Abstract
Clinical treatments for ischemic stroke are limited. Neural stem cell (NSC) transplantation can be a promising therapy. Clinically, ischemia and subsequent reperfusion lead to extensive neurovascular injury that involves inflammation, disruption of the blood-brain barrier, and brain cell death. NSCs exhibit multiple potentially therapeutic actions against neurovascular injury. Currently, tissue plasminogen activator (tPA) is the only FDA-approved clot-dissolving agent. While tPA’s thrombolytic role within the vasculature is beneficial, tPA’s non-thrombolytic deleterious effects aggravates neurovascular injury, restricting the treatment time window (time-sensitive) and tPA eligibility. Thus, new strategies are needed to mitigate tPA’s detrimental effects and quickly mediate vascular repair after stroke. Up to date, clinical trials focus on the impact of stem cell therapy on neuro-restoration by delivering cells during the chronic stroke stage. Also, NSCs secrete factors that stimulate endogenous repair mechanisms for early-stage ischemic stroke. This review will present an integrated view of the preclinical perspectives of NSC transplantation as a promising treatment for neurovascular injury, with an emphasis on early-stage ischemic stroke. Further, this will highlight the impact of early sub-acute NSC delivery on improving short-term and long-term stroke outcomes.
Highlights
Stroke remains a leading cause of death and long-term disability in the United States, and ischemic stroke accounts for 87% of all strokes [1]
While current clinical trials focus on the outcome of stem cells on neuro-restoration by injecting cells during the chronic stroke stage [25], this review will focus on the therapeutic mechanisms and potential of Neural stem cell (NSC) transplantation in the early phase of ischemic stroke, improving long-term outcome
While knockout of matrix metalloproteinases (MMPs)-3 in stroke mice reduced the tissue plasminogen activator (tPA)-enhanced risk of intracerebral hemorrhage (ICH), delayed tPA administration (4 h post-MCAO) in the thrombotic ischemic stroke model was found to further augment MMP-3 expression selectively in
Summary
Stroke remains a leading cause of death and long-term disability in the United States, and ischemic stroke accounts for 87% of all strokes [1]. Major limitations of tPA treatment include a narrow therapeutic window within 4.5 h after stroke onset [8], and a greater potential for hemorrhagic transformation [9]. New strategies are needed to extend tPA’s therapeutic window, minimize deleterious effects, and improve stroke outcome. Preclinical studies demonstrate that engrafted NSCs improve stroke outcome through multiple mechanisms, such as protection of the BBB, decreased cerebral vascular inflammation, increased neurogenesis and angiogenesis, and enhanced neurological function [23,24]. While current clinical trials focus on the outcome of stem cells on neuro-restoration by injecting cells during the chronic stroke stage [25], this review will focus on the therapeutic mechanisms and potential of NSC transplantation in the early (subacute) phase of ischemic stroke, improving long-term outcome
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