When blood flow to the brain ceases as the result of a blood clot, trauma, or injury, the brain suffers from a shortage of oxygen. Such an incident is known as a stroke and it can result in the death of neurons and the loss of those functions to which the dead neurons contributed. Treatment for stroke is largely supportive, but regenerative treatments that replace the dead neurons would be the most ideal treatment.
A research consortium at Lund University in Lund, Sweden has found that neurons made from induced pluripotent stem cells integrate into the brains of mice that had suffered strokes. This experiment takes a closer step towards the development of a regenerative treatment for strokes.
In the aftermath of a stroke, nerve cells in the brain die. At the Lund Stem Cell Center, the research groups of Zaal Kokaia and Olle Lindvall teamed up to develop a stem cell-based method to treat stroke patients.
After a stroke, the cerebal cortex tends to take the bulk of the damage and neuron loss from the cerebral cortex underlies many of the symptoms following a stroke, such a paralysis and speech problems. The method developed by the Lund Institute scientists should make it possible to generate nerve cells for transplantation from the patient’s own skin cells.
First, the Lund team isolated skin fibroblasts from the afflicted mice and used genetic engineering techniques to convert them into induced pluripotent stem cells (iPSCs), which have many of the differentiation capabilities of embryonic stem cells. These iPSC lines were differentiated into cortical neurons, which tend to populate the cerebral cortex. However, transplanting fully differentiated neurons into the brain tend to not work terribly well because the mature neurons are unable to divide and have poor abilities to connect with other cells. Therefore, the neuron progenitor cells that will give rise to cortical neurons are a better candidate for transplantation.
After generating long-term self-renewing neuroepithelial-like stem cells from iPSCs in the laboratory, the Lund group scientists showed that these stem cells could give rise to neural progenitors that expressed the types of genes found in mature cortical neurons. When these neural progenitor cells were transplanted into rats that had suffered strokes, two months after transplantation, the cortically fated cells showed less proliferation and more efficient differentiation into mature neurons with the right shape, size, and structure of cortical neurons and expressed the same proteins as cortical neurons. These tranplanted cells also extended more axons than those cells that were not fated to form cortical neurons. Transplantation of both the cortical neuron-fated and non-cortical neuron-fated cells caused recovery of the impaired function in the stepping test in comparison to controls. At 5 months after stroke, there was no tumor formation and the grafted cells had all the electrophysiological properties of mature neurons and showed full evidence that they had integrated into the existing neural circuitry.
These results are very promising and represent a very early but important step towards a stem cell-based treatment for stroke in patients. Further experimental studies are necessary if these experiments are to be translated into the clinic in a responsible way.