The Prospects for Enhancing Repair Systems in the Brain to Treat Stroke Patients

A sizable fraction of the regenerative medicine community is interested in finding ways to improve existing repair systems in the body, and particularly in the central nervous system, which exhibits little ability to recover from injury in mammals. Initiatives in progress include efforts to increase the rate at which new neurons are created and integrated into the brain, work on ways to encourage more glial cells to adopt a pro-regenerative state, and the usual range of approaches based on delivering signal molecules found to be significant in stem cell therapies or heterochronic parabiosis studies. This open access review paper looks over some of the areas of present research. One of the more interesting points made by the authors is that the window of time for a successful regenerative intervention to restore function is very long, years or more. Any significant advance in the field will bring benefits to a large number of existing patients.

A stroke is caused by a sudden interruption of cerebral blood supply to a specific region of the brain, resulting in regional brain tissue death. Once a stroke occurs, brain tissue that is located inside and outside the infarct/lesion area undergoes significant changes over time. The major pathological cascades include primary neuron loss, secondary neuron loss, brain edema, neuroinflammation, dead cell removal, neuron functional reorganization, blood vessel regeneration, and neural network rewiring. Stroke represents a very serious medical condition and causes huge medical and financial burdens throughout the world. It remains the leading cause of long-term disability and the second leading cause of death worldwide.

Over the past few decades, major advances have been made in understanding of the pathophysiology of stroke, while there has not been much progress in the development of stroke treatment, especially for stroke recovery. Extensive efforts have been devoted to developing neuroprotective therapies to rescue dying neurons within the limited hours post-stroke, and this approach has been shown effective in animal models; unfortunately, the neuroprotective agents have all failed in clinical trials.

Despite the permanent brain tissue damage, spontaneous recovery occurs days, weeks, and months after stroke onset. This type of recovery occurs during the first 3-6 months after stroke with the most dramatic recovery from neurological impairments in the first 30 days. The mechanism underlying the spontaneous recovery after stroke has not been fully understood. Early recovery post-stroke is associated with resolution of edema and reperfusion of the ischemic tissue. Later recovery is related to brain plasticity. Brain plasticity is an intrinsic ability of the brain to reorganize its function and structure in response to stimuli and injuries from both internal and external sources. Brain plasticity is centered on neuronal plasticity, which is coupled with the changes of other types of cells in the brain such as astrocytes, microglia, and blood vascular cells. Convincing evidence shows that brain plasticity exists throughout a person's lifespan.

The involvement of astrocytes and microglial cells in neuroinflammatory responses during the early stage of stroke has been intensively studied. Microglia, the brain tissue resident macrophages, are classified into pro-inflammatory phenotype (M1 type) and anti-inflammatory phenotype (M2 type) based on their responses to local environment. The pro-inflammatory phenotype microglia release destructive pro-inflammatory cytokines, whereas the anti-inflammatory phenotype microglia produce molecules and trophic factors that participate in anti-inflammatory and tissue repair. M2 type microglia have shown beneficial effects in neurogenesis, axonal regeneration, angiogenesis, and vascular repair.

Neural stem cells (NSCs) or neural progenitor/precursor cells (NPCs) are multipotent cells that have the capacity for self-renewal and differentiation into neurons, astrocytes, and oligodendrocytes. Although extensive research has been done over the past decade, understanding the role of endogenous NSCs/NPCs in brain self-repair and spontaneous functional recovery after stroke still remains incomplete. The original hypothesis has been proposed that the NSC/NPC-generated new neurons may replace the stroke-damaged neurons, leading to brain self-repair and functional recovery after stroke. The vast majority of studies have been directed by this hypothesis and are searching for evidence that stroke-induced NSC/NPC proliferation, migration, differentiation, and survival/integration are linked to spontaneously functional recovery.

In total, convincing evidence supports that the brain has the intrinsic ability to repair itself, which is the foundation of spontaneous functional recovery after stroke. However, the capability of brain self-repair post-stroke is limited, especially in severe stroke, as spontaneous recovery is often incomplete in most stroke patients. Clearly, the brain needs more help for reinforcing the repair process. Can we provide extrinsic interventions or treatments to enhance the intrinsic ability of brain self-repair for further strengthening stroke recovery? Emerging evidence has renewed our knowledge on the time window for stroke recovery, which is much longer than previously thought. By contrast to the limited several-hour-effective window of thrombolytic/thrombectomy treatment, the therapeutic window of restorative/rehabilitative interventions is much broader, from years after stroke to lifelong applicability. Recognizing this unique feature of restorative approach will direct stroke research into a fruitful direction and provide great opportunities to develop more treatments for maximizing stroke recovery.


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