Rehabilitation following a stroke that causes significant loss of function is a slow, painful, and uncertain process. The concept underlying these efforts is that the brain will attempt to rebuild neural connections given sufficient efforts to use lost and diminished function. This does happen to some degree, but far less so in aged patients. Changes in brain circuitry require neuroplasticity: the creation of new neurons that integrate into existing neural networks, and the creation of new synaptic connections between neurons. Neuroplasticity is well demonstrated to decline with age, though there is some debate over which of the contributing factors are more versus less important. Stem cells decline in their activity, and the aged tissue environment is more inflammatory and less conducive to regeneration.
In today's open access paper, researchers report on a demonstration of improved rehabilitation in mice following stroke via reprogramming. Reprogramming involves exposing cells to some or all of the Yamanaka factors; if kept up for long enough, cells undergo rejuvenation of their patterns of gene expression and a change of state into pluripotent stem cells. Ideally in a therapeutic use, the exposure lasts long enough to produce epigenetic rejuvenation but not so long as to produce change in cell state. It is worth noting that for the purposes of a mouse study, in which the mice will be sacrificed and examined at the end of the assessment, it isn't necessary to be as careful about crossing the line into the creation of pluripotent stem cells that can generate cancers as one would have to be in human medicine.
Here, researchers used a viral vector to introduce plasmids encoding the Yamanaka factors Oct4, Sox2, and Klf4 into neurons in the corticospinal tract of mice, which links the cortex to the spinal cord and carries the signaling necessary for control of limbs. Expression of the Yamanaka factors was transiently induced by treatment with doxycycline, a necessary limit on the process of reprogramming. After inducing a stroke in the animals, those mice with reprogrammed neurons exhibited greater neuroplasticity and functional recovery. This is one of a number of interesting demonstrations of the capabilities of cellular reprogramming, but questions on safety, and how to ensure it in various different therapeutic contexts, will no doubt slow down the field for some years yet.
Rehabilitative training is widely adopted in the clinic to achieve functional recovery following stroke. The rationale of rehabilitative training is based on the Hebb theory, which predicts simultaneous pre- and post-synaptic activities that will facilitate synaptogenesis and ultimately lead to the formation of new circuits. However, the effectiveness of rehabilitative training is highly dependent on the level of neuroplasticity and, consequently, is limited in aged patients. Thus, a logical strategy to improve outcomes of rehabilitative training is to identify avenues that are capable of rejuvenating adult neurons in the central nervous system (CNS).
Epigenetic changes are well recognized as hallmarks of ageing. The transcription factor-based cellular reprogramming can refresh the epigenetic landscape and thus presents an innovative method for the rejuvenation of aging cells. Recent studies have shown that overexpression of Oct4, Sox2, and Klf4 (referred to as OSKTFs) reverses epigenetic changes in aged retinal ganglion cells and enables them to regrow their injured axons, a process typically absent in the mature mammalian CNS.
In the current study, we first showed that unilateral photothrombotic stroke ablated corticospinal neurons, leading to severe impairments in skilled but not gross motor function. We further demonstrated that expression of OSKTFs in corticospinal neurons partially rescued the developmental decline of major epigenetic regulators. Ectopic expression of OSKTFs in corticospinal neurons had minimal impact on corticospinal tract (CST) axons' spinal termination and function in intact animals but moderately promoted the collateral outgrowth of the CST axons in the cervical spinal cord and skilled motor recovery in animals with photothrombotic stroke.
OSKTFs expression synergized with rehabilitative training through enhanced mTOR activity, producing additive benefits on CST collateral sprouting and skilled locomotion recovery. Mechanistically, the observed axon sprouting and functional recovery depend on mTOR activation and are driven by newly formed CST collaterals. Taken together, our study revealed an effective avenue to rejuvenate corticospinal neurons, thereby providing new thoughts to optimize the otherwise modest effects of rehabilitative training that is widely used for treating patients with traumatic CNS injuries.
View the full article at FightAging
