Induced Pluripotent Stem Cells Repair Spinal Cord Injury in Mice

Induced pluripotent stem cells (iPSCs), are made from adult cells by means of genetic engineering and share many, though not all, of the characteristics of embryonic stem cells. The regenerative capacity of iPSCs is truly remarkable, but there are definitely safety concerns with them. The procedure that makes iPSCs from adult cells drives them to divide quickly and often. These cell divisions produce high rates of genetic mutations, some of which are of little consequence, and others that are. Also prolonged culture of iPSCs can select for cells that acquire cancer-causing mutations. Laboratory tests have established that iPSCs have a capability to cause tumors in laboratory animals that at least equals that of embryonic stem cells.

Nevertheless, some labs have designed protocols to screen iPSC lines for tumor-causing or non-tumor-causing lines. Also, iPSCs have been successfully used in therapeutic experiments in laboratory animals without generating tumors. Therefore, iPSCs might be closer to therapeutic use than we think.

With this comes a fascinating publication from the Laboratory of Molecular Neuroscience in the Graduate School of Biological Sciences at the Nara Institute of Science and Technology in Ikoma, Japan; specifically from the laboratory of Kinichi Nakashima. In this experiment, workers in Nakashima’s laboratory used iPSCs that were made from mouse adult cells to make neural stem cells (NSCs).

NSCs are found in the central nervous system and they replace cells in the central nervous system or augment the central nervous system in response to learning and memory or things like that. NSCs are not a monolithic cell population, since some NSCs have the ability to make specific populations of neurons (the cells responsible for neural impulses), while others form glial cells (the cells that support and maintain the neurons).

Nakashima’s laboratory has designed a highly efficient protocol for converting iPSCs into NSCs. They predicted that these NSCs would represent a much less mixed population. Nakashima surmised that such NSCs would almost certainly do a better job of repairing a spinal cord injury. Therefore, led by Yusuke Fujimoto, his colleagues produced several iPSC lines and converted them into NSCs. They called these cell lines “neuroepithelial-like stem cells from human iPS cells” or hiPS-lt-NES cells.

Characterization of these cells in culture showed that they were a homogeneous population that differentiated into many different types of spinal-specific neurons and glial cells. Next, as predicted by Nakashima, Fujimoto and his colleagues transplanted these hiPS-lt-NES cells into the spinal cords of mice that had suffered spinal cord injuries.

The results were remarkable. The transplanted hiPS-lt-NES cells differentiated into neural cells in the spinal cord and promoted functional recovery of hind limb motor function. This is a remarkable finding, but perhaps the transplanted cells only secreted growth factors that helped heal the spine and played no real role in regenerating the spinal cord. Nakashima was not satisfied with this result.

To determine if the transplanted cells were actually regenerating the spinal cord, Fujimoto and the rest of his laboratory workers used two different tracers and also killed off the transplanted cells. The nerve cell tracers showed that the transplanted cells and nerve cells that were already in the spinal cord formed the new neural networks and connections to restore normal hind limb function. Neurons native to the spinal cord and the newly introduced neurons hat were formed from transplanted hiPS-lt-NES cells reconstructed the corticospinal tract by forming proper connections with other neurons and integrating neuronal circuits. Then, when they deliberately killed off the transplanted cells, no neural regeneration occurred. Thus the transplanted hiPS-lt-NES cells not only contributed to the regeneration of the spinal cord and its neural circuits, but they initiated and drove the process.

These fascinating findings suggest a new way to treat spinal cord injury and it does not require the killing of embryos.