This patient presented with signs and symptoms consistent with a potentially catastrophic L MCA stroke that could have left her hemiplegic and aphasic. Fortunately she recanalized secondary to thrombolytic therapy in the emergency room and later in ICU and recovered her neurological function to near baseline. This is not the outcome of many strokes and far more patients while regaining some prior neurological function are still nevertheless often left with some kind of permanent disability for the remainder of their lives. And although prevention of stroke is key, one must also consider what can be done for patients who have already suffered infarction of cortical tissue. While it is known that the CNS does retain some plasticity, normally infarcted cortical tissue does not regenerate to any significant extent in the context of a cortical stroke as suffered by Ms. X. I would like to discuss current avenues that are being investigated for stimulating endogenous neurogenesis and eventual cortical tissue genesis as a potential post-stroke therapy designed to regain functions currently considered permanently lost.
The CNS tissue is mainly composed of terminally differentiated neurons and glial cells. However, it has been widely identified that there are two regions in the CNS that harbor proliferating neural stem cells, the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone of the dentate gyrus in the hippocampus. Under normal conditions the SVZ cells continuously migrate into the olfactory bulb in a process termed the rostral migratory stream where a small portion integrate into bulbar circuitry presumably for continued olfaction and odor discrimination. The SGZ neural progenitors predominantly give rise to the dentate gyrus granular layer neurons, and via their incorporation into this structure it is thought they are a vital component to ongoing adult learning and memory.
In an experimental model of stroke termed transient middle cerebral artery occlusion (tMCAO), focal ischemic injury has been found to increase SVZ proliferation for up to four months post insult. In this condition, the normal rostral migratory stream is disrupted and SVZ cells migrate toward areas of focal ischemia directed by inflammatory cytokines and tunneling with the aid of matrix metalloproteinases. Although many of these neuroblasts will migrate to areas of injury, for example the striatum, unfortunately few will terminally differentiate and incorporate to recreate viable neuronal tissue. The reason for this lack of functional incorporation and thus its utility as a therapy for stroke is unknown. Current hypotheses abound and several regulatory factors have been identified experimentally. One may involve inflammatory mediators secreted by astrocytes and microglia that pose as inhibitors to the process of functionally integrating into these cells into existing neural circuits. Also SVZ neurogenesis has been found to globally decrease with advanced age, the mechanism not thought to be intrinsic to the neural progenitor cell, instead largely as a result of an aged cell microenvironment, termed “niche”. Many other soluble factors have been found to modulate both SVZ and SGZ proliferation, survival, and neuronal differentation and are the subject of many current investigations as potential therapeutics for post stroke neuronal regeneration; brain-FGF, heparin binding EGF, VEGF, BDNF, EPO, glutamate, 5-HT, and NO. As well, neuroendocrine states have been shown to modulate endogenous progenitor proliferation in post stroke states as it has been identified that adrenal steroids are inhibitors of SVZ and SGZ progenitor cell mitoses. Another promising avenue for investigation is serotonin’s positive effect on neurogenesis, a mechanism observed in rodents treated with SSRI’s. To this end clinical trial NCT00967408 is currently investigating the functional outcomes of stroke patients treated with escitalopram in an acute setting. The results of this trial are eagerly being awaited; treating stroke patients with SSRI may prove to be as important to recovery as administration of statin.
Central to any cellular therapy for CNS regeneration is the cellular microenvironment, one in which astrocytes and microvasculature play key roles. In several basic science investigations, astrocytes have been shown to promote neuroblast proliferation and differentiation. Additionally, soluble brain endothelial factors positively regulate SVZ/SGZ cells, and that microglia (mentioned previously) may actually be inhibiting neurogeneiss by means of upregulation of inflammatory mechanisms leading to reactive gliosis. However it is important to realize that even though increasing neural progenitor cell proliferation has potential as stroke therapy, many cell mechanisms must be regulated. For example Columbia’s own Doetsch et al found that EGF receptor expression in SVZ may actually contribute to glioma formation, and isolated BDNF infusions into mouse hippocampi induce limbic seizure in 25% of cases. These findings illustrate that controlled neurogenesis is an elegant process and will be more complicated to modulate than merely a crude exogenous cell graft.
Adult CNS regeneration as a therapy has complications, even if endogenous neural progenitors proliferate in response to ischemia and can spontaneously migrate to peri-infarcted cortical areas, restoration of function depends on new neural connections being appropriately formed, and in the case of a cortical stroke of the precentral gyrus, UMN neurons have very long connections. Amazingly, patial restoration of corticospinal neuronal connection of this length have been demonstrated in mice by Chen et al, an exciting prospect, but have yet to be scaled up to primate models a key step for translating this phenomenon into clinical medicine. A separate problem revolves around whether or not progenitors differentiate into the proper subtype of neuron; because it has been observed that these cells do not appear to differentiate into neocortex. Furthermore this is compounded by the observation in mice that neural progenitors have not yet been shown to integrate into peri-infarcted cortical circuits. In contrast neural progenitor differentiation into striatal structures has been demonstrated, but functional restoration from this incorporation has not yet been reported.
Although no regenerative therapy exists for neurological dysfunctions as a result of stroke there are novel therapies on the horizon involving both endogenous stem cell proliferation and exogenous stem cell graft. Before these therapies can safely enter clinical medicine the cellular mechanisms of migration and cortical circuit integration must be more fully described. The field must reliably demonstrate how to substantially increase the small pool of endogenous neural precursors in order to adequately mount the task of replenishing large areas of cell loss from cortical infarcts that may lead to functional recoveries. Mechanisms of migration and functional integration into existing circuits are still imprecise and require further illumination. Discoveries found in mouse models must be scaled up to primate models to more closely approximate human physiology. Despite these unknowns, many clinical trials are underway attempting to demonstrate clinical efficacy of cell therapy in stroke. If resources are continually invested in unearthing the biology of neural progenitors, the employment of cell therapy for regenerative treatment for the disabilities wrought by stroke may one day be a standard of care in clinical medicine.
References
1. Effects on Clinical and Functional Outcome of Escitalopram in Adult Stroke Patients http://www.clinicaltrials.gov
2. Chen J, Magavi SS, Macklis JD. 2004. Neurogenesis of corticospinal motor neurons extending spinal projections in adult mice. Proc Natl Acad Sci USA 101:16357-62
3. Doetsch F et al. 2002. EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron 36: 1021-34
4. Erlandsson et al. 2010. Immunosuppresion promotes endogenous neural stem and progenitor cell migration and tissue regeneration after ischemic injury. Exp Neurol epub ahead of print
5. Kernie, Steven G., Parent J M. 2010. Forebrain neurogenesis after focal ischemic and traumatic brain injury. Neurobiology of Disease 37:267-274
6. Lichtenwalner R J, Parent J M. 2006. Adult neurogenesis and the ischemic forebrain. Journal of Cerebral Blood Flow & Metabolism 26:1-20.
7. Martin JH. Neuroanatomy: text and atlas 3rd edition. McGraw Hill 2003
8. Scharfman HE, Goodman JH, Sollas AL, Croll SD. 2002. Spontaneous limbic seizures after intrahippocampal infusion of brain-derived neurotrophic factor. Exp. Neurol 174:201-14
9. Hung CW et al. 2010. Stem cell-based neuroprotective and neurorestorative strategies. Int J Mol Sci, 5:11(2039-55)
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