Fight Aging!

Like much of the nervous system, the brain doesn't regenerate well at all. Lost cells remain lost, and lost function is often permanent. One of the most important goals in the field of regenerative medicine is repair of the brain, which might be achieved in the decades ahead via delivery of new neurons that can integrate with existing neural circuits. Far from being a class of therapy only deployed following evident injury such as the aftermath of a stroke, this could take the form of periodic treatments that maintain the brain by repairing the lesser damage and loss of neurons that accumulates in an ongoing fashion over a lifetime.

As illustrated by the painful and usually partial recovery that can be achieved by some people following injury to the brain, the brain is capable of adaptation. Uninjured areas can take on new functions. This is why it is reasonable to expect therapies based on delivery of new neurons to allow restored function following injury. Indeed, it is demonstrated by researchers in this paper, in which human neurons derived from induced pluripotent stem cells integrate with the existing neural networks of a damaged rat brain to restore motor control and other capabilities. The researchers engineered a series of tests to prove that the human neurons were active and responsible for the restored functions in treated rats - this isn't just a matter of transplanted cells secreting signals that assist regeneration undertaken by native cells.

Researchers successfully repair stroke-damaged rat brains

Researchers have succeeded in restoring mobility and sensation of touch in stroke-afflicted rats by reprogramming human skin cells to become nerve cells, which were then transplanted into the rats' brains. Several previous studies have shown that it is possible to transplant nerve cells derived from human stem cells or from reprogrammed cells into brains of rats afflicted by stroke. However, it was not known whether the transplanted cells can form connections correctly in the rat brain in a way that restores normal movement and feeling.

"We have used tracking techniques, electron microscopy, and other methods, such as light to switch off activity in the transplanted cells, as a way to show that they really have connected correctly in the damaged nerve circuits. We have been able to see that the fibres from the transplanted cells have grown to the other side of the brain, the side where we did not transplant any cells, and created connections. No previous study has shown this. It is remarkable to find that it is actually possible to repair a stroke-damaged brain and recreate nerve connections that have been lost. The study kindles hope that in the future it could be possible to replace dead nerve cells with new healthy nerve cells also in stroke patients, even though there is a long way to go before achieving that."

Activity in grafted human iPS cell-derived cortical neurons integrated in stroke-injured rat brain regulates motor behavior

Stem cell transplantation can improve behavioral recovery after stroke in animal models but whether stem cell-derived neurons become functionally integrated into stroke-injured brain circuitry is poorly understood. Here we show that intracortically grafted human induced pluripotent stem (iPS) cell-derived cortical neurons send widespread axonal projections to both hemispheres of rats with ischemic lesions in the cerebral cortex. We find that at 6 months after transplantation, host neurons in the contralateral somatosensory cortex receive monosynaptic inputs from grafted neurons. Immunoelectron microscopy demonstrates myelination of the graft-derived axons in the corpus callosum and that their terminals form excitatory, glutamatergic synapses on host cortical neurons.

We show that the stroke-induced asymmetry in a sensorimotor (cylinder) test is reversed by transplantation. Light-induced inhibition of halorhodopsin-expressing, grafted neurons does not recreate the impairment, indicating that its reversal is not due to neuronal activity in the graft. However, we find bilateral decrease of motor performance in the cylinder test after light-induced inhibition of either grafted or endogenous halorhodopsin-expressing cortical neurons, located in the same area, and after inhibition of endogenous halorhodopsin-expressing cortical neurons by exposure of their axons to light on the contralateral side.

Our data indicate that activity in the grafted neurons, probably mediated through transcallosal connections to the contralateral hemisphere, is involved in maintaining normal motor function. This is an example of functional integration of efferent projections from grafted neurons into the stroke-affected brain's neural circuitry, which raises the possibility that such repair might be achievable also in humans affected by stroke.