Abstract:

The restricted neurogenesis limits the brain ability to overcome neuronal cell death following ischemic lesion: Failure of the damaged brain to regenerate following cerebral ischemia results in functional deficits those are most often irreversible and can further deteriorate, causing mortality and severe disability, progressive memory loss and cognitive impairments,known as dementia. This is caused by massive neuronal cell death and neurotoxicity following limited blood supply to the brain. Ischemic death of brain neurons (acute or delayed after lesion) has been the etiology of vascular dementia, the second most common type of dementia after Alzheimer’s disease. Multiple types of vascular dementia exist, common in cognitive decline that gradually worsens and variable in where strokes happen (subcortical dementia) or how severe lesions are (e.g., major stroke,series of small strokes or brief transient ischemic attacks). It has emerged a synergistic combination of both Alzheimer’s disease and vascular disease that often comes (mixed dementia). For over the last three decades after the ischemia-induced neuronal cell death had been discovered, intense research has been focused on withdrawing or, at least, attenuating neurodegeneration to improve restoring function in experimental models of poststroke cognitive impairments while mimicking focal ischemia, permanent or transient brain lesions, hypertension or reproducing Alzheimer’s disease combined with vascular pathology [for review].Long-standing perspectives that ischemic neuronal death might be potentially suspended through activation of endogenous neuroprotection stay with genomic reprogramming and/or gene activation for de novo protein synthesis, relied on the hypoxia-activated signaling pathways. On the other hands, pre-clinical studies, including our own works, have reported functional impairments at the later times (weeks) post-ischemia (as in principal neurons as within network), with controversial effectiveness of pharmacological therapeutics utilized after lesion. Unfulfilled regeneration convinces experimental neuroscientists to focus on cell-based therapies for neuronal replacement strategies used to overcome massive neuronal loss in the brain tissue subjected to ischemia. The major issue, however, remains how this therapy should be utilized in order to promote beneficial effects timely,namely via engraftment of neural stem progenitor cells (NSPCs) or already differentiated stem cell-derived neurons into the damaged brain. From that,the other conceptual question arises regarding the regulatory role of a host environment in either NSPC neurogenesis or functional integration of the grafted stem cell-derived cells. If choose the latter, what ‘proper’ proportion of the entirely different phenotypes needs to be grafted to possibly succeed? More insights into this are essential when considering cell therapy while aiming at remodeling of the damaged post-stroke brain from mixed stem cell-derived cells for restoring the broken functionality of such a complex tissue as the brain.