased cells in the brain, the international group of scientists showed, both in tissue culture and in mice, that the stem cells actively bring diseased neurons back from the brink via cross-talk through gap junctions, the connections between cells that allow molecular signals to pass back and forth. Significantly, the stem cells do not need to differentiate into the specific type of neuron to provide this therapeutic effect. The researchers also believe this protective mechanism may be active in other cell types and play a role in many diseases. For example, some of their preliminary work shows that these mechanisms may rescue damaged neural fibers in adult spinal cord injuries.

"We showed a while ago that stems cells may exert a therapeutic effect on damaged or diseased host systems by secreting therapeutic factors and 'bathing' the dying cells," said Evan Snyder, M.D., Ph.D., director of the Stem Cell and Regenerative Biology program at Sanford-Burnham. "However, we did not know that stem cells can also exert their action through direct cell-to-cell contact. Indeed, we believe that this may be a newly-recognized way in which stem cells communicate with the cells around them, not only under diseased conditions but during normal development."

"Grafted neural stem cells of mouse and human origin make early gap junction contact with cells in the host brain that benefit endangered host neurons, even rescuing them from impending cell death," added Richard L. Sidman, M.D., Professor of Neuropathology (Neuroscience) at BIDMC, Boston and Harvard Medical School.

Beginning with tissue culture studies, the team found that neural stem cells (NSCs, including human NSCs) integrated into the neural circuitry, coordinated signaling (as measured by calcium fluxes) and protected injured neurons. The team replicated these findings in diseased mice (including those that have a disorder similar to Huntington's disease) and spinal-injured rats. The scientists, led by Eric Herlenius, Ph.D., of the Karolinska Institutet and Dr. Snyder, hypothesized that communication through gap junctions was the mechanism for the protective effect. Subsequently, the researchers disabled gap junctions, which diminished the therapeutic effect and validated the gap junction hypothesis.